Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1
Yield: 55 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine (2.0 g; 7.5 mmole) and cyclohexyl isocyanate (1.6 g; 12.8 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure, and the residual oil was dissolved in ethanol (10 ml). The crude product was precipitated as a white solid by the addition of water, collected by filtration and recrystallized twice from cyclohexane to yield 1-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}-3-cyclohexylurea (1.62 g; 56% yield) as a white crystalline solid, m.p. 109°-112° C. This product in methylene chloride (20 ml) was precipitated as the dihydrochloride by the addition of excess anhydrous hydrogen chloride. Recrystallization from water provided the title compound as colorless crystals, m.p. 184°-187° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH3:8])[N:28]=2)=[CH:19]1
Reactant: Cc1ccccc1N
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 33.2 %

Procedure:
Using the procedure of example 1, o-toluidine (87 mg) was reacted with compound 1f (100 mg) to provide compound 8 (27 mg, 33%). 1H NMR (400 MHz, CD3OD) δ 8.55 (d, J=8.0 Hz, 1H), 8.24 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.29 (q, J=7.6 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 7.11 (dd, J=7.6 Hz, 4.8 Hz, 1H), 2.35 (s, 3H). MS (ESI) m/z: 302 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[N+:4]([O-:6])=[O:5].CO[C:13](OC)([CH3:15])[CH3:14]>Cl.C(#N)C>[CH3:14][C:13]1([CH3:15])[O:8][CH2:7][C:3]([CH2:9][OH:10])([N+:4]([O-:6])=[O:5])[CH2:2][O:1]1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CC#N
Product: CC1(C)OCC(CO)([N+](=O)[O-])CO1
Temperature: 80 °C
Yield: 82 %

Procedure:
To a 250 ml round bottom flask equipped with a stir bar was added 5 g (0.03 mol) tris(hydroxymethyl) nitromethane, 3.75 g (0.36 mol) 2,2-dimethoxypropane, 100 ml acetonitrile and 6 drops concentrated hydrochloric acid. The reaction was heated to 80° C. for 18 hours. After cooling to room temperature tte volatiles were removed in vacuo to give a white solid 2,2-dimethyl-5-hydroxy methyl-5-nitro-1,3-dioxane in 82% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:12][NH:13][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:19]1[CH:18]=[C:17]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:32]4[C:28]([CH3:27])=[N:29][O:30][C:31]=4[CH3:36])=[CH:8][CH:9]=3)[CH2:14][NH:13][CH2:12]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=S(=O)(Oc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1)C(F)(F)F
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1
Yield: 48 %

Procedure:
Following the procedure in Example 24, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (225 mg, 0.53 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (114 mg, 0.8 mmol), cesium carbonate (521 mg, 1.6 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) in N,N-dimethylformamide (4 mL) and water (2 mL) gave 4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole (95 mg, 48%) as a brown oil: 1H NMR (CD3OD, 500 MHz) δ 7.46 (d, J=8.3 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.13-7.08 (m, 3H), 6.92 (d, J=8.0 Hz, 1H), 4.24-4.05 (m, 3H), 3.39 (dd, J=12.9, 5.7 Hz, 1H), 3.01 (dd, J=12.9, 8.3 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H); ESI MS m/z 373 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]4)=[N:22][CH:23]=2)=[N:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 59.1 %

