Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:34][CH2:33][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.[Br:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(Cl)Cl>[Br:42][C:43]1[CH:44]=[C:45]([S:49]([N:15]2[CH2:34][CH2:33][C:18]3[N:19]=[C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[N:21]=[CH:22][C:17]=3[CH2:16]2)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ncc2c(n1)CCN(S(=O)(=O)c1cccc(Br)c1)C2)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid 6.2 ml (81 mmol) was added to a solution of 2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 487 mg (1.25 mmol) in CH2Cl2 (8 ml) under nitrogen as inert gas and stirring was performed for 1.5 h at RT. After removal of the solvent, the intermediate (3-chloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (15 ml). After the addition of triethylamine 820 μl (5.84 mmol), the solution was cooled to 0° C. and 3-bromo benzenesulfonyl chloride 311 mg (1.37 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-3-chloro-benzamide 525 mg (81% of theoretical) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20](=[O:21])[N:19]([CH2:22][CH2:23][N:24]5C(=O)C6C(=CC=CC=6)C5=O)[N:18]=[C:17]4[CH2:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([CH:43]5[CH2:45][CH2:44]5)=[O:42])[CH2:37]4)=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.NN.C1(=O)NC(=O)C2=CC=CC=C12>C(O)C>[NH2:24][CH2:23][CH2:22][N:19]1[C:20](=[O:21])[N:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH:2]=[CH:3][C:4]=4[CH:9]=3)=[CH:11][CH:12]=2)[C:17]([CH2:35][C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[CH2:37]2)=[N:18]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2nn(CCN3C(=O)c4ccccc4C3=O)c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CCO
Product: NCCn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a 50 mL round bottom flask containing 2-[2-(4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (130 mg, 0.216 mmol) and ethanol (4 mL) was added hydrazine monohydrate (82 mg, 2.55 mmol, 11 eq). The flask was equipped with a condenser and the reaction was stirred at 60° C. for 1 h. Analysis by LC/MS displayed the phthalimide deprotection was complete. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 10-45% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (65 mg, 63%). MS(ES)+ m/e 472.2 [M+H]+.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O:21][C:22](=[O:36])[C@H:23]([CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[NH2:24])C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([NH:24][C@H:23]([C:22]([OH:36])=[O:21])[CH2:25][C:26]([OH:28])=[O:27])(=[O:13])[CH2:2][NH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C[C@H](NC(=O)CNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material was synthesised as follows. To a solution of hippuric acid (0.90 g, 5×10−3 moles) and L-aspartic acid dibenzyl ester (2.31 g, 5×10−3 moles) in DMF (35 ml) was added 1-hydroxybenzotriazole (0.73 g, 5.5×10−3 moles), triethylamine (1.4 ml, 9.7×10−3 moles) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide, HCl salt (1.05 g, 5.5×10−3 moles). The mixture was stirred for 4 hours at room temperature then poured into water (450 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated sodium bicarbonate solution, water, 2N HCl and water. The organic phase was dried over MgSO4 and evaporated to dryness to obtain the desired starting material as a yellow oil. 1.90 g (80%)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][S:6]1)=[O:4].[Cl:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=1[Cl:11])=[O:4]
Reactant: COC(=O)C1SCCC1=O
Reactant: Cc1cccc(N)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1sccc1Nc1cccc(C)c1Cl
Reaction time: 1 h

Procedure:
15.9 g (0.1 mole) of 3-oxotetrahydro-2-thiophencarboxylic acid methyl ester, 14.2 g of 2-chloro-3-methylaniline and 200 mg of p-toluenesulfonic acid are heated in 500 ml of toluene for six hours using a water separator. 24.6 g (0.1 mole) of chloranil are then added, and the mixture is boiled for a further one hour. It is cooled and filtered; the filtrate is washed with 100 ml each of 2 N sodium hydroxide solution, sodium dithionite solution and water and concentrated; the residue is purified by column chromatography (silica gel, toluene/ethyl acetate 4/1). 