Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C3CCCCO3)=[O:29])=[CH:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)(=[O:4])=[O:3].Cl>CO>[OH:31][NH:30][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH:22]=1
Reactant: CS(=O)(=O)Nc1ccccc1-c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1ccccc1-c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
A mixture of 0.220 g (E)-3-[1-(2′-methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 6.0 ml methanol and 13.0 ml 1M aqueous HCl is stirred at ambient temperature for 24 h. During evaporation the product starts to crystallize. The crystals are washed with water and diisopropylether. The crude product is purified by PLC plates chromatography. By this method 0.081 g of a red oil are obtained.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH:20]1([C:23]([NH2:25])=[NH:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[N:24]=[CH:4][C:5]3[CH2:6][C:7](=[O:18])[NH:8][C:9]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=4[C:11]=3[N:25]=2)[CH2:22][CH2:21]1
Reactant: N=C(N)C1CC1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Agent: Cl
Product: O=C1Cc2cnc(C3CC3)nc2-c2cc(F)ccc2N1
Yield: 88 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropanecarboxamidine hydrochloride. Yield: 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].O=[C:11]([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]([CH2:17][CH3:18])=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 64.9 %

Procedure:
In a 300 mL-flask were placed 3,5-dichloroaniline (25.0 g, 154 mmol), methyl 3-oxopentanoate (22.1 g, 170 mmol) and toluene (160 mL). To this solution was added p-toluenesulphonic acid monohydrate (0.59 g, 3.1 mmol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 21 kPa for 3 hours, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. p-Toluenesulphonic acid monohydrate (0.59 g, 3.1 mmol) was then added, and reflux was continued for 1 hour. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. After distillation of the solvent under reduced pressure, the residue was distilled under reduced pressure to give 27.4 g of the title compound. The yield was 64.8%.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:22])[NH2:21])=[CH:16][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N1CCOCC1)C.Cl.[NH2:54][C@@H:55]([CH:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1)[C:56]([NH:58][CH2:59][CH:60]1[CH2:65][CH2:64][N:63]([C:66](=[NH:68])[NH2:67])[CH2:62][CH2:61]1)=[O:57]>CN(C)C=O>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:22])[NH2:21])=[CH:16][CH:15]=2)[C:10]([NH:54][C@H:55]([C:56](=[O:57])[NH:58][CH2:59][CH:60]2[CH2:65][CH2:64][N:63]([C:66](=[NH:67])[NH2:68])[CH2:62][CH2:61]2)[CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)c1ccc(CC(C(=O)O)c2cccc(Br)c2)cc1
Reactant: N=C(N)N1CCC(CNC(=O)[C@@H](N)C2CCCCC2)CC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)NCC2CCN(C(=N)N)CC2)C2CCCCC2)c2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-(3-bromo-phenyl)-3-(4-carbamimidoyl-phenyl)-propionic acid hydrochloride (188 mg, 0.49 mmol) in dimethylformamide (30 ml) was added TOTU (164 mg, 0.5 mmol) and N-ethylmorpholine (127 μl, 1 mmol) at 0° C. The mixture was stirred for 30 min at 0° C., 2-amino-N-(1-carbamimidoyl-piperidin-4-ylmethyl)-2-(S)-cyclohexyl-acetamide hydrochloric acid salt (180 mg, 0.49 mmol) was added and the mixture was then allowed to warm to room temperature. After evaporation, the residue was purified by chromotography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and hydrochloric acid and lyophilized. Yield: 82 mg of the more polar diastereomer and 71 mg of the less polar diastereomer, MS (FAB) m/z: 624 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C:19](=[O:22])[CH2:20][Cl:21])[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CN(C=O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+]>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:22])[CH2:20][Cl:21])[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[N:11][C:10]=2[CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc(C(=O)CCl)c2s1
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CN(C)C=O
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H](O)CCl)c2s1
Temperature: 30 °C
Yield: 102.2 %