Procedure:
Following general procedure II, (S)-tert-butyl 1-{5-[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}piperidin-3-ylcarbamate (98 mg, 0.19 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (87 mg, 0.30 mmol) to afford the desired product (73 mg, 60%) as a red-brown solid: 1H NMR (500 MHz, CDCl3) δ 11.55 (br s, 1H), 9.29 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.46 (s, 2H), 7.32 (dd, J=9.0, 2.8 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 4.78-4.72 (m, 1H), 3.87-3.69 (m, 3H), 3.29-3.07 (m, 2H), 2.79-2.71 (m, 1H), 1.98-1.69 (m, 2H), 1.45 (s, 9H), 1.31-1.22 (m, 2H), 1.16-1.06 (m, 2H); ESI MS m/z 649 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[C:14]([CH:13]=2)[C:22]([O:24][CH3:25])=[O:23])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Temperature: 122.5 °C
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (47.1 g, 0.30 mole), dimethyl 5-hydroxyisophthalate (63.0 g, 0.30 mole), anhydrous potassium carbonate (41.4 g), potassium iodide (0.2 g) and DMF (200 mL) was heated at 120-125° C. for 1.5 hours, under a slow nitrogen sweep allowing some distillate to be removed (about 75 mL) via a Dean-Stark trap. Additional DMF (50 mL) was added back to the reaction mixture and heating continued for an additional 1.5 hours while an additional amount of distillate (25 mL) was allowed to collect in the Dean-Stark trap. The reaction mixture was allowed to cool to about 45° C. A heavy slurry of pale yellow product resulted which was diluted further by the addition of an ice-water mixture (350 g) with good stirring. Filtration followed by washing with water and drying in air gave the pale yellow dimethyl 5-(4-nitrophenoxy)isophthalate (90.7 g) (structure supported by FDMS) which was used in Example 12c.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C(N(C(C)C)CC)(C)C.Cl.[C:34]1([C:40]2([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C@@H:48]3[C@@H:44]([CH2:45][NH:46][CH2:47]3)[C@@:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])([OH:49])[CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:58]1([C:40]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:48]3[C@@H:44]([CH2:45][N:46]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:47]3)[C@@:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])([OH:49])[CH2:42][CH2:41]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
0.025 g of 1-hydroxybenzotriazole, 0.38 g of (S)-2-(2-methoxyphenyl)propionic acid and 0.32 cm3 of diisopropylethylamine are added to a suspension of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry dichloromethane, this solution is then cooled to +5° C. and a suspension of 0.43 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 cm3 of dry dichloromethane is quickly added. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 2 hours, washed with 20 cm3 of water and then washed with 20 cm3 of an aqueous saturated solution of sodium chloride (twice), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting fractions of 25 cm3. Fractions 9 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of acetonitrile and diisopropyl ether. 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2methoxyphenyl)propionyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 244° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].[CH3:23][N:24]1[CH:28]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][N:26]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:25]1=[O:53].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:49]([F:52])([F:51])[F:50])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:30][CH2:29][CH:28]2[CH2:27][N:26]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[C:25](=[O:53])[N:24]2[CH3:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1cccc(O)c1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1cccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)c1)Oc1ccc(C(F)(F)F)cc1
Temperature: 65 °C
Yield: 116.2 %

Procedure:
A mixture of 3-(3-hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.100 g, 0.271 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.136 g, 0.298 mmol) and Cs2CO3 (0.133 g, 0.408 mmol) in DMF (8 mL) was heated to 65° C. under N2 for 17 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 hexanes:acetone to afford 0.113 g (64%) 2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester. 1H NMR. MS (ES+) Calc'd for C33H35N2O5F6 (M +1) 653. Found m/z 653 (100%).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:27])=[O:26])=O)(C)(C)C.S(=O)(=O)(O)O.[C:33](=O)(O)[O-].[Na+]>CO>[CH3:33][O:27][C:25]([C:9]1[NH:8][C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[C:11]2[CH:10]=1)=[O:26]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2[nH]1
Temperature: 25 °C
Yield: 78 %

Procedure:
The suspension of 0.2 g (0.54 mmol) 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester (intermediate G) and 30 μl of concentrated sulfuric acid in 2 ml methanol was heated under reflux. After 1.5 h another 2 ml methanol and 30 μl of concentrated sulfuric acid were added. The resulting clear solution was refluxed 3 hours and after cooling down to room temperature was poured on saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 0.12 g (78%) of the product as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:11][C:10]([C:14]([F:15])([F:17])[F:16])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Yield: 79.3 %

