Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[C:7]([O:29]C(=O)C)=[CH:8][C:9]2[C:10](=[O:28])[CH2:11][C@@H:12]3[C@@H:21]([C:22]=2[CH:23]=1)[CH2:20][CH2:19][C@@:17]1([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]1[O:24]C(=O)C)[CH3:4]>CO>[CH2:3]([O:5][C:6]1[C:7]([OH:29])=[CH:8][C:9]2[C:10](=[O:28])[CH2:11][C@@H:12]3[C@@H:21]([C:22]=2[CH:23]=1)[CH2:20][CH2:19][C@@:17]1([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]1[OH:24])[CH3:4]
Reactant: CCOc1cc2c(cc1OC(C)=O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc2c(cc1O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
A 20% solution of KOH in methanol (5 mL) was added drcpwise to a suspension of estradiol (7) (0.95 g, 2.3 mmol) in anhydrous methanol (12 mL). The resulting reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure at 42-45° C. The residue was diluted with ice-water mixture (30 mL), and extracted with ethyl acetate (3×125 mL). The combined organic layer was washed with ice-cold water (30 mL), brine (30 mL) and dried over anhydrous sodium sulfite. The organic layer, on evaporation under vacuum, gave estradiol (10) (0.7 g, 92%). An analytical sample was prepared by a short column chromatography on silica gel using EtOAc, followed by EtOAc--MeOH (18:1), and finally chloroform: mp 194-196° C.; IR (KBr) 3400-3200, 2960-2842, 1650, 1590, 1500, 890, 852 cm-1 ; 1H NMR (DMSO-d6 +D2O) δ 0.85 (s, 3 H), 1.20-1.80 (m, 10 H), 1.82-2.82 (m, 8 H), 3.72 (t, J=8.5 Hz, 1 H), 4.20 (q, J=6.4 Hz, 2 H), 6.85 (s, 1 H), 7.58 (s, 1 H). Anal. (C20H26O4) C, H.
Reaction SMILES: [O:1]=[C:2]([C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)[CH2:3][CH:4]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[ClH:37]>C(O)C>[ClH:37].[ClH:37].[NH:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH3:11])[CH2:3][C:2]([C:31]3[CH:36]=[CH:35][N:34]=[N:33][CH:32]=3)=[O:1])=[CH:17][CH:16]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(C2CCNCC2)cc1
Yield: 101 %

