Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33]O)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33][N:39]4[C:35](=[O:45])[C:36]5[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:38]4=[O:40])[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 16 h

Procedure:
trans-{-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (290 mg, 0.47 mmol), phthalimide (82 mg, 0.56 mmol), and resin-bound triphenylphosphine (PS-Ph3P [Argonaut, 2.16 mmol/g]) (324 mg) were dissolved in 2.5 mL of THF, evacuated, placed under nitrogen atmosphere and charged with DIAD (0.11 mL, 0.56 mmol). After stirring for 16 h, the resin was filtered, washed with CH2Cl2 (5×) and concentrated to an orange-colored oil. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 1% MeOH/CH2Cl2 to 2% ˜7N NH3 in MeOH/CH2Cl2] to afford the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.17-1.29 (m, 2H), 1.60-1.61 (m, 1H), 1.87-2.07 (m, 4H), 2.12-2.23 (m, 2H), 2.92-3.02 (m, 1H), 3.64 (d, 2H, J=6.8 Hz), 5.25 (s, 2H), 7.11 (d, 1H, J=5.6 Hz), 7.24-7.26 (m, 1H), 7.45-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.72-7.75 (m, 2H), 7.86-7.95 (m, 5H), 8.17-8.20 (m, 2H), 8.25 (d, 1H, J=8.8 Hz), 8.38-8.39 (m, 1H); MS (ES+): m/z 579.0 [MH+]; HPLC: tR=2.9 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: Br.[CH2:2]([O:4][C:5](=[O:13])[CH2:6][N:7]1[CH:11]=[CH:10][S:9][C:8]1=[NH:12])[CH3:3].[C:14]12([C:24](O)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:2]([O:4][C:5](=[O:13])[CH2:6][N:7]1[CH:11]=[CH:10][S:9]/[C:8]/1=[N:12]\[C:24]([C:14]12[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2)=[O:25])[CH3:3]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)Cn1ccsc1=N
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1ccs/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 65 °C
Yield: 81 %

Procedure:
To a solution of the product from Example 77A (0.75 g, 2.8 mmol) and 1-adamantanecarboxylic acid (0.56 g, 3.1 mmol) in 14 mL of THF at 0° C. was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 g, 3.1 mmol) and diisopropylethylamine (1.1 mL, 6.2 mmol). The mixture was heated to 65° C. for 2.5 hours, cooled to ambient temperature and then diluted with ethyl acetate. The mixture was washed twice with water, saturated aqueous sodium bicarbonate, and brine. The organic extract was dried over magnesium sulfate, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 30-50% ethyl acetate/hexanes gradient) afforded 0.79 g (81%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.29 (t, J=7.1 Hz, 3H), 1.69-1.76 (m, 6H), 1.93-1.94 (m, 6H), 1.99-2.04 (m, 3H), 4.25 (q, J=7.3 Hz, 2H), 4.84 (s, 2H), 6.60 (d, J=5.1 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H); MS (DCI/NH3) m/z 349 (M+H)+. Anal. Calculated for C18H24N2O3S: C, 62.04; H, 6.94; N, 8.04. Found: C, 62.24; H, 7.08; N, 8.04.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:42]=[CH:41][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=4)=[CH:20][C:19]=3[N:32]([CH3:40])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:43].O1CCOCC1>>[ClH:43].[OH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:42][CH:41]=3)[N:32]([CH3:40])[C:19]=2[CH:20]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(O)c3)cc21
Reaction time: 18 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.18 g) and 4N hydrogen chloride/dioxane (20 ml) was allowed to stand at ambient temperature for 18 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and the mixture was irradiated by ultrasonic waves. The insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (0.86 g).
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.I([O-])(=O)(=O)=[O:29].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[S:18]([N:15]1[C:12]2=[N:13][CH:14]=[C:9]([CH:1]=[O:29])[N:10]=[C:11]2[CH:17]=[CH:16]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/c4ccccc4)cnc32)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reaction time: 24 h
Yield: 79.9 %