Procedure:
A suspension of 1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-chloro-ethanone (70 g, 204.8 mmol) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.954 g, 3.07 mmol) in methanol/DMF (1330 ml/70 ml) was degassed and refilled with N2 three times. A degassed preformed mixture of formic acid (28.3 g) in Et3N (124.3 g) was added slowly while keeping the internal temperature between 15 to 20° C. The resulting yellow suspension was warmed up to 30° C. After 2 h the reaction mixture is cooled to 25° C., water (750 ml) was then added into the reaction mixture followed by the addition of acetic acid (56 ml) in one portion. The mixture was concentrated and then diluted with TBME (1000 ml). Aqueous phase was separated and extracted with TBME (1000 ml). The combined organic phase was washed sequentially with water and brine and then dried with Na2SO4 and concentrated under vacuum to give (R)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanol (72 g).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[OH:27])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:1]1([CH:7]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[OH:27])[C:9]2=[O:29])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2ccc3c(c2O)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, (diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (82%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.39-7.24 (m, 9H), 6.95-6.79 (m, 3H), 6.58 (d, J=8.0 Hz, 1H), 6.35-6.30 (m, 2H), 4.21 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]C(OC(C)(C)C)=O)[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(C)c([N+](=O)[O-])cc1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (62.5 g, 276 mmol) from Part B, K2CO3 (20.0 g, 145 mmol), and DMF (100 mL) was heated with stirring in a hot water bath to 90° C. for 1 h. Gas evolution was noted during the heating period and had ceased after 1 hour. The mixture was poured into stirred ice water (600 mL), with washing of the reaction flask with a small volume of acetone. The resulting precipitate was collected by filtration and air dried to give 2-methoxy-3,6-dimethyl-5-nitropyridine (48.5 g, 96% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 4.02 (s, 3H), 2.76 (d, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.37, 151.63, 139.44, 135.02, 119.39, 54.45, 24.18, 15.16. An analytical sample was recrystallized from hexanes to give tan needles: mp 85.9-90.5° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[O:7][CH2:6][C@H:5]([N:17]2[CH2:24][C:23]3[C:19](=[N:20][N:21]([CH2:25][C:26](O)=[O:27])[CH:22]=3)[CH2:18]2)[CH2:4]1.[BH4-].[Na+]>CO>[NH2:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[O:7][CH2:6][C@H:5]([N:17]2[CH2:24][C:23]3[C:19](=[N:20][N:21]([CH2:25][CH2:26][OH:27])[CH:22]=3)[CH2:18]2)[CH2:4]1
Reactant: N[C@H]1C[C@@H](N2Cc3cn(CC(=O)O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N[C@H]1C[C@@H](N2Cc3cn(CCO)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of product obtained in Example 3 (400 mg, 1.019 mmol) in MeOH (10 mL) was added sodium borohydride (154 mg, 4.18 mmol). The mixture was stirred at RT for 2 h and then concentrated. The resulting material was purified on silica gel eluting with 0-5% MeOH (containing 10% NH4OH)/CH2Cl2 to give the title compound as a white solid. LC/MS=365.25 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH3:15])[CH:10]=2)[N:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH3:15])[CH:10]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:17]=2)[N:3]=1
Reactant: CCn1ccc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)c1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCn1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)N(C)C2=O)c1
Yield: 75.7 %