Procedure:
To a solution of tert-butyl 4-(4-(3-oxo-3-(pyridazin-4-yl)-1-o-tolylpropyl)phenyl)-piperidine-1-carboxylate (66 mg, 136 μmol) in ethanol (1.5 mL) was added hydrogen chloride solution (4 M in 1,4-dioxane, 0.34 mL, 1.36 mmol), then after 18 h the reaction mixture was concentrated in vacuo to produce 3-(4-piperidin-4-yl-phenyl)-1-pyridazin-4-yl-3-o-tolyl-propan-1-one dihydrochloride (63 mg, light brown foam, MS: 386.4 [M+H]+). This was dissolved in dichloromethane (2.5 mL), then after addition of N,N-diisopropylethylamine (87.8 mg, 680 μmol) the reaction mixture was cooled to 0° C. and treated with methanesulfonyl chloride (31.1 mg, 272 μmol) was added. After 30 min the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (SiO2; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25) afforded the title compound (45 mg, 71%). Light yellow foam; MS: 464.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[CH2:12]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 Å. After stirring at ambient temperature overnight, the mixture was cooled down to ca. −10° C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3×100 mL). The combined aqueous solution was cooled to 0° C., basified with sat. NaHCO3 and extracted with CHCl3 (3×100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[N:4]=[CH:5][N:6]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:20](=[O:23])[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2]1[N:3]([C:7]2[N:11]([CH2:21][C:20]([C:19]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:17]([CH3:16])[CH:18]=3)=[O:23])[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[N:4]=[CH:5][N:6]=1
Reactant: Nc1ncnn1-c1nc2ccccc2[nH]1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)Cn2c(-n3ncnc3N)nc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 3-amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole (0.15 g, 0.75 mol), 3,4-dimethyl phenacyl bromide (0.204 g, 0.9 mmol) and dry potassium carbonate (0.258 g, 1.87 mmol) is stirred at room temperature for 16 hours. The mixture is diluted with water and the product extracted with ethyl acetate. The product is purified by chromatography on silicagel. M.p. 190-193° C., 1H-NMR (400 MHz, d6-DMSO): 7.84 (m, 1H); 7.77 (m, 3H); 7.65 (m, 2H); 7.50 (s, 1H); 7.33 (d, 1H); 6.22 (s, 2H); 2.30 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[CH2:33][C:34](O)=O.CCN=C=NCCCN(C)C>C(O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=1[CH2:33][C:34]1[NH:1][C:2]2[C:3](=[O:20])[N:4]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: O=C(O)Cc1cc(OC(F)(F)F)ccc1F
Reactant: COc1ccc(Cn2c(=O)c(N)c(N)n(C)c2=O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cc(OC(F)(F)F)ccc4F)nc3n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (80 mg, 0.289 mmol, intermediate 59) in ethanol (2 mL) was added 2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetic acid (68.8 mg, 0.289 mmol) followed by EDCI (66.5 mg, 0.347 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated. The residue was dissolved in ethanol (3 mL) and 1 mM sodium hydroxide (1 mL) was added. The resulting mixture was stirred at reflux for 3 h. The reaction was concentrated and residue was partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give a crude solid product, which was triturated with ethanol, collected and dried to afford 8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (67 mg, 48.4% yield) as a light yellow solid. LCMS retention time 1.611 min; LCMS MH+ 479.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[CH:8]1)C.[OH-].[Na+].CCOC(C)=O>C(O)C>[C:12]1([C:10]2[N:9]=[CH:8][N:7]([CH2:6][CH2:5][C:4]([OH:18])=[O:3])[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCn1cnc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCn1cnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
3-(4-phenylimidazol-1-yl)propionic acid ethyl ester (2.442 g, 10 mmol) was dissolved in 50 mL of ethanol, added with 0.5N-NaOH (20 mL) and then stirred at room temperature. Initiation and termination of the reaction was confirmed with TLC (EtOAc). Upon completion of the reaction, ethanol was removed by distillation under reduced pressure to obtain the target compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([NH:8][CH:9]2[C:18]3[CH2:17][S:16][N:15]=[C:14]([N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:13]4=[N:34][N:35]([CH2:37][C:38]5[C:43]([CH3:44])=[C:42]([O:45][CH3:46])[C:41]([CH3:47])=[CH:40][N:39]=5)[N:36]=[C:11]([C:12]=34)[CH2:10]2)[CH2:7][CH2:6]1.ClCCl.C(N(CC)CC)C>C(OCC)(=O)C>[NH2:19][C:14]1[C:13]2[C:12]3[C:11](=[N:36][N:35]([CH2:37][C:38]4[C:43]([CH3:44])=[C:42]([O:45][CH3:46])[C:41]([CH3:47])=[CH:40][N:39]=4)[N:34]=2)[CH2:10][CH:9]([N:8]([CH:5]2[CH2:7][CH2:6]2)[C:1](=[O:3])[CH3:2])[C:18]=3[CH2:17][S:16][N:15]=1
Reactant: CC(=O)Cl
Reactant: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C)cnc(CN2N=C3CC(N(C(C)=O)C4CC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
Acetyl chloride (14 μL) was added to a mixture composed of the above di-tert-butyl {8-(cyclopropylamino)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (100 mg), dichloromethane (2 mL) and triethylamine (42 μL) under cooling in an ice bath, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (4 mL) and trifluoroacetic acid (1 mL) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (55 mg, 75%) as an oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1)[CH3:35]>CN(C=O)C.[Cu]I>[F:1][C:2]1[C:10]2[N:9](/[CH:33]=[C:34](/[C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][CH:37]=3)\[CH3:35])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=CBr)c1ccc(C)nc1
Reactant: CN1CCc2[nH]c3c(F)cccc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cccc(F)c31)CN(C)CC2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (203 mg, 0.8 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0.20 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (212 mg, 1 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.10 (s, 1H), 8.30 (d, 1H), 7.62 (m, 1H), 7.22 (s, 1H), 7.18 (d, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 5.80 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.30 (m, 2H), 3.05 (s, 3H), 2.95 (m, 1H), 2.80 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:49]>C(O)C>[Na+:49].[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (110 mg) is dissolved in ethanol (2 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (233 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (69 mg). The resulting carboxylic acid is dissolved in ethanol (0.2 mL) and thereto is added 2N-aqueous sodium hydroxide solution (50 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (70 mg). MS (m/z): 679 [M−Na]−
Reaction SMILES: CC[C@H]1OC(=O)[C@H](C)[C@@H]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](O)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@]1(O)C>Cl>[O:20]=[CH:21][CH2:22][C@:23]([C@H:24]([C@H:25]([CH3:27])[OH:26])[OH:28])([O:30][CH3:31])[CH3:29]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: Cl
Product: CO[C@](C)(CC=O)[C@@H](O)[C@H](C)O
Yield: 97 %

