Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:22])[C:19](O)=[O:20])[CH2:11][CH2:10]2.CO>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:22])[CH2:19][OH:20])[CH2:11][CH2:10]2
Reactant: CC(C(=O)O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(CO)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
The 2-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid (see example 3) (0.029 g, 0.058 mmol) was diluted in tetrahydrofuran (0.5 mL) and borane-methyl sulfide complex was added (0.017 mL, 0.175 mmol) at −20° C. The mixture was stirred 2 h from −20° C. to room temperature. Methanol was added and the solvents evaporated under vacuum. The resulting solid formed was purified by chromatography (SiO2, CH2Cl2/MeOH 9:1 v:v) to give the title compound as a white solid (0.018 g, 94%). MS: m/e=330.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([O:26]CC)=[O:25])[N:6]2[CH2:21][O:22][CH3:23].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[N:6]2[CH2:21][O:22][CH3:23]
Reactant: CCOC(=O)c1cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCn1c(C(=O)O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a mixed solution of ethyl 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.45 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.25 g), and the mixture was stirred at room temperature for 18 hr. The reaction solution was acidified with aqueous citric acid solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.41 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH:29]=O)[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH2:29][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=1
Reactant: O=Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Cl)c2)c1-c1nc2c(Br)cc(CN3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of (S)-7-Bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzimidazole-5-carbaldehyde (130 mg, 0.27 mmol) in methanol (60 mL) was added morpholine (0.2 mL, excess). The reaction mixture was stirred 1 h at room temperature. Then NaCNBH3 (1M THF solution, 1.35 mL, 1.35 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by prep. HPLC to yield the title compound (68 mg, 45%). 1H NMR (400 MHz, CD3OD) δ 7.83 (1H, s), 7.69 (1H, s), 7.68 (1H, s), 7.24–7.54 (4H, m), 6.30 (1H, d, J=7.6 Hz), 4.89–5.02 (1H, m), 4.50 (2H, s), 3.66–3.71 (4H, m), 3.17–3.43 (6H, m). LCMS (M+H)+ m/z 558 (t=1.41 min.).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)=[N:18][N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH:29]1([C:23]2[CH:22]=[C:21]([C:19]3[O:20][C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([OH:8])=[C:10]([CH2:34][CH3:35])[CH:11]=4)=[N:17][N:18]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
Pd/C (150 mg, 10% Pd) is added to a solution of 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-cyclopentyl-6-methoxy-pyridine (750 mg, 1.60 mmol) in THF (20 mL) and methanol (20 mL). The mixture is stirred under 1 bar of H2 at rt for 24 h. The catalyst is removed by filtration and the filtrate is concentrated and dried to give 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (495 mg) as a white solid; LC-MS**: tR=0.91 min, [M+H]+=380.25; 1H NMR (D6-DMSO): δ 1.20 (t, J=7.5 Hz, 3H), 1.65-1.74 (m, 2H), 1.76-1.88 (m, 4H), 1.99-2.09 (m, 2H), 2.29 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 7.26 (d, J=1.0 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H).
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[N:9]=[N:8][C:7]([N:10]([CH3:12])[CH3:11])=[N:6][CH:5]=1>C(O)(=O)C>[Br:3][C:4]1[C:5](=[O:1])[NH:6][C:7]([N:10]([CH3:12])[CH3:11])=[N:8][N:9]=1
Reactant: OO
Reactant: CN(C)c1ncc(Br)nn1
Solvent: CC(=O)O
Product: CN(C)c1nnc(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
Hydrogen peroxide (27% strength solution in water, 0.53 ml, 4.56 mmol) was added at 5° C. to a solution of 6-bromo-3-dimethylamino-1,2,4-triazine (IX) (J. Org. Chem. 43 (1978) 2514) (500 mg, 2.46 mmol) in glacial acetic acid (4 ml), and the reaction mixture was stirred at 25° C. for 12 hours. The resulting precipitate was collected, washed with water, dried in the air and recrystallized from ethanol. The ketone (X) (368 mg, 68%) was obtained as white crystals of melting point 261-262° C. (ethanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(OCC)C>[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
Hydrogen chloride gas was bubbled into an ice-bath cooled solution of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 0.00783 mol, prepared as in Example 2) in DCM (100 mL). The resulting suspension was stoppered and stirred at RT overnight, then diluted with diethyl ether (200 mL). The solid was collected by filtration, washed with diethyl ether, and dried to give the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (4.01 g, 92%). Melting point 200° C. HPLC, C18 reverse phase, 10%-95% gradient of 0.1% TFA/CH3CN in 0.1% TFA/H2O during 22 minutes: 99.0% at 11.04 minutes. MS (APCI) M++1: calc'd, 448.2, found, 448.3. Anal. calc'd for C24H29N7O2.2.4H2O.1.85 HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Found: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:11][N:9]1[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:10]1
Reactant: C1COCCN1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Product: CN1CC(CCN2CCOCC2)Oc2ncccc2C1=S
Reaction time: 6 h

