Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[CH:37]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[N:4]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:3]=[C:2]([CH3:1])[C:10]4=[C:9]([O:11][CH3:37])[CH:8]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc(=O)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc2c1c(C)nn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate (330 mg, 0.87 mmol, 1.00 equiv) in tetrahydrofuran (15 mL), PPh3 (488 mg, 1.86 mmol, 2.20 equiv), MeOH (36 mg, 1.12 mmol, 1.10 equiv). To the resulting mixture was then added DEAD (237 mg, 1.36 mmol, 2.00 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined. The resulting mixture was washed with water (1×3 mL). The resulting mixture was dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (PE-1:100) to yield 4-[4-(4-methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a white solid. MS (m/z): 500 [MH+].
Reaction SMILES: C(OC1C=CC(CO)=CC=1)CC1C=CC=CC=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:31]([CH3:30])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:23][CH:22]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCc1ccc(OCCc2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure in J. Org. Chem. 1996, 61 (11), 3849–3862, methyl-4-formylbenzoate (0.821 g, 5.00 mmol) was dissolved in 1,2-dichloroethane (75 ml) at room temperature. N-methylaniline (0.542 ml, 5.00 mmol) was added followed by sodium triacetoxyborohydride (1.484 g, 7.00 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by flash chromatography on silica eluted with 4:1 hexane/acetone to give 1.097 g (85.9%) of a slightly yellow oil of 4-[(methyl-phenyl-amino)-methyl]-benzoic acid methyl ester. Reduction to {4-[(methyl-phenyl-amino)-methyl]-phenyl }-methanol, condensation with(R)-2-isocyanato-3-phenyl-propionate of formula 5 and hydrolysis as described for example in Example 1 Steps 2–4, yielded about 1.5 g of 2-{4-[(methyl-phenyl-amino)-methyl]-benzyloxycarbonylamino}-3-phenyl-propionic 169, mp. 69.6–70.1° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1.CO>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5B (0.500 g, 0.992 mmol) and (trans)-cyclohexane-1,4-diamine (1.360 g, 11.91 mmol) in NMP (2.5 mL) was subjected to 110° C. in a 300 W CEM Discover microwave for 20 min. The mixture was diluted with MeOH and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=42 min. 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (0.500 g, 54.6% yield) was obtained as a light yellow solid. LC/MS, m/z 582.1 (M+1). HPLC Rt=3.211 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (1H, d, J=1.76 Hz), 8.69 (1H, d, J=2.77 Hz), 8.46-8.53 (1H, m), 8.41-8.47 (1H, m), 8.28 (1H, dd, J=4.78, 1.26 Hz), 8.01 (1H, s), 7.89 (2H, d, J=4.28 Hz), 7.57-7.72 (1H, m), 7.26 (2H, d, J=8.81 Hz), 7.18 (1H, d, J=7.81 Hz), 7.11 (1H, d, J=8.31 Hz), 7.03 (1H, dd, J=6.55, 5.04 Hz), 6.83 (2H, d, J=8.81 Hz), 6.52 (1H, s), 5.43 (2H, s), 3.72-3.84 (1H, m), 3.64-3.72 (3H, s), 3.06 (1H, d, J=4.78 Hz), 2.03-2.15 (2H, m), 1.95 (2H, d, J=10.07 Hz), 1.34-1.49 (2H, m), 1.26 (2H, d, J=12.34 Hz).
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-])=O)#[N:2].[ClH:21]>C(O)C.C(OCC)(=O)C.O1CCOCC1.[Ni]>[ClH:21].[ClH:21].[NH2:2][C:1]1[NH:18][C:5]2[CH:6]=[C:7]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: COc1ccnc(-c2ccc(NC#N)c([N+](=O)[O-])c2)c1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc3nc(N)[nH]c3c2)c1

Procedure:
A suspension of N-cyano-4-(4-methoxypyridin-2-yl)-2-nitroaniline (200 mg) in ethanol (10 ml) was hydrogenated over Raney-nickel (500 mg) under a hydrogen atmosphere for 12 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 20 g, dichloromethane:methanol:aqueous ammonia=100:10:1). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 2-amino-5-(4-methoxypyridin-2-yl)benzimidazole dihydrochloride (142 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2csc(Cn3ncc(N)n3)c2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:9][C:10]1C=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][C:11]=1C(O)=O)[CH3:8]>CN(C)C=O.ClCCl>[ClH:4].[CH2:7]([O:9][C:10]1[CH:11]=[CH:15][C:16]([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:17][C:1]=1[C:2]([Cl:4])=[O:3])[CH3:8]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Oxalyl chloride (11.7 ml, 134 mmol) was added dropwise to an ice cold suspension of 2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)benzoic acid (EP 812845 A1) (20.0 g, 60.9 mmol) and dimethylformamide (2 drops) in dichloromethane (200 ml) over 15 minutes, and the reaction mixture stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, the residue triturated with ether then ethyl acetate and dried at 40° C. for 16 hours, to afford the title compound, (19.6 g).
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:16]([C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]O>>[CH3:25][O:23][C:22]([CH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:14][CH2:15]1)=[O:24]
Reactant: CO
Reactant: COc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(OC)cc21