Procedure:
Erythromycin A (Merck Index, 10th Edition Entry No. 3624) (50g) was dissolved in 1N aqueous hydrochloric acid (70 mL) and water (500 mL) and the mixture subjected to liquid-liquid extraction using diethyl ether for 99 h. The ether extract was evaporated to dryness to give L-cladinose (11.7 g, 97%) as a colorless viscous oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH2:24][CH2:25][N:26]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:27]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=5)=[CH:30][C:28]=4[CH:29]=3)=[O:22])=[CH:16][CH:15]=2)=[CH:10][N:9]=[CH:8]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[CH2:24][CH2:25][N:26]([CH2:48][CH:49]([CH3:50])[CH3:51])[C:27]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=5)=[CH:30][C:28]=4[CH:29]=3)=[O:22])=[CH:18][CH:19]=2)=[O:60])=[CH:10][N:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of [5-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]thio]methyl]-1H-imidazol-1-yl]ethyl acetate (200 mg) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.11 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica get, ethyl acetate:hexane 4:1→9:1), to give [5-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]ethyl acetate (Preparation of Compound 427) (117.6 mg) as yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:24]=3[N:25]=2)=[C:15]([Cl:32])[CH:14]=1)(=[O:11])=[O:10].[N:33]([Si](C)(C)C)=[N+:34]=[N-:35].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([Cl:32])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[NH:35][N:34]=[N:33][N:31]=4)=[CH:26][C:24]=3[N:25]=2)=[C:17]([Cl:19])[CH:18]=1)(=[O:11])=[O:10]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2nc3cc(-c4nnn[nH]4)ccc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 90 °C
Yield: 76.9 %

Procedure:
To a solution of 2,4-dichloro-N-[3,5-dichloro-4-(5-cyano -benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in toluene (5 mL), was added azidotrimethylsilane (Aldrich, 0.12 mL, 0.90 mmol) and dibutyltin oxide (Aldrich, 11 mg, 0.045 mmol). The resulting mixture was heated at 90° C. overnight (15 hours). A 1M aqueous solution of HCl (50 mL) and ice was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH2Cl2, then 10% MeOH in CH2Cl2) to yield 209 mg (77%) of product as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)=[N:20][CH:21]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Product: Cc1ccc(Nc2ncc(-c3cccnc3)c3cccnc23)nc1

Procedure:
The title compound, MS: m/e=314.0 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 2-bromo-5-methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH3:18])[C:11]([OH:13])=[O:12])=[O:8])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Cl)s1)C(=O)O

Procedure:
Prepared analogously to Example 2e from tert.-butyl(R)-2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionate with TFA in dichloromethane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:29][CH3:30])=[N:19][N:20]3[C:25]([OH:26])=[CH:24][C:23]([CH2:27]Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:29][CH3:30])=[N:19][N:20]3[C:25]([OH:26])=[CH:24][C:23]([CH2:27][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nn2c(O)cc(CCl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CSc1nn2c(O)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
1.57 ml (15.70 mml) of 1-methyl-piperazine were added to a solution of 2.9 g (7.84 mmol) of 3-benzenesulphonyl-5-chloromethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 0.5N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 4:1) yielded 1.85 g (53%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder, m.p.>220°.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])=[CH:13][CH:12]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccccn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.61 g, 25 mmol) was added to a solution of 2-hydroxypyridine (2 g, 21 mmol) in DMF (20 mL) at 0 C. After stirring for 15 min, p-fluorobenzyl bromide (4.4 g, 2.9 mmol, 23 mmol) was added and the reaction mixture allowed to warm gradually to RT. The reaction mixture was quenched by addition of ice then poured into ether and extracted several times with ice water. The organic phase was then dried over Na2SO4, concentrated and the resulting yellow oil purified by normal phase Gilson chromatography eluting with 10% DCM, 70% Hexane, 20% EtOAc. 1-(4-Fluorobenzyl)pyridin-2(1H)-one was isolated as a white solid.
Reaction SMILES: C(N1CC(O)(C2C=CC(C)=CC=2)C[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O.C(CCCC(Cl)=S)(=O)C.[C:36]([S:39][CH2:40][CH2:41][CH2:42][C:43]([N:45]1[CH2:52][C:51](O)([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[CH2:50][C@H:46]1[C:47]([OH:49])=[O:48])=[O:44])(=[O:38])[CH3:37]>>[C:36]([S:39][CH2:40][CH2:41][CH2:42][C:43]([N:45]1[CH2:52][C:51]([C:53]2[CH:54]=[CH:55][C:56]([CH3:59])=[CH:57][CH:58]=2)=[CH:50][C@H:46]1[C:47]([OH:49])=[O:48])=[O:44])(=[O:38])[CH3:37]
Reactant: CC(=O)SCCCC(=O)N1CC(O)(c2ccc(C)cc2)C[C@H]1C(=O)O
Agent: CC(=O)CCCC(=S)Cl
Agent: Cc1ccc(C2(O)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)cc1
Product: CC(=O)SCCCC(=O)N1CC(c2ccc(C)cc2)=C[C@H]1C(=O)O

Procedure:
The 3,4-dehydro-4-[(4-methyl)phenyl]-L-proline from part (a) is reacted with 4-acetylthiobutyroyl chloride according to the procedure of Example 3 (b) to yield (2S)-1-[4-(acetylthio)-1-oxobutyl]-2,5-dihydro-4-[(4-methyl)phenyl]-1H-pyrrole-2-carboxylic acid.