Procedure:
To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.2 g, 3.2 mmol) in 1,4-dioxane (20 mL) and water (2.0 mL) was added sodium periodate (2.73 g, 12.8 mmol) followed by osmium tetroxide (2.5% in t-BuOH, 4.01 mL, 0.320 mmol). After about 1 day at ambient temperature, additional sodium periodate (2.73 g, 12.78 mmol) and osmium tetroxide (2.5% in t-BuOH, 4.01 mL, 0.320 mmol) were added. After about 2 days, a solution of aqueous Na2S2O3 (100 mL) and EtOAc (100 mL) was added. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with heptane to remove benzaldehyde. The resulting solid was dried in vacuo to provide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde as a brown solid (0.77 g, 80%): LC/MS (Table 2, Method a) Rt=2.01 min; MS m/z: 334 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].[I-].[Na+]>>[CH2:25]([N:27]([CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=3[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:8][CH2:9][C:10]2=[N:14][N:13]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CBr)n1-2
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 1, 8-fluoro-1-(bromomethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with diethylamine in the presence of sodium iodide to give 1-[(diethylamino)methyl]-8-fluoro-6-(o-fluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:28])[C:26]=1[OH:27])[CH:22]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:22][C:21]3[CH:20]=[C:19]([F:18])[C:26]([OH:27])=[C:25]([F:28])[CH:24]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cc(F)c(O)c(F)c1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 3,5-difluoro-4-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:26])[NH2:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:6])[CH3:5].[CH2:27](N)[CH2:28][CH3:29]>C(O)C>[ClH:1].[CH3:2][N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:26])[NH:25][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:5])[CH3:6]
Reactant: CCCN
Reactant: CC(C)N(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: Cl
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN(C)C(C)C)c1ccccc1S2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 10-{(2RS)-1-[N-methyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbothioamide hydrochloride (1.6 g) and propylamine (4.8 cc) in absolute ethanol (32 cc) is heated for 16 hours at a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is dissolved in ethyl ether (100 cc) and the solution obtained is washed with N aqueous sodium hydroxide solution (4 cc) and then with saturated aqueous sodium chloride solution (2×10 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual red-brown gum is purified by chromatography on a column (height: 25 cm; diameter: 3 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (97:3 by volume) (1 liter) of methylene chloride and methanol and collecting 60-cc fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.85 g) is dissolved in ethyl ether (50 cc) in the presence of charcoal 3S. The mixture is filtered and a 3N solution (1 cc of hydrochloric acid in ethyl ether is added to the yellow filtrate, and the mixture is stirred for 1 hour at a temperature in the region of 20° C. The solid formed is drained washed with ethyl ether (5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-{(2RS)-1-[N-Methyl-N-(1-methylethyl)amino]-2-propyl}-N-propyl-2-phenothiazinecarbothioamide hydrochloride (0.58 g) is thereby obtained in the form of a yellow solid, m.p. about 140° C. (melts forming a a paste).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:31])(=[O:30])[NH2:32])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A benzene (30 ml) solution containing 3.00 g (12.8 mmol) of 3-cyclohexylmethoxybenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.43 g (14.1 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 n hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from acetonitrile to obtain 2.80 g (yield: 56.0%) of the title compound NMR (CDCl3) δ: 1.00-1.39 (5 H, m), 1.68-1.90 (6 H, m), 3.82 (2 H, d J=7 Hz), 4.95 (2 H, s), 7.10 (1 H, ddd, J=8 Hz, 2 Hz, 1 Hz), 7.25 (1 H, ddd, J=8 Hz, 8 Hz, 1 Hz), 7.38 (1 H, dd, J=8 Hz, 8 Hz), 7.45-7.50 (2 H, m), 7.62 (1 H, ddd, J=8 Hz, 8 Hz, 2 Hz), 7.96 (1 H, dd, J=8 Hz, 2 Hz), 8.53 (1 H, dd, J=8 Hz, 1 Hz), 10.03 (1 H, s)
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:23][C:22](=[O:24])[O:21][N:20]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.Br[CH2:41][CH2:42][Cl:43].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:43][CH2:42][CH2:41][N:23]1[C:22](=[O:24])[O:21][N:20]=[C:19]1[C:9]1[C:8]2[CH:25]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:26]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: ClCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)n4CCCl)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of Example 8D (3.20 g, 5.82 mmol), 1-bromo-2-chloroethane (2.413 mL, 29.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.843 mL, 12.23 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. for 2 hours. Additional 1-bromo-2-chloroethane (2.413 mL, 29.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.843 mL, 12.23 mmol) were added and the mixture was heated at 100° C. for another 1 hour. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed repeatedly with brine, dried with sodium sulfate, filtered and concentrated to give the title compound as a solid which was used without purification (3.55 g, quantitative yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(Cl)([Cl:15])=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(I)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1cc(I)ccc1C(=O)Cl