3-(2-Chloro-3-methylanilino)-2-thiophencarboxylic acid methyl ester is obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[C:62]([C:64]([NH2:66])=[O:65])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[C:62]([C:64](=[O:65])[NH2:66])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: NC(=O)c1nc([C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.5 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (0.107 g; 0.341 mmol) was dissolved in methylene chloride/dimethyl formamide (5:1; 20 ml). 1-Hydroxybenzotriazole (0.046 g; 0.341 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.071 g; 0.369 mmol) were added. The reaction mixture was stirred 15 min at room temperature and 2-((1R)-1-amino-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide (0.106 g; 0.284 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. The reaction mixture was washed with water (20 ml), sodium hydrogensulfate (10%; 20 ml), sodium hydrogencarbonate (satd; 20 ml), water (20 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×15 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.22 g of ((1R)-1-((1R)-1-(4-carbamoyl-5-phenyl-1,3-thiazole-2-yl)-2-(2-naphthyl)-ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:13][OH:14])([CH2:11]O)[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)(OCC)OCC.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:9][OH:10])[CH2:11][O:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)(CO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: OCC1(c2cccc(Cl)c2)COC1
Temperature: 190 °C

Procedure:
A mixture of Example 86C (1.1 g, 5.10 mmol), diethyl carbonate (722 mg, 6.10 mmol), and KOH (15 mg) was heated at 80° C., allowing the mixture to become homogeneous. The mixture was then heated at 95° C. for 4 hours during which time EtOH distilled off from the mixture. Distillation was continued until the pot temperature was 190° C., and then the pressure was reduced to 50 mm, maintaining the pot temperature at 190° C. for 1 hour. The residue was purified by Prep-TLC (eluted with petroleum ether:ethyl acetate=1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:26][C@H:27]1[C:35]2[C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=[N:31][C:30]=2[C@H:29]([OH:42])[CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:14]([N:39]2[CH2:40][CH2:41][N:36]([C:34]3[C:35]4[C@H:27]([CH3:26])[CH2:28][C@@H:29]([OH:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:37][CH2:38]2)=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c21
Yield: 88.6 %

Procedure:
(S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.1765 g, 0.5194 mmol) was combined with (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1596 g, 0.5194 mmol) and then slurried in methylene chloride (4.5 mL). The suspension was treated with diisopropylethylamine (0.2714 mL, 1.558 mmol) then with HBTU (0.1970 g, 0.5194 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with 10% Na2CO3 and then separated. The aqueous portion was washed twice with dichloromethane. The combined organic portions were dried with Na2SO4 and concentrated in vacuo. The residue was subjected to chromatography on SiO2 eluting with 4% MeOH/dichloromethane to yield (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (0.256 g, 89%). MS (ESI+) [M+H] 556.1/558.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH:16]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])=[CH:25][CH:26]=3)[C:21]2=[O:39])[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:40](O)([C:42](F)(F)F)=O.[CH2:47]1C[CH2:48]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl>[CH:40]1([CH2:42][CH:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:16]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])=[CH:25][CH:26]=3)[C:21]2=[O:39])[CH:17]([CH3:18])[CH3:19])[CH2:48][CH2:47]1
Reactant: O=C(O)C(F)(F)F
Reactant: C1CC1
Reactant: CC(C)C(COC1CCN(C(=O)OC(C)(C)C)CC1)N1CCc2ccc(Oc3ccc(F)cc3F)cc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(C(CC1CC1)OC1CCNCC1)N1CCc2ccc(Oc3ccc(F)cc3F)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 4-{2-[7-(2,4-difluoro-phenoxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-butoxy}-piperidine-1-carboxylic acid tert-butyl ester 15 (40 mg, 0.07 mmol) in dichloromethane (5 mL) was added 1 mL of TFA and the reaction was stirred at room temperature for 2 hours, at which time the solvent was removed and the crude material was re-suspended in dichloroethane, then carboxaldehyde cyclopropane (7.7 mg, 0.11 mmol), DIEA (39 mL, 0.22 mmol), and triacetoxyborohydride (31 mg, 0.148 mmol) were added. The mixture was stirred at 60° C. for six hours, then diluted with 10 mL of CH2Cl2 and extracted with saturated brine (10 mL). The solvent was removed and the crude oil was loaded onto a silica gel column and eluted with 10% MeOH in CH2Cl2 to yield 4.4 mg of 2-[1-(1-cyclopropylmethyl-piperidin-4-yloxymethyl)-2-methyl-propyl]-7-(2,4-difluoro-phenoxy)-3,4-dihydro-2H-isoquinolin-1-one 16 as a white solid. 