Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:8]([O:10]CC)=O)#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(=O)C>[OH:10][C:8]1[N:23]2[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[CH:25]=[C:24]2[N:26]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:1]=1
Reactant: COc1ccc(-c2cc(N)[nH]n2)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)n2nc(-c3ccc(OC)cc3)cc2n1
Reaction time: 3 h

Procedure:
Diethyl acetylenedicarboxylate (883 μL, 5.6 mmol) was added to a solution of 3-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.1 g, 5.6 mmol) in acetic acid (5 mL). The very thick mixture was allowed to stand at room temperature with occasional stirring for 3 h. Ethyl acetate (5 mL) and hexanes (15 mL) were added and the precipitate was filtered, and dried under high vacuum. Yield: 1.26 g (76%); LCMS m/z 314.1 (M+H)+, ret. time=2.25 min.
Reaction SMILES: [P:1](Cl)([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[O:2].N1C=CC=CC=1.[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23]>ClCCl>[P:1]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CC(C)COP(=O)(Cl)OCC(C)C
Reactant: CCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOP(=O)(OCC(C)C)OCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diisobutyl chlorophosphate (130.3 g, 0.57 mole) in 600 mL of dichloromethane and 55.37 g (0.70 mole) of pyridine was cooled to 0° C. n-Butanol (42.25 g, 0.57 mole) was added dropwise over 1 hour. The formation of a white precipitate was immediately observed. The reaction mixture was then stirred for 24 hours at room temperature. The pyridinium hydrochloride was filtered off and the solution washed with water (2×250 mL), aqueous 0.5 N HCl (2×250 mL) and water (2×250 mL). The organic phase was dried over anhydrous magnesium sulfate for 12 hours. Filtration of the drying agent, followed by the removal of the solvent using a Roto-vap, yielded n-butyl diisobutyl phosphate as a clear colorless liquid. Distillation of the crude product (68° C. at 0.02 torr) gave 125 g of 96% n-butyl diisobutyl phosphate (BDIBP).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[OH:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:17][CH2:18][C:19]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-(bromomethyl)-4′-fluorobiphenyl (398 mg, 1.16 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (280 mg, 0.96 mmol) were combined in dimethylformamide (5 mL) and cooled to 0° C. The reaction was treated with sodium hydride (46 mg, 1.92 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 470 mg (73%). 1H-NMR (CDCl3, 500 MHz) δ 7.51 (s, 1H), 7.28-7.42 (m, 6H), 7.19-7.23 (m, 2H), 7.06-7.14 (m, 3H), 4.34 (s, 2H), 3.69-3.74 (m, 2H), 3.40 (s, 2H), 2.98-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.81-1.90 (m, 2H), 1.41 (s, 9H). Mass spec.: 556.37 (MH)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][C@H:16]([OH:19])[CH2:17][CH3:18]>>[C@@H:16]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:17][CH3:18])[CH3:15]
Reactant: CC[C@H](C)O
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A14(c) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) and (S)-butan-2-ol. MS (m/e): 271.1 ([M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=[O:21])[CH3:20]
Reactant: Cc1ccc2c(n1)CCNC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C)ccc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al., Chem. Pharm. Bull., 32 2522, (1984)] (2.73 g, 0.0184 mol) in CH2Cl2 (30 ml) and triethylamine (5.1 ml, 0.0368 mol) was added acetyl chloride (1.57 ml, 0.0221 mol) at 0° C. The reaction mixture was stirred for 24 h at room temperature, after which time the reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate, H2O, saturated brine, dried over MgSO4 and evaporated under reduced pressure to afford the subtitle compound (3.27 g, 93%). Rf 0.5 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 191 (MH+).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH2:6][C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])(S(C3C=CC=CC=3)(=O)=O)[CH:4]2[CH3:29])[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[C:4]=1[CH3:29]
Reactant: CC1C2(CCCC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC1=C(CCCCCCCCCCO)CCCC1=O
Yield: 45 %

