Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1.[C:10]([CH2:12][C:13](=O)[CH3:14])#[N:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:13]([CH3:14])=[CH:12][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: CC(=O)CC#N
Reactant: NCc1ccc(Cl)nc1
Product: CC(=CC#N)NCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 85 %

Procedure:
1.4 g of 2-chloro-5-pyridylmethylamine and 0.8 g of 1-cyano-2-propanone were mixed and the mixture was stirred at room temperature over night. The solvent was then distilled off and the residue was purified by column chromatography on silica gel to afford 1.7 g of compound No. 528. m.p. 95°-98° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([O:30][CH:31]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[N:26][CH:27]=[N:28][CH:29]=2)=[O:22])[N:20]=1>C(Cl)Cl>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([O:30][CH:31]3[CH2:35][CH2:34][NH:33][CH2:32]3)=[N:26][CH:27]=[N:28][CH:29]=2)=[O:22])[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cncnc1OC1CCNC1)c1csc(-c2c(F)cccc2F)n1
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
At room temperature, TFA (trifluoroacetic acid) (0.5 mL) was added to a solution of Compound 1A (20 mg, 0.0394 mmol) in CH2Cl2 (1 mL) and stirred for 10 min. The mixture was the concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with NaOH (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated in vacuo to obtain the title compound 1 (12 mg, 0.0298 mmol)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:24]=1)#[N:2].[OH-:25].[K+]>C(O)C>[CH3:23][N:20]1[CH2:21][CH2:22][C:17](=[C:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]3[CH:24]=[C:3]([C:1]([NH2:2])=[O:25])[CH:4]=[CH:5][C:6]2=3)[CH2:18][CH2:19]1
Reactant: [OH-]
Reactant: CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Agent: [K+]
Solvent: CCO
Product: CN1CCC(=C2c3ccc(C(N)=O)cc3CCc3cccnc32)CC1
Yield: 66 %

Procedure:
Ethanol (150 ml) was added to 2 g of 8-cyano-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine so that the latter was dissolved in the former. An aqueous solution of 2.8 g of potassium hydroxide was added further, followed by reflux for 3.5 hours. After the reaction, the solvent was distilled off under reduced pressure and a brine was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol 25:1 and 10:1), 1.4 g of 11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-8-carboxamide were obtained (yield: 66%).
Reaction SMILES: Br.Br.[CH3:3][C@H:4]1[CH2:9][NH:8][C@@H:7]([CH3:10])[CH2:6][NH:5]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](Cl)=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:5]2[CH2:6][C@H:7]([CH3:10])[NH:8][CH2:9][C@@H:4]2[CH3:3])=[N:14][N:13]=1
Reactant: C[C@H]1CN[C@@H](C)CN1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1

Procedure:
(2S,5S)-2,5-dimethylpiperazine dihydrobromide (1.16 g, 4.20 mmol), 1,4-dichlorophthalazine (700 mg, 3.52 mmol), potassium carbonate (973 mg, 7.04 mmol), and N-methylpyrrolidinone (7 mL) were heated at 120° C. for 22 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes+2.5% triethylamine/0-100% ethyl acetate+2.5% triethylamine gave a pale yellow semi-solid. MS (M+H)+=277.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][N:7]=[C:8]=[O:9].[N+:15](=[C:17]1[N:21]=[CH:20][N:19]=[C:18]1[C:22]([NH2:24])=[O:23])=[N-:16]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][N:7]1[C:8](=[O:9])[N:21]2[CH:20]=[N:19][C:18]([C:22]([NH2:24])=[O:23])=[C:17]2[N:15]=[N:16]1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: COc1ccc(CN=C=O)cc1OC
Solvent: CS(C)=O
Product: COc1ccc(Cn2nnc3c(C(N)=O)ncn3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 3,4-dimethoxybenzyl isocyanate (4 mmol) was added to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product was removed by filtration and purified by column chromatography to give the title compound as a white solid. Yield: 0.068 g, 10%. IR vmax/cm−1 1734, 1686, 1616. 1H NMR δH (DMSO-d6) 3.73 (3H, s, OMe), 3.74 (3H, s, OMe), 5.42 (2H, s, CH2Ar), 6.91-6.98 (2H, m, ArH), 7.03 (1H, d, J=1.9, ArH), 7.70 (1H, br s, NH), 7.82 (1H, br s, NH), 8.83 (1H, s, 6-H). δC (DMSO-d6) 52.2, 56.0, 56.0, 112.1, 112.4, 121.1, 128.3, 129.4, 131.3, 134.9, 139.6, 149.1, 149.2, 162.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[NH:10]2)[CH3:4].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[CH3:4]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(C(=O)OC)cc2)c(CC)n1
Yield: 72.1 %