1H NMR (CDCl3) δ 0.08 (m, 2H), 0.2 (m, 2H), 0.85 (m, 1H), 0.91 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H), 1.62 (m, 2.5H), 1.70 (m, 1H), 1.87 (m, 2.5H), 2.10 (m, 1H), 2.25 (m 3H), 2.78 (m, 2H), 2.89 (m, 2H), 3.30 (n, 1H), 3.49 (m, 1H), 3.59 (m, 1H), 6.84 (m, 1H), 6.90 (m, 1H), 7.06 (m, 2H), 7.14 (d, J=8.3 Hz, 1H), 7.57 (d, J=2.6 Hz, 1H). ESI [M+1] found 499.3; C29H36F2N2O3 requires 498.27.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][C:3]1([CH3:14])[CH3:13].[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[CH2:4][C:3]2([CH3:14])[CH3:13])[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)CC(=O)c2ccccc2C1O
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one (2.87 g, 13.88 mmol) and methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.25 g, 9.72 mmol) in THF (80 mL) at 0° C. is added triphenylphosphine (3.68 g, 13.88 mmol) and dimethyl azodicarboxylate (40% in toluene, 5.14 mL, 13.88 mmol) and the cooling bath is removed. After 15 hours, the mixture is concentrated and the resulting residue is dissolved in ethyl acetate (250 mL) and is extracted five times with 1M aqueous HCl (40 mL portions). The acidic aqueous phases are cooled to 0° C. and the pH is adjusted to ca. 12 with 4M aqueous NaOH at 0° C. The aqueous phase is then extracted three times with dichloromethane. The combined organic layers are dried over MgSO4 and filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1) to give 3-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 299.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (s, 3 H), 1.15 (s, 3 H), 2.63 (d, J=16.8 Hz, 1 H), 2.74 (d, J=16.8 Hz, 1 H), 3.93 (s, 3 H), 6.79 (s, 1 H), 7.02 (d, J=7.6 Hz, 1 H), 7.35 (s, 1 H), 7.47 (t, J=7.6 Hz, 1 H), 7.55 (td, J=7.6, 1.5 Hz, 1 H), 7.86 (s, 1 H), 8.13 (dd, J=7.6, 1.5 Hz, 1 H);
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[SH:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O.O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=CN1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 75.4 %

Procedure:
To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.58 g, 10 mmol), 2-mercaptobenzimidazole (5.56 g, 37 mmol), and triphenylphosphine (9.26 g, 35.3 mmol) in dimethylformamide (100 mL), diethyl azodicarboxylate (5.19 g, 29.8 mmol) was added dropwise over 5 minutes with ice-cooling and stirring under argon. The mixture was stirred for 80 minutes at room temperature, and then water (2 mL) was added to the mixture so as to deactivate the reagent. The reaction mixture was concentrated under reduced pressure, and chloroform (200 mL) was added to the residue. Insoluble material was removed through filtration, and the filtrate was concentrated under reduced pressure. 2N Hydrochloric acid (20 mL) and ethyl acetate (100 mL) were added to the residue, and the liquid was partitioned. The organic layer was extracted with 2N hydrochloric acid (20 mL×2). The aqueous extract and the aqueous layer were combined, and the mixture was washed with chloroform (50 mL×2) . The pH of the mixture was adjusted to about 9 through addition of potassium carbonate, followed by extraction with chloroform (50 mL×3), washing the organic layer with saturated brine, drying over sodium sulfate anhydrate, and removing the solvent. The thus-formed crude product was crystallized from acetone-diethyl ether, thereby yielding 2.19 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 76%) as a colorless crystalline powder. The crystallization mother liquor was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (eluent: chloroform:methanol=50:1 to 20:1), thereby yielding 0.42 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 14%) as a colorless crystalline powder. The overall yield was 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:20]([O:21][C:22]([O:24]C3C=CC=CC=3)=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:31])=[N:7]2.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(OC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:20]([O:21][C:22]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:31])=[N:7]2
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2c(Cl)ccnc2n1
Reactant: CN1CCNCC1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3c(Cl)ccnc3n2)CC1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