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 388 mg of 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-2-methyl-3-(phenylsulfonyl)-cyclohexane in 30 ml of chloroform and 6 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture was added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 3-(10-hydroxydecyl)-2-methyl-2-cyclohexen-1-one was obtained in the form of a colorless oil. Yield: 45%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[I:14]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:13])[C:12]=2[I:14])=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc(Br)cc2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(Br)cc2)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-bromophenyl)-1-methyl-1H-imidazole (Step 2 product, 2.8 g, 9.45 mmol) in dichloromethane (30 mL) was added N-iodosuccinimide (1.913 g, 8.50 mmol) and six drops of trifluoroacetic acid. The reaction mixture was stirred at rt for 16 h. The mixture was neutralized with aqueous sodium bicarbonate and the organics were extracted with dichloromethane. The organics were then washed with aqueous sodium thiosulfate, followed by three washes with water then dried (MgSO4). The solvent was concentrated to afford 4-(4-bromophenyl)-5-iodo-1-methyl-1H-imidazole, which was used with out further purification. LCMS: [M+1]+=363.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CC(C)=O>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)c1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 16.3 g of 2-aminobenzamide, 82 ml of saturated aqueous sodium acetate solution and 82 ml of acetic acid was added a solution of 21 g of 4-chlorobenzoyl chloride in 14 ml of acetone. The mixture was stirred at room temperature for one hour after addition was complete. The tan precipitate was collected by filtration and recrystallized from ethanol to give 24.1 g of light tan 2-(4-chlorobenzamido)benzamide, m.p. 205°-207°, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[NH:12][C:11]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:10]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:3][O:4][C:5]1[C:13]2[N:12]([CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[OH:19])[C:11]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:10]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c3c(n(CC(O)c4ccncc4)c12)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.6 %

Procedure:
Sodium hydride (60%) (555 mg, 13.88 mmol) was added portionwise to a solution of 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.629 mmol) in DMF (10 mL) and stirred at RT for 15 min, the suspension was allowed to cool at 0° C. 4-(Oxiran-2-yl)pyridine (896 mg, 7.407 mmol) was added dropwise and reaction mixture was stirred at RT for 48 h. The reaction mixture was poured in to ice-cooled water and extracted with EtOAc (3×50 mL), and the organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo, afforded crude was purified by reverse phase HPLC to afford 2-(6-methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol (165 mg) as the formate salt. 1H NMR (CDCl3, freebase) δ (ppm): 8.60 (d, 2H), 7.31 (d, 2H), 7.02 (m, 2H), 6.66 (d, 1H), 5.08 (dd, 1H), 4.66 (dd, 1H), 4.12 (dd, 1H), 3.99 (s, 3H), 3.60 (d, 1H), 3.56 (d, 1H), 2.9 (m, 1H), 2.81 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H), 2.55 (s, 3H). Separation by chiral HPLC provided enantiomers 44a and 44b.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH2:8].[N:14]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH:17]=[C:16]([C:20](OC)=[O:21])[CH2:15]1>C(Cl)Cl>[Br:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH:8][C:20]([C:16]1[CH2:15][N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH:17]=1)=[O:21]
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(F)cc1Br
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2ccc(F)cc2Br)C1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
Trimethylaluminium (2.0 M in hexanes, 3.98 mL, 7.96 mmol) was added dropwise to a solution of 2-bromo-4-fluoroaniline (1.26 g, 6.63 mmol) in DCM (15 mL) under N2. After gas evolution ceased, 1-tert-butyl 3-methyl 5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.60 g, 6.63 mmol) in DCM (10 mL) was added and the resulting mixture was refluxed overnight. After cooling to about 0° C., the reaction was quenched by the addition of saturated aqueous NaHCO3 solution. The organic layer was separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 6:1) to give tert-butyl 3-(2-bromo-4-fluorophenylcarbamoyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.33 g, 50%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.36 (dd, J=9.2, 6.0 Hz, 1H), 7.87 (br s, 1H), 7.32 (dd, J=7.6, 2.8 Hz, 1H), 7.07 (ddd, J=9.2, 6.0, 2.8 Hz, 1H), 6.82 (br s, 1H), 4.27 (s, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.38 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:19][NH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[OH:25]O>C(O)(=O)C.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[S:15](=[O:25])[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[NH:18][CH2:19]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Reactant: OO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2=O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A solution of N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (20 mg, 0.058 mmol) in acetic acid (500 μL) was treated with hydrogen peroxide (12 μL of aq. 30% w/w, 0.12 mmol) and stirred at room temperature for 2 h. The reaction was diluted with DMF and purified by HPLC (10-99% CH3CN/5 mM HCl) to provide N-(4-tert-butyl-3-hydroxy-phenyl)-1-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxamide (8 mg, 38% yield). LC/MS m/z 359.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1.Br[CH2:47][CH2:48][CH2:49][CH2:50][Cl:51]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:47][CH2:48][CH2:49][CH2:50][Cl:51])[C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:9][CH:10]=1
Reactant: ClCCCCBr
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCCCCl)c3ccccc23)cc1
Yield: 92.6 %

Procedure:
Substantially the same procedure as in Reference Example 2 was repeated using Compound 1 (5.0 g, 7.99 mmol) and 1-bromo-4-chlorobutane (1.0 ml, 8.78 mmol) to give 5.3 g (yield: 93%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=1Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].O1CCOCC1>O>[Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: COC(=O)CCCCCOc1n[nH]c(=O)c(Cl)c1Cl
Reactant: COc1ccc(CN)cc1OC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCCCCOc1n[nH]c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Reaction time: 8 h