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione, 4.5 g (0.018 mole) was dissolved in morpholine (30 ml). The solution was heated with stirring to 50°-60° C., for 6 hr. The morpholine was then removed by rotary evaporation (90° C., vacuum pump). The residue was taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2×30 ml). The organic layer was concentrated by rotary evaporation (60° C., water aspirator). The residue was recrystallized from ethanol giving 3.26 g (60%) of light yellow crystals, m.p. 152°-153° C.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.[OH-].[Na+].C1(C)C=CC=CC=1>CN(C=O)C>[OH:12][CH2:13][CH2:14][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nc1ncnc2c1ncn2CCO
Reaction time: 2 h

Procedure:
Adenine (9.1 g), ethylene carbonate (6.0 g), and sodium hydroxide (0.14 g) in DMF (68 ml) were heated at reflux for 2 hr. The solution was cooled to 0°, then 70 ml of toluene were added. After sitting for 2 hr at 0°, the precipitate was collected, rinsed with 100 ml of toluene, then cold ethanol, and dried to afford N9 -hydroxyethyladenine.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:16][C:15]([C:8]1[C:7]2[CH:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=1)=[O:17]
Reactant: CO
Reactant: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Yield: 32.4 %

Procedure:
To a stirred suspension of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg, 3.00 mmol) in MeOH was added H2SO4 (440 mg, 4.50 mmol) and then heated at reflux for 3 h. Methanol was distilled off completely under reduced pressure and the residue basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 100-200) by eluting 5% ethyl acetate in petroleum ether to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (240 mg, 32.4%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (d, J=6.8 Hz, 6H), 3.84 (s, 3H), 3.88 (s, 3H), 4.81-4.78 (m, 1H), 6.86 (d, J=3.2 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H). LCMS (ES+): m/z=248.16[M+H].
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:26][CH2:25]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])#[N:7]
Reactant: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c([N+](=O)[O-])c2)CC1
Temperature: 70 °C
Yield: 96.8 %

Procedure:
To a solution of a mixture of compound 17 (3 g, 13.27 mmol) and 1-boc-piperazine hydrochloride (3.53 g, 15.92 mmol) in DMF (30 mL) was added Et3N (4.4 mL, 31.8 mmol), and the mixture was heated at 70° C. for 6 h. The mixture was cooled to room temperature, extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated. Trituration with diethyl ether afforded 4.27 g (97%) of compound 18 as bright yellow solid, m.p. 138-139° C.; IR (KBr) νmax. cm−1: 3042 (Ar—H), 2252 (CN), 1690 (C═O), 1610, 1520, 1412 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=1.39 (s, 9H, (CH3)3C); 3.44 (br. s, 4H, 2 CH2); 7.19 (dd, 1H, J=2.6, 9.4 Hz, H-5); 7.46 (d, 1H, J=2.7 Hz, H-2); 8.17 (d, 1H, J=2.7 Hz, H-6); 13C NMR (125.7 MHz, DMSO-d) δ=28.11 (CH3)3C), 45.92 (CH2), 46.02 (CH2), 79.56 (CH3)3C), 109.24 (C-4), 115.61 (C-2), 116.46 (CN), 119.03 (C-6), 128.09 (C-5), 135.85 (C-3), 153.30 (C-1), 154.13 (C═O). Calculated (%) for C16H20N4O4(332.15); C, 57.82; H, 6.07; N, 16.86. found (%); C, 57.76; H, 6.11; N, 16.80.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17]C)=[N:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br>C(O)C>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(-c2cc(C)c(N)c(C=O)c2)cn1
Agent: Br
Solvent: CCO
Product: Cc1cc(-c2ccc(O)nc2)cc(C=O)c1N