Procedure:
Sodium hydride (50% dispersion in oil; 1.05 g) was added to a stirred solution of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (4.0 g) in DMF (75 ml) and the mixture was stirred until effervescence ceased. Methyl 4-bromomethylbenzoate (4.58 g) was added and the mixture was stirred under argon for 4 hours. The mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried (MgSO4) and solvent was removed by evaporation. The resultant solid was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (3:1 v/v gradually increasing to 1.0 v/v) to give methyl 4-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)-methyl]benzoate as a solid (5.0 g); m.p. 128°-130° C.; NMR (d6 -DMSO): 1.15(t, 3H), 1.25(t, 3H), 2.69(q, 2H), 3.06(q, 2H), 3.83(s, 3H), 5.56(s, 2H), 6.71(d, 1H), 7.04(s, 1H), 7.35(d, 2H), 7.91(d, 2H), 8.22(d, 1H); mass spectrum (+ve FAB, methanol/DMSO/NBA): 351 (M+H)+ ; microanalysis, found: C, 71.8; H, 6.3; N, 8.2%; C21H22N2O3 requires: C, 72.0; H, 6.3; N, 8.0%.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)N(C)CC(F)(F)F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(F)(F)F)C(=O)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To methyl 6-(methyl(2,2,2-trifluoroethyl)carbamoyl)nicotinate (425 mg, 1.54 mmol) in tetrahydrofuran (17 mL) and water (8.5 mL) was lithium hydroxide monohydrate (193 mg, 4.60 mmol) added and the reaction mixture was stirred at ambient temperature over night. The organic solvent was evaporated, 1M hydrochloric acid added until an acidic pH was reached followed by extraction with ethyl acetate (3×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield 366 mg (91%) of the title compound as a solid; MS (APPI/APCI) m/z 263[M+H+].
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.Cl.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]([Cl:10])=[O:6])[CH2:18][CH2:17]1
Reactant: COC1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CCN(C(=O)Cl)CC1

Procedure:
To a stirred solution of triphosgene (7.4 g, 0.025 mmol) in dichloromethane (200 ml) at ice bath was added dropwise a solution of 4-methoxy-piperidine hydrochloride salt (10 g, 0.066 mmol) and pyridine (10.9 g, 0.139 mmol) in dichloromethane (100 ml). The mixture was stirred over night and filtered through a silica pad, eluting with dichloromethane and evaporated. After trituration with diisopropyl ether, the mixture was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:20])C(Cl)(Cl)Cl)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[OH2:21].[OH-].[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([OH:20])=[O:21])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: O
Reactant: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)n2c1COCC2
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 4a) (11 g, 32.3 mmol) in tetrahydrofuran (60 ml) was added water (110 ml) and potassium hydroxide (1.72 g, 30.7 mmol). The mixture was stirred for 5 min, then an additional portion of potassium hydroxide (250 mg) was added and the mixture was stirred for 2 h at 25° C. Tetrahydrofuran was evaporated in vacuo. After addition of 50 ml water, the mixture was acidified with 10 M aqueous hydrochloric acid. The precipitate was filtered off, washed with a small portion of water and dried in vacuo at 55° C. to give 6.56 g (85%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester as a white solid. LC/MS (method 3): Rt=1.34 min; m/z=240.03 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[O:6][CH2:5]2.[CH3:24][N:25](C)C=O.C(N)CN>C1(C)C=CC=CC=1>[CH3:22][N:21]([CH2:20][CH2:19][CH2:18][C:7]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:6][CH2:5][C:4]2[CH:3]=[C:2]([C:24]#[N:25])[CH:10]=[CH:9][C:8]1=2)[CH3:23]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(Br)ccc21
Reactant: CN(C)C=O
Solvent: NCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 145 °C