The procedure of Example 11 is followed but starting with 2-(5-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (6.7 g.), 4-methylpiperazine (15.8 g.) and dimethylformamide (32 cc.) and stirring for 15 minutes at 23° C. The reaction mixture is then diluted by adding diisopropyl ether (320 cc.). The precipitate is filtered off, washed with diisopropyl ether (3 × 30 cc.) and then dried. A product (3.8 g.) is obtained which is recrystallised from acetonitrile (300 cc.) to yield 2-(5-chloro-1,8-naphthyridin-2yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (2.9 g.) melting at 240° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1.Br>C(OC(=O)C)C>[Br:1][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:10]1=[O:13]
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: BrBr
Agent: Br
Solvent: CCOC(C)=O
Product: O=C1c2cc(Cl)ccc2CC1Br
Reaction time: 3 h

Procedure:
A solution of 9.59 g (60.0 mmoles) of bromine in 20 ml of acetic acid ethyl ester is added dropwise to a solution of 10.0 g (60.0 mmoles) of 6-chloro-1-indanone in 80 ml of acetic acid ethyl ester and 0.5 ml of 48% strength aqueous hydrobromic acid. After stirring for 3 hours, the reaction solution is concentrated to dryness, the residue is stirred with 50 ml of water and the precipitate is filtered off. The crude product of melting point 84°-87° is recrystallized from petroleum ether 60/70 and gives the pure product of melting point 92°-94° C.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[C:25]2([CH3:33])[CH3:32])[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[ClH:42]>CO.O1CCOCC1>[ClH:34].[ClH:42].[ClH:34].[ClH:34].[ClH:34].[Cl:34][C:19]1[N:20]=[C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[C:25]2([CH3:32])[CH3:33])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(C)C1CCN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C1CCN(c2nc(Cl)nc(NN)c2F)C1(C)C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.4618 g, 0.766 mmol) in MeOH (5 mL) was added 4 N HCl in dioxane (5 mL). The solution was stirred for 3 days, and then concentrated in vacuo to afford racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,2,2-tetramethyl-3-pyrrolidinamine pentahydrochloride (0.3673 g, 99% yield) as an orange oil that crystallized under vacuum. LCMS: (M+H)+: 303.1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([NH2:37])([CH3:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([NH:37][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)([CH3:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (750 mg, 2.20 mmol), 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (525 mg, 2.50 mmol) and diisopropylethylamine (1.36 mL, 7.80 mmol) in propan-2-ol (30 mL) was heated to reflux for 65 hours. The cooled reaction mixture was filtered and the yellow solid further purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in cyclohexane) to afford 910 mg (79%) of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester. LCMS (Method H, ESI): RT=4.35 min, m+H=516.2; 1H NMR (400 MHz, DMSO) δ: 9.42 (s, 1H), 8.95 (s, 1H), 8.15 (dd, 2H), 7.84-7.76 (m, 2H), 7.66 (m, 2H), 7.06 (d, 1H), 3.57 (m, 2H), 3.23-3.08 (m, 1H), 2.09 (d, 2H), 1.80 (m, 2H), 1.57 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](=S)=[S:16].[H-].[Na+].IC.[CH3:22][S:23]([CH3:25])=O>>[CH3:14][O:13][C:11](=[O:12])[C:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])=[C:22]([S:16][CH3:15])[S:23][CH3:25]
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: CS(C)=O
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)C(=C(SC)SC)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl phenylsulfonylacetate (5 g, 23.3 mmol) was mixed with carbon disulfide (1.77 g, 23.3 mmol) in anhydrous DMSO (100 ml) at room temperature. Sodium hydride (60% in mineral oil, 1.2 g, 48.9 mmol) was added portionwise. After stirring at room temperature for 1 hour, iodomethane (6.9 g, 48.9 mmol) was added neat and the reaction mixture was stirred overnight. The reaction mixture was quenched by the addition of water, and the resulting mixture extracted with dichloromethane. The organic layer was purified via flash chromatography and concentrated in vacuo to provide crude 2-benzenesulfonyl-3,3-bis-methylsulfanyl-acrylic acid methyl ester, which was further purified by recrystallization from methanol to yield 3.7 grams of white solid. 1H NMR (500 MHz, CDCl3): δ 8.1 (d, 2H), 7.6 (t, 1H), 7.5 (t, 2H), 3.9 (s, 3H), 2.4 (s, 3H), 2.2 (s, 3H).