Procedure:
2-Amino-5-(2-methoxypyrid-5-yl)-3-methylbenzaldehyde (0.92g) was added to a stirred solution of hydrobromic acid (3 cm3 of a 60% w/w aqueous solution) in absolute ethanol (100 cm3) under nitrogen and the mixture was heated under reflux for 2 hours. The cooled solution was evaporated in vacuo, and the residue partitioned between 10% sodium carbonate solution (30 cm3) and dichloromethane (50 cm3). The organic phase was dried (MgSO4) and evaporated in vacuo to give a solid residue which was chromatographed in silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 10:1. Combination and evaporation of appropriate fractions followed by recrystallisation from ethyl acetate afforded the title compound, m.p. 231°-234° (0.26 g).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[CH2:18](S)[CH2:19][CH2:20]C>>[CH2:1]([S:2][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCCCS
Product: CCCCSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The procedure described for making bis(p-chlorophenyl)methyl methyl sulfide was followed except that n-butyl mercaptan was used. The product obtained was greater than 90 percent pure.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])[CH2:4][CH2:3]1.[NH2:19][NH2:20]>CO>[O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:19][NH2:20])=[O:12])[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Temperature: 65 °C
Yield: 30.9 %

Procedure:
Methyl 3-(1,1-dioxidothiomorpholino)benzoate (95 mg, 0.353 mmol) was added to the hydrazine (22.61 mg, 0.705 mmol) in methanol and refluxed for 12 h at 65° C. Following cooling, Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography (2% CH3OH/CH2Cl2) afforded the title compound 3-(1,1-dioxidothiomorpholino)benzohydrazide (32 mg, 0.109 mmol, 31.0% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.34 (m, 1H), 7.29 (t, 1H, J=8.4 Hz), 7.18 (d, 1H, J=7.6 Hz), 6.70 (dd, 1H, J=4.8 & 8.0 Hz), 3.85 (m, 4H), 3.05 (m, 4H). Mass [M+H]+:270.1
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:21][C:5]([S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Cc1ccccc1)(C(=O)O)S(=O)(=O)c1cccs1

Procedure:
2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-methyl-3-phenyl-2-(thiophen-2-sulfonyl)-propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL). Yield 5.6 g MS 310.0 (M+H).
Reaction SMILES: O.[OH-].[Li+].O.C[O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:10]=1)=[O:8]>O1CCCC1>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1ccn(-c2cccc3ncccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccn(-c2cccc3ncccc23)c1
Reaction time: 15 h
Yield: 89 %

Procedure:
0.36 g (8.58 mmol) of lithium hydroxide monohydrate and 20 mL of water are added to a solution at a temperature in the region of 22° C. of 0.5 g (1.98 mmol) of 3-methoxycarbonyl-1-(quinol-5-yl)-1H-pyrrole in 20 mL of tetrahydrofuran. After stirring at the reflux point of the solvent for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in water. The resulting solution is adjusted to pH 7 using N hydrochloric acid and then it is extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of 3-carboxy-1-(quinol-5-yl)-1H-pyrrole is thus obtained in the form of a white solid. IR spectrum (KBr): 3423, 3105, 1665, 1536, 1275, 1188, 1107, 965 and 796 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:4]2[CH:3]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:4]2[CH:3]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Brc1ccn2c(I)c(C3CC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C4CC4)nc4cc(Br)ccn34)cc2COc2cc(F)ccc21
Yield: 97.9 %

Procedure:
[step 3] Using 7-bromo-2-cyclopropyl-3-iodoimidazo[1,2-a]pyridine (4.6 g, 13 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (2.3 g, 7.9 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{8-[(7-bromo-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (4.1 g, 98%) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH:10](O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[Cl:3][CH:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=2[CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2CCc2ccccc21
Solvent: c1ccccc1
Product: ClC1c2ccccc2CCc2ccccc21