Procedure:
According to the procedure described in Example 161C, to a solution of 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (2.346 g, 9.57 mmol) in THF (25 mL) and K2CO3 (2.63 g, 19 mmol) was added phenyl chloroformate (1.948 g, 12.4 mmol). The crude product was purified by silica gel chromatography (with 5-20% EtOAc/hexane as eluants) to afford phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (2.772 g, 79%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 2H), 7.40 (m, 2H), 7.27 (m, 3H), 7.14 (m, 2H), 6.97 (br, 1H), 6.85 (s, 1H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:28]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:29])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)C2CCCCC2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2S, 4R)-4-aminomethyl-2-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 mmol, Example 39C) in dichloromethane (2 mL) at room temperature was added cyclohexanecarbonyl chloride (0.092 g, 0.65 mmol) and triethylamine (0.10 mL, 0.75 mmol). The mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure and the residue taken up in water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed consecutively with saturated aqueous NaHCO3, 10% KHSO4 (aq), brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-40% ethyl acetate:hexane to provide the title compound. MS (CI) m/z 408 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.40-4.28 (m, 1 H), 3.88-3.66 (m, 2 H), 3.56-3.25 (m, 4 H), 3.22-3.16 (m, 2 H), 2.57 (m, 2 H), 2.55 (m, 1 H), 1.99-1.61, (m, 13 H), 1.41 (m, 9 H), 1.51 (m, 2 H).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 91.5 %

Procedure:
1.03 g (5 mmol) of 1,1-dimethylethyl 1,4-diazepane-1-carboxylate, 1.19 g (5 mmol) of 2,5-dibromopyridine and 0.7 g (5 mmol) of potassium carbonate suspended in 0.90 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is heated at 150° C. for 22 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate, and the organic solution is washed with water and then brine, and dried over sodium sulfate. The filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 99.5/0.5 mixture of dichloromethane and methanol. 1.63 g of product are obtained in the form of an oil, and are used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([O:24]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[N:38]=1.CS(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:43][C:39]4[N:38]=[N:37][CH:42]=[CH:41][CH:40]=4)(=[O:22])=[O:24])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: Nc1cccnn1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
A RBF was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.68 g, 1.199 mmol) and pyridazin-3-amine (0.137 g, 1.438 mmol). DMSO (2.2 ml) was added to give a solution which was then diluted with THF (7.14 ml). The flask was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (2.64 ml, 2.64 mmol) was added dropwise, slowly over 2 min. After 15 min, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 10-70% of a 3:1 EtOAc/EtOH solution in heptane with 10% DCM as additive). Fractions containing pure product were combined and concentrated to give 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (0.25 g, 0.523 mmol, 43.6% yield) as an off-white solid. m/z (ESI) 478.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[N:18]1([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[NH4+].[OH-].CO>C(Cl)Cl>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: OB(O)c1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CN4CCCCC4)c3)nc12

Procedure:
2,2-Dimethyl-1-[2-(3-piperidin-1-ylmethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(piperidin-1-ylmethyl)phenylboronic acid hydrochloride following general procedures as described in these Examples. Silica gel chromatography using 0-20% [5% NH4OH:MeOH]/DCM as eluant gave a brown solid which was washed with 1:2 Et2O/Hexanes to provide 70 mg (36%) of a pale brown solid. MP 176-177° C., M+H=377.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[CH2:19][CH2:20][CH:16]([CH:14]2[CH2:15][CH:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[C:17]1=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CC1C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.8 %

Procedure:
To 30 ml of a dimethylformamide solution of 2.288 g (10.2 mmol) of 3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one was added 406.2 mg (10.2 mmol) of sodium hydride under cooling with ice, followed by stirring at room temperature for 1.5 hours. Then, 1.81 ml (15.3 mmol) of benzyl chloride was added thereto dropwise, followed by stirring for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.121 g (35.0%) of 1-benzyl-3-(2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer A: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid. The column was then eluted with hexane:ethyl acetate=l:l to give 670.9 mg (20.9%) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer B: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:24][CH2:23][CH2:22][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOc1ccc(C2=NNC(=O)SC2CC)cc1OC
Reactant: ClCCCN1CCCC1
Product: CCC1SC(=O)N(CCCN2CCCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
of 5-(3-methoxy-4-ethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-3-pyrrolidinopropane:
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([S:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [S-2]
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: O
Product: c1ccc(CSCc2ccccc2)cc1
Reaction time: 8 h
Yield: 188.5 %

Procedure:
Sodium sulphide nonahydrate (2.40 g, 0.01 mol), benzyl chloride (1.26 g, 0.01 mol), water (3 ml) and compound 1 (0.5 mmol) were stirred at 70°-78° C. for 20 minutes. The reaction mixture was poured into water and left overnight at room temperature. The white crystals thus obtained were filtered off and dried to give 2.02 g of benzyl sulphide.