Procedure:
A mixture comprising 4.13 g of 4,5-dichloro-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone, 6.70 g of 3,4-dimethoxybenzylamine, 130 ml of 1,4-dioxane and 130 ml of water, was refluxed with stirring overnight. The solvent was evaporated under reduced pressure, and water was poured to the residue, whereupon the product was extracted with chloroform. The extract was washed with dilute hydrochloric acid, water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-n-hexane-diethyl ether to obtain 5.28 g of the above identified compound as colorless crystals having a melting point of from 111° C. to 112° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Reactant: CCCCOCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(Cn2cc(-c3ccc(N)nc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2,6-diamine (20 mg, 0.11 mmol) described in Manufacturing Example 36-1-2 in N,N-dimethylformamide (4 mL) was added sodium hydride (5.9 mg, 0.15 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.) Following 30 minutes of stirring at room temperature, 1-butoxymethyl-4-chloromethyl-benzene (26.7 mg, 0.13 mmol) described in Manufacturing Example 33-1-4 was added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate) to obtain the title compound (29.0 mg, 72%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][S:5][CH2:4][CH2:3][S:2]1.Cl.[CH2:9]([O:19][C:20](=[O:25])[C@H:21]([CH2:23][SH:24])[NH2:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[SH:2][CH2:3][CH2:4][S:5][CH2:6][C:1]([NH:22][CH:21]([C:20]([O:19][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:25])[CH2:23][SH:24])=[O:7]
Reactant: CCCCCCCCCCOC(=O)[C@@H](N)CS
Reactant: O=C1CSCCS1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOC(=O)C(CS)NC(=O)CSCCS
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.42 g (0.1 mol) of 2,5-dithia cyclohexanone dissolved in 250 ml of anhydrous dichloromethane are added by dropping, and in an argon atmosphere, to a solution of 29.79 g (0.1 mol) of cysteine decyl ester hydrochloride and 10.12 g (0.1 mol) of triethyl amine in 500 ml of anhydrous dichloromethane. The reaction mixture is kept agitated overnight at room temperature and then washed three times with 2% aqueous citric acid, saturated sodium hydrogencarbonate solution and with water. After drying above sodium sulfate, the solvent is evaporated under reduced pressure. The oily residue is crystallized by trituration with diethyl ether.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].F[C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: COc1cccc(N)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1cccc(Nc2cc(F)c(F)cc2C(=O)O)c1
Yield: 94.4 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 3-methoxy-aniline (1.91 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.48 g of the crude title compound.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[Li]CCCC.[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])[CH2:15][CH2:14]1>O1CCCC1>[CH:1]1([CH:4]([C:13]2([OH:12])[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:17][CH2:18]2)[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: N#CCC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C(C#N)C4CC4)CC3)c(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of cyclopropyl acetonitrile (28 mmol) and was treated with n-BuLi (28 mmol) at −78° C. in tetrahydrofuran and was stirred for 1 hour. Addition of (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (14.32 mmol) was done to the reaction mixture and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and was extracted with ethyl acetate. The organic layer was concentrated, dried and evaporated to afford a residue which was purified on silica gel column chromatography to provide title compound in 64% yield. M.P. 170-72° C. and MS (M+1)=431 (H+, 100%) for M.F.=C22H27FN4O4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[NH:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:15]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:15]1
Reactant: COC(=O)c1cc[nH]n1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccn(-c2ccc(OC)cc2OC)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dimethoxyphenylboronic acid 1 (2.88 g, 15.8 mmol, 1.00 equiv) in DMF (100 mL) was added methyl 1H-pyrazole-3-carboxylate (3.00 g, 23.7 mmol, 1.50 equiv), Cu(OAc)2 (5.70 g, 31.6 mmol, 2.00 equiv), and pyridine (3.76 g, 47.4 mmol, 3 equiv). The resulting solution was stirred for 2 h at 90° C. The solids were filtrated off by filtration and the filtrate was extracted by EtOAc (200 mL×3). The combined organic layers were dried by anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE/EA (3/1). This resulted in 1.5 g (36%) of methyl 1-(2,4-dimethoxyphenyl)-1H-pyrazole-3-carboxylate 2 as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J=2.4 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.59 (s, 1H), 7.73, 6.58 (d, J=8.7 Hz, 1H). LC-MS: m/z=263 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:31])=[O:30]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(Cl)cc2Cl)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,4-dichlorobenzenesulphonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a white solid. MS (ESI+) for C18H18Cl2N2O3S m/z 414 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[I:12]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: NCCNc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(NCCNc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and N-phenylethylenediamine in dioxane. ES-MS m/e (%): 422 (M+H+, 100).