Procedure:
Cuprous cyanide (85.4 g, 0.95 mol) was added to 5-bromo-1-(3-dimethylaminopropyl) 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (200 g, 0.53 mol) and contents were heated to 140-150° C. After completion of reaction, N,N-dimethylformamide (200 ml) was added and reaction mass was further diluted with toluene (500 ml). The reaction mixture was cooled to 80° C. where aqueous ethylenediamine (50% w/v) was added and layers were separated. The organic layer was washed sequentially with aqueous EDTA (2% w/v) and water (2×200 ml). The organic layer was concentrated under reduced pressure to remove toluene. The residue was distilled in vacuum and crude Citalopram was obtained as oil. Yield: 110 g. The crude product contained 7% of desmethyl citalopram by HPLC.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]([CH3:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH:8]([CH3:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC1CN(Cc2ccccc2)CC=C1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C2=CCN(Cc3ccccc3)CC2C)c1
Temperature: 100 °C

Procedure:
A mixture of 1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (3 g, 9.0 mmol), [3-(ethoxycarbonyl)phenyl]boronic acid (2.26 g, 11.6 mmol), PdCl2(PPh3)2 (315 mg, 0.44 mmol), and potassium carbonate (2.5 g, 18.0 mmol) in Toluene:EtOH (10:1, 50 mL) were heated to 100° C. for 18 hr. The cooled reaction mixture was partitioned between EtOAC and H2O and the aqueous layer was extrated with EtOAc (4×). The organics were combined, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a gradient of hexane:EtOAc to yield ethyl 3-(1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate as a clear oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:14][CH:13]=2)[N:4]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH3:28][N:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:24])[F:25])=[N:4]2)=[CH:13][CH:14]=1)[C:20](=[O:23])[CH:21]=[CH2:22]
Reactant: CI
Reactant: C=CC(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(=O)N(C)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reaction time: 0.08 h
Yield: 26 %

Procedure:
A stirred solution of N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide (241 mg, 0.69 mmol) in dimethylformamide (5 ml) under argon was treated with sodium hydride (60% suspension in mineral oil, 28 mg, 0.7 mmol). The reaction mixture was stirred for 5 minutes then methyl iodide (0.05 ml) was added and the reaction mixture stirred for a further 1 hour. Reaction mixture was then quenched with 3 drops of water and 5 ml of 1M ammonia in methanol. Excess ammonia and methanol were removed by rotary evaporation. Reaction mixture was separated between ethyl acetate and brine. Organic layer was retained, dried over sodium sulphate and the solvent removed by rotary evaporation. Sample was purified by 5 g pre-pack silica column eluted with 50% ethyl acetate/petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a yellow oil (66 mg, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:13][C:14](=[O:15])[NH:1]2
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Product: O=c1[nH]c(=O)c2c(Cl)cc(Cl)cc2[nH]1
Temperature: 160 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of 2 g (10 mmol) of 2-amino-4,6-dichlorobenzoic acid and 1.6 g (30 mmol) of urea was heated to 160° C. for 2 hrs. and at 180° C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 880 mg (40%) of 5,7-dichloro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as beige crystals;
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[S:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)(=[O:10])(=[O:9])[NH2:8]>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([S:7]([NH2:8])(=[O:9])=[O:10])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(CO)cc1
Temperature: 0 °C

Procedure:
LiAlH4 (235 mg, 6.2 mmoles) was suspended in dry THF (10 mL) under nitrogen atmosphere. The suspension was cooled to 0° C. and 4-sulphamoyl-benzoic acid (500 mg, 2.48 mmoles, as a suspension in 10 mL of dry THF) was added. The resulting mixture was then refluxed for 18 hours. The reaction was quenched by addition of 3N HCl at 0° C. The quenched mixture was extracted with AcOEt, the organic layer was dried over Na2SO4 and evaporated to dryness. The crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 1/1) to yield the title compound in amount of 105 mg.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1[CH:9]=[C:8]2[O:10][S:11]([C:14]3=[CH:15][CH:16]=[CH:17][C:6](=[C:7]23)[CH:5]=1)(=[O:13])=[O:12]>>[OH:10][C:8]1[CH:9]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:14]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:15][CH:16]=[CH:17]2
Reactant: O=S1(=O)Oc2cccc3cccc1c23
Reactant: CNC
Product: CN(C)S(=O)(=O)c1cccc2cccc(O)c12
Reaction time: 20 h