Procedure:
A mixture of 4-iodo-2-methoxybenzoic acid (750 mg) and thionyl chloride (7 ml) was stirred at reflux for 15min and then evaporated to give 4-iodo-2-methoxybenzoyl chloride. A solution of Intermediate 6 (629 mg) in THF (30 ml) was treated with a solution of sodium hydroxide (227 mg) in water (10 ml), followed by the 4-iodo-2-methoxybenzoyl chloride, and the mixture stirred at 23° under nitrogen for 24 h. 5M-Hydrochloric acid (1.5 ml) was added, followed by aqueous saturated sodium bicarbonate (10 ml), and the mixture evaporated. The residue was treated with water (50 ml), extracted with ethyl acetate (10×100 ml), and the combined, dried organic extracts were evaporated. The residue was adsorbed from hot ethanol (ca. 40 ml) onto silica gel (Merck 7734, 10 ml), and purified by FCC eluting with System A (945:50:5) to give a solid (780 mg). Crystallisation from ethanol (10 ml) gave the impure title compound, a portion of which (102 mg) was recrystallised from ethanol to give the pure title compound as fine white crystals (37 mg), m.p. 168°-170°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].O>C1COCC1>[C:23]([NH:1][CH2:2]/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH2:7][C:8]2[C:13]\1=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(=CCN)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)/C(=C/CNC(C)=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a solution of 1-(2-aminoethylidene)-7-methoxy-1,2,3,4-tetrahydronaphthalene (2.0 g, 9.74 mmol) and triethylamine (1.5 g, 14,6 mmol) in THF (20 ml) was gradually added dropwise, under ice-cooling, acetyl chloride (0.76 g, 9.74 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate), followed by recrystallization from ethyl acetate/hexane to give the above-titled compound (yield 0.96 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10](=[O:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[Cl:18].[BH4-].[Na+]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:4][C:3]=1[Cl:18]
Reactant: CC(C)(C)NCC(=O)c1cc(Cl)c(N)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(C#N)c1

Procedure:
m.p. 125°-133° C., was prepared from 4'-amino-3'-chloro-5'-cyano-2-tert.butylamino-acetophenone and sodium borohydride analogous to Example 2.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:32][Si](C)(C)C>CC(CC)=O>[ClH:32].[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 3 h

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-[3-(1H-indol-3-yl)propyl]-acetamide (68 mg, 0.162 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.033 ml, 0.245 mmol) was added. After 3 h it was possible to isolate the product as a colourless solid in a yield of 65% (54 mg) with an m.p. of 162-170° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:26])[C:23](Br)(Br)[C@H:20]3[S:19](=[O:27])[C:18]2([CH3:29])[CH3:28])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[Bi+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Bi+3].[Cl-].[Na+].CO>ClCCl.[Fe].O>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:26])[CH2:23][C@H:20]3[S:19](=[O:27])[C:18]2([CH3:29])[CH3:28])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Br)(Br)[C@H]2S1=O
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Agent: [Bi+3]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1=O
Yield: 89.9 %

Procedure:
A 42 g quantity of Compound 1 was dissolved in 300 mL of dichloromethane. To the solution was added 0.9 g of bismuth sulfate and 57 mL of 20% aqueous solution of sodium chloride with stirring. To the mixture were added 10 g of iron powder and 17 mL of methanol with stirring at room temperature for 9 hours. Further, the mixture was stirred for 10 hours with adding 0.8 g of bismuth sulfate, and stirred at 35° C. for 2 hours. After completion of reaction, 100 mL of water was added and an orgaic layer was separated. The organic layer was washed with 100 mL of 5% aqueous solution of sodium chloride. The organic layer was concentrated to give Compound 2.
Reaction SMILES: [CH2:1]([C:3]1[S:35][C:6]2[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([C:3]1[S:35][C:6]2[N:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:31][N:32]=[N:33][N:34]=4)=[CH:22][CH:23]=3)[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2sc(CC)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc2c(=O)c(C(=O)O)cn(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2s1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
Ethyl 2-ethyl-7-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (600 mg, 1.235 mmol) was dissolved in 6 ml of 1N sodium hydroxide and the mixture was heated at 100° C. for 20 minutes with stirring. After cooling, 7 ml of 1N hydrochloric acid was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting crystal was washed with dichloromethane and dried to give 550 mg of the title compound as colorless crystals. This product was identified by comparing with NMR and IR spectra of the compound obtained in Working Example 1B.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10]2.[C:31](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:31])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[CH:15]=1)[NH:12][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(OCCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(OCCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 5-(3-methoxypropoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (3.97 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (30 mL) was added methyl iodide (1.56 g) at room temperature, and the reaction mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was crystallized from ethyl acetate-hexane, and the crystals were washed with hexane to give the title compound (3.63 g, yield 88%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 98-99° C.