Procedure:
To a solution of 2-amino-5-(3-bromophenyl)-5-(1-ethyl-1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one (80 mg, 0.22 mmol) in DME (3 mL) is added pyrimidin-5-ylboronic acid (57 mg, 0.44 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmo) and a solution sodium carbonate (93 mg, 0.88 mmol) in H2O (0.5 mL) at room temperature. The reaction mixture is refluxed for 1 h and cooled. After evaporation of the solvent, the crude material is purified by chromatography (silica gel, EtOAc/2M ethanolic NH3: 92/8) to give the title compound (60 mg, 75%) as a solid. mp: 100-102° C.; MS (+) ES: 361 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]([C:21]3[S:22][CH:23]=[C:24]([C:26]([O:28]CC)=[O:27])[N:25]=3)([F:20])[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:31][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][C:17]([C:21]3[S:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=3)([F:20])[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1csc(C2(F)CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(C2(F)CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoropiperidin-4-yl)-1,3-thiazole-4-carboxylate (300 mg) in tetrahydrofuran (3 ml) and water (1 ml) was added, at room temperature, lithium hydroxide monohydrate (40 mg). The mixture was stirred at room temperature for 3 hours, and then ice-cold 1N HCl solution was added. The aqueous phase was extracted with ethyl acetate and then the combined organic phases were dried over sodium sulphate. The solids were filtered off and the solvent was distilled off. This gave 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoropiperidin-4-yl)-1,3-thiazole-4-carboxylic acid (230 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:3]=1.FC1C=C(CC(OC(C)(C)C)=O)C=C2C=1C=CC=N2.Cl>C(O)(=O)C.O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Cc1cc(F)cc2ncccc12
Agent: CC(C)(C)OC(=O)Cc1cc(F)c2cccnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(F)cc2ncccc12
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of tert-butyl 2-(7-fluoroquinolin-5-yl)acetate and tert-butyl 2-(5-fluoroquinolin-7-yl)acetate (0.50 g, 1.91 mmol) in acetic acid (5 mL) was added 4M hydrochloric acid in 1,4-dioxane (10 mL). The reaction mixture was heated in an oil bath set at 60° C. under condenser with N2 (g) inlet overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica, 60:40 ethyl acetate/hexane followed by 20:80 methanol/dichloromethane). Further purification and separation by prep HPLC yielded the single regio-isomer 2-(7-fluoroquinolin-5-yl)acetic acid (0.025 g, 6%). Retention time (min)=0.337, method [4], MS(ESI) 206.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:11](=[O:21])[C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:13][C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[I-].[K+]>>[CH2:22]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:11](=[O:21])[C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:13][C:6]3=[CH:5][C:4]=2[CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC1(c2ccccc2)Sc2cc3cc(O)ccc3n2C1=O
Reactant: CCCCCCBr
Agent: [I-]
Agent: [K+]
Product: CCCCCCOc1ccc2c(c1)cc1n2C(=O)C(C)(c2ccccc2)S1
Yield: 92.5 %

Procedure:
To a solution of 7-hydroxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one (2.86 g), n-hexyl bromide (1.76 g) and a small amount of potassium iodide, and the mixture was heated and refluxed for 33 hours. The reaction mixture was allowed to cool. Then insoluble matter was filtered. The solvent was evaporated off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (diluting solvent: n-hexane/ethyl acetate=9:1) to give 3.4 g (yield: 93%) of 7-hexyloxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3-(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12](O)[CH2:13][N+:14]([O-:16])=[O:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CC(O)C1(c2ccc(Cl)cc2)CCC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])/C=C/C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(1-(4-Chlorophenyl)cyclobutyl)-2-nitroethanol (5.2 g, 20.34 mmol) was dissolved in dichloromethane (41 ml) and trifluoroacetic acid anhydride (2.87 ml, 20.34 mmol) was added. The reaction mixture was cooled to 0° C. and triethylamine (5.67 ml, 40.7 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with dichloromethane and washed with aqueous hydrochloric acid (1 N). The organic layer was dried (magnesium sulfate) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 3.99 g (16.79 mmol, 83%)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[C-:11]#[N:12].[K+].O.[I-].[K+]>CC(=O)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:11]#[N:12])=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(F)ccc1CCl
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(F)ccc1CC#N
Yield: 87.2 %

Procedure:
A mixture of 16 parts of 1-(chloromethyl)-4-fluoro-2-methylbenzene, 7.8 parts of a solution of potassium cyanide in a small amount of water, 0.1 parts of potassium iodide and 240 parts of 2-propanone is stirred and refluxed for 22 hours. The reaction mixture is cooled and filtered. The filtrate is evaported. The residue is taken up in water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 13 parts (87.2%) of 4-fluoro-2-methylbenzeneacetonitrile as a residue.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:22]=[O:23]>S(=O)(=O)(O)O>[CH2:28]([O:27][C:26]1[CH:25]=[CH:24][C:21]([CH:22]([OH:23])[C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:20][C:19]=1[O:18][CH3:17])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Product: COc1cc(C(O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Reaction time: 0.75 h