Procedure:
350 ml of thionyl chloride are added dropwise at a temperature of 30° to 40° to a solution of 201.5 g of crude 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol in 700 ml of dry benzene over a period of 40 minutes. Subsequently, the mixture is heated to boiling under reflux for an additional 1.5 hours and concentrated in vacuo. The residue is diluted 2 to 3 times with 300 ml of benzene each time and in each case again evaporated. There is obtained 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as a beige crystalline mass of melting point 99°-101° which is used in the next step without further purification. By recrystallization from carbon tetrachloride there is obtained material of melting point 104°-105° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[C:11]([CH2:24][NH:25][C:26]([C@@H:28]2[CH2:33][N:32]([CH3:34])[CH2:31][CH2:30][N:29]2[C:35](=[O:42])[C@H:36]([OH:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:27])[CH:10]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH2:13][C:12]1[CH:22]=[CH:23][C:9]([Cl:8])=[CH:10][C:11]=1[CH2:24][NH:25][C:26]([C@@H:28]1[CH2:33][N:32]([CH3:34])[CH2:31][CH2:30][N:29]1[C:35](=[O:42])[C@H:36]([OH:41])[C:37]([CH3:39])([CH3:40])[CH3:38])=[O:27]
Reactant: CN1CCN(C(=O)[C@H](O)C(C)(C)C)[C@H](C(=O)NCc2cc(Cl)ccc2CNC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@H](O)C(C)(C)C)[C@H](C(=O)NCc2cc(Cl)ccc2CN)C1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL, 50% solution in CH2Cl2) was added to a solution of tert-Butyl 4-chloro-2-[{(S)-1-{(R)-2-hydroxy-3,3-dimethylbutanoyl}-4-methylpiperazine-2-carboxamido}methyl]benzylcarbamate (0.022 g, 0.0043 mmol) in CH2Cl2 (1 mL) and the reaction mixture was stirred under nitrogen for 1 h. The solvent was removed at reduced pressure and the residue was azeotroped with toluene (5 mL). The solid was washed with ether (2×4 mL) and dried under high vacuum to afford the title compound as a white hygroscopic solid. 1H NMR (MeOD-d4, 300 MHZ) (δ) ppm: 7.36-7.55 (m, 3H), 5.21-5.38 (m, 1H), 4.37-4.53 (m, 3H), 4.26-4.28 (m, 3H), 3.95-3.68 (m, 2H), 3.16-3.22 (m, 1H), 2.55-2.73 (m, 5H), 0.97 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].[CH:15]([NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23](Br)[N:22]=1)=[O:20])([CH3:17])[CH3:16]>CN(C=O)C.C(OCC)(=O)C.[Cu](Cl)Cl>[CH:15]([NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:11])([F:1])[F:12])[CH:5]=2)[N:22]=1)=[O:20])([CH3:17])[CH3:16]
Reactant: Oc1cccc(SC(F)(F)F)c1
Reactant: COc1cc(Br)nc(C(=O)NC(C)C)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(SC(F)(F)F)c2)nc(C(=O)NC(C)C)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
1.25 g (0.0029×2.2 mol) of 3-(trifluoromethylthio) phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.23 g (ca. 60% in mineral oil; 0.0029×2.0 mol) of NaH and then with 0.80 g (0.0029 mol) of N-(i-propyl)-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.15 g (0.0029×0.5 mol) of copper chloride (I), the obtained solution was stirred at about 110° C. for about 6 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH3:12])[CH:6]=1
Reactant: COc1cccc(S)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(SC)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Methyl iodide (14.67 ml, 0.235 mol) was added dropwise to a solution of 3-methoxy-benzenethiol (30 g, 0.214 mol) and potassium carbonate (29.6 g, 0.214 mol) in acetone (400 ml) under nitrogen at 3° C. The reaction was allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (300 ml) and the aqueous layer was extracted with diethylether (3×200 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give 1-Methoxy-3-methylsulfanyl-benzene (32.87 g) as a pale yellow liquid.