Procedure:
Dry dimethylamine gas was passed through a solution of 1,8-naphthasultone [5.0 g, 24 mmoles, described by I. Hideo, Japanese Patent 4927, Aug. 31, 1951; Chem. Abstr., 47, 9364b (1953)] for 1.5 hr at 20°-22° C. The mixture was stirred for 20 hr. The resulting yellow crystals were collected by filtration. The filtrate was concentrated to give more crystals. The two batches of crystals were combined giving 5 g of 8-hydroxy-N,N-dimethyl-1-naphthalenesulfonamide; mp 95° C.; NMR (CDCl3) δ 2.88 (s, 6H), 7.1-8.3 (m, 6H).
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1.ClCCl.ClC1C=CC=C(C(OO)=[O:29])C=1>C(OC)(C)(C)C>[CH3:17][C:2]1([CH2:3][C:4]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH2:1][O:29]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(c2ccccc2)CCNC(=O)O1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC1(CC2(c3ccccc3)CCNC(=O)O2)CO1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25° C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-(S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was used directly in Step 5.
Reaction SMILES: [OH-].[K+].C1COCC1.C([O:10][C:11](=[O:43])[C@:12]([N:18]([CH3:42])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:11]([C@:12]([N:18]([CH3:42])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])([OH:43])=[O:10]
Reactant: CCOC(=O)[C@](C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)[C@@](C)(C(=O)O)N(C)C(=O)c1ccc(-c2ccc(OCCN3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
An aqueous solution (2.0 mL) of potassium hydroxide (0.11 g) was added to a THF (2.0 mL)-methanol (2.0 mL) solution of 4-{2-[(4′-{[(2S)-1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]ethyl}morpholine (93 mg) as obtained in Example 19-(3), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was adjusted to pH 6 with a 10% aqueous solution of citric acid, and extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure to obtain 4-{2-[(4′-{[(2S)-2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]ethyl}morpholine (light brown oil) (58 mg, 65%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:15])=[O:14]>C(Cl)CCl>[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N+:18]=1[O-:9])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cccc[n+]1[O-]
Reaction time: 8 h

Procedure:
Meta-chloroperbenzoic acid, 85% solution, 1.27 g., 6 mmoles) was added to 2-(methylsulfonylmethyl)-pyridine .08 g., 6 mmoles) in 10 mls. of ethylene chloride. The resulting solution was allowed to stand at room temperature overnight and then was chilled and filtered. The filtrate was evaporated and cyrstallization of the oily residue was induced by scratching. Recrystallization from toluene and isopropanol gave 0.6 g. of the title compound as white needles (melting range 153-155° C.). Analysis for C7H9NO3S:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C=C(C2NC3=NC=CC=C3C=2)C2C=CC(S(C)=[O:40])=CC=2)CCCC1.[Mn]([O-])(=O)(=O)=O.[K+]>CO.O>[CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:16])(=[O:40])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reactant: CS(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reaction time: 1.5 h
Yield: 23 %

Procedure:
A solution of the mixture of 2-[2-cyclopentyl-1-(4-methanesulfinyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine and 2-[2-cyclopentyl-1-(4-methanesulfinyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (1.7 g) in methanol (50 mL) at 0° C. was treated dropwise with a solution of potassium permanganate (800 mg, 5.09 mmol) in water (15 mL). The resulting mixture was stirred to 1.5 h. The mixture was then partitioned between water (100 mL) and chloroform (100 mL). The aqueous layer was then extracted with ethyl acetate (2×100 mL). The combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Purification using a Biotage flash chromatography system (40 M column, 50% ethyl acetate/hexanes) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (420 mg, 23%) as a yellow foam which still contained some impurities. After standing overnight, a white solid had formed and this was then collected by filtration and the solids lightly washed with 10% ethyl acetate/hexanes to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (300 mg) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 9.81 (br s, 1H), 8.18 (dd, J=4.8, 1.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.81-7.90 (m, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.05 (dd, J=7.7, 4.8 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 4.25 (t, J=7.9 Hz, 1H), 3.02 (s, 3H), 2.19-2.31 (m, 1H), 2.05-2.17 (m, 1H), 1.61-1.88 (m, 5H), 1.41-1.54 (m, 2H), 1.08-1.24 (m, 2H).