Procedure:
92 ml of n-butyl lithium solution (1.6M in hexane) are added dropwise at -70° within 20 minutes to 33.0 g of 4-bromobenzotrifluoride (dissolved in 150 ml of tetrahydrofuran). After stirring at -70° for 45 minutes, 36 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 ml of tetrahydrofuran) are added dropwise thereto at between -70° and -60°. The reaction mixture is stirred at -70° for 2 hours and at 0° for 1 hour, poured into a mixture of ice and 100 ml of 2N sulfuric acid and extracted twice with 500 ml of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. There is obtained 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol which can be used directly in the subsequent reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][C:11](=[O:13])[O:17][C:15](=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Yield: 92 %

Procedure:
Heat a combination of the product of Step 2 (100 g) and acetyl chloride (300 mL) at reflux for 5 hours. Cool the reaction mixture, azeotrope with toluene, and concentrate under reduced pressure. Slurry he residue with Et2O (250 mL) and filter to afford 3-(3,4-dichlorophenyl)-glutaric anhydride (86 g).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].Cl.[S:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:8]=[CH:7]1.C=O>ClCCl>[CH3:1][N:11]1[CH2:12][CH2:13][C:14]2[S:6][CH:7]=[CH:8][C:9]=2[CH2:10]1
Reactant: c1cc2c(s1)CCNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
Sodium cyanoborohydride (10 g, 160 mmol) was slowly added to a mixture of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (7.0 g, 40.0 mmol) and formaldehyde (35% in water, 10 mL) in dichloromethane (100 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. Work-up: the reaction mixture was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1:5˜1:1) to afford the title compound as a white solids (2.0 g, 33%). 1H NMR (DMSO-d6, 400 MHz): δ 7.26 (d, 1H), 6.77 (d, 1H), 3.37 (s, 2H), 2.80-2.77 (m, 2H), 2.64-2.60 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:3]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:45]OS(O)(=O)=O>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:45])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)n1
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a clear solution of Example 32 (10 mmol) in tetrahydrofuran (60 ml) at 0° C., n-BuMgCl (2M solution in THF, 25 ml, 50 mmol) is added over 10 minutes. After stirring for an additional 20 minutes, the ice bath is removed and the solution is stirred for 2 hours. The reaction mixture is recooled to 0° C. and triethylborane (1M solution in THF, 60 ml, 60 mmol) is added. After stirring for 1 hour, the reaction is heated to reflux for 72 hours. The reaction mixture is cooled to room temperature and treated with aqueous sodium acetate 5.5 g in 22 ml water). After stirring for 5 minutes, solid hydroxylamine-o-sulfonic acid (5.5 g) is added and the mixture stirred for 24 hours. The reaction mixture is diluted with water and extracted with ether. The ethereal layer is dried over sodium sulfate, filtered and concentrated. The crude solid is purified by chromatography on silica gel using mixtures of hexane and isopropanol to give the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:10]([OH:12])[CH3:11]>>[CH2:10]([O:12][CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)[CH3:11]
Reactant: CCO
Reactant: O=Cc1ccc(CCl)o1
Product: CCOCc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
5-(Chloromethyl)furfural (CMF, 1) (1.24 g, 8.58 mmol) was dissolved in absolute ethanol (60 mL) and the solution was stirred at room temperature for 8 h. The excess ethanol was recovered by distillation and the residue was chromatographed (silica gel, CH2Cl2:Et2O, 2:1) to give EMF (5) (1.26 g, 95%) as a pale yellow liquid, 1H NMR (CDCl3); 1.04 (t, 3H), 3.39 (q, 2H), 4.32 (s, 2H), 6.34 (d, 1H), 7.06 (d, 1H), 9.40 (s, 1H), 13C NMR (CDCl3); 14.1, 63.6, 65.3, 110.3, 121.8, 151.8, 157.9, 176.7.