Procedure:
Analogously to the description in Example 2, 4.7 g of 5-benzoyl-6-methoxy-indane-1-carboxylic acid methyl ester and 20 ml of N sodium hydroxide solution in 50 ml of methanol give 5-benzoyl-6-methoxy-indane-1-carboxylic acid of melting point 126°-128° C (from ether-petroleum ether).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br)[CH3:21].CN1CCOCC1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[CH:17][CH:16]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Yield: 18.1 %

Procedure:
A solution of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (1.7 g, 6.43 mmol), 4-bromo-n-butyric acid ethyl ester (1.88 g, 9.64 mmol), 4-methylmorpholine (1.0 mL, 9.64 mmol), and DMF (10 mL) was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v) to provide 27 (0.44 g, 18%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H), 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m, 2H), 2.43 (t, 2H), 2.51 (t, 2H), 3.19 (m, 4H), 4.14 (q, 2H), 6.54 (d, 2H), 7.00 (d, 2H). m/z (ESI) 379.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH:27]=[CH:26][N:25]=1
Reactant: BrCc1ccnc(Br)c1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(Br)c1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (950 mg, 3 mmol), (prepared as described for the starting material in Example 24), 2-bromo-4-bromomethylpyridine (765 mg, 3 mmol) and potassium carbonate (2.38 g 17 mmol) in DMF (10 ml) was heated at 80° C. for 2 hours. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane and the solid product collected by filtration, washed with ethyl acetate/hexane and dried to give 7-((2-bromo-4-pyridyl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (647 mg, 44%). m.p. 210-212° C. 1H NMR Spectrum: (DMSOd6) 3.98(s, 3H); 5.40(s, 2H); 7.25(s, 1H); 7.30(d, 1H); 7.50(s, 1H); 7.50(d, 1H); 7.55(m, 2H); 7.74(s, 1H); 7.86(s, 1H); 8.35(br s, 1H); 8.42(d, 1H); 9.56(s, 1H) MS-ESI: 489 [MH]30
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:22][C@@H:23]([CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)=[O:25]>>[CH2:43]([O:42][CH2:41][C@H:23]([NH:22][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([C:3]([F:2])([F:21])[F:20])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)=[O:25])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(c2ncccc2C(F)(F)F)CC1
Agent: Cl
Product: O=C(CN1CCN(c2ncccc2C(F)(F)F)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 32.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 112, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)acetamido)propanamide (16.9 mg, 32.4%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.54 (d, 1H), 8.06 (t, 2H), 7.61 (d, 2H), 7.30 (m, 4H), 7.27-7.19 (m, 4H), 7.04-6.98 (m, 4H), 4.72 (m, 1H), 4.53 (s, 2H), 3.76 (m, 2H), 3.20 (t, 4H), 3.08 (s, 2H), 2.63 (m, 4H). MS (EI) for C34H33F4N5O4. found 652.6 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2)[OH:14]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: c1ccc2c(c1)CCCN2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: OC(c1ccc2c(c1)CCCN2)(C(F)(F)F)C(F)(F)F
Temperature: 120 °C
Yield: 69.3 %

Procedure:
Two hundred grams of 1,2,3,4-tetrahydroquinoline and 2 g anhydrous aluminum chloride are added to a one liter stainless steel reactor. The reactor is cooled and evacuated, 265 g (1.60 moles) hexafluoroacetone is added, and it is sealed and heated to 120° C. with shaking for ten hours. The reactor is then cooled to room temperature and vented. The contents are decanted to give a red semicrystalline solid, which is treated with 250 ml of methylene chloride and filtered. The filter cake is washed with three additional 250 ml portions of methylene chloride. The residual orange solid is treated with decolorizing carbon in hot chlorobutane and filtered. From the filtrate is obtained 310 g (1.04 moles) α,α-bis(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol, as a pale yellow crystalline solid, m.p. 115°-116° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1>C(Cl)(Cl)Cl.CN(C=O)C>[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([S:17]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2o1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(S(=O)(=O)N3CCCCC3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Piperidine (2.2 g, 26 mmol) was added drop wise to a solution of Compound 8 (3.0 g, 10 mmol) in chloroform (30 ml) and DMF (10 ml). The combined mixture was stirred at room temperature for 1 hour, and then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was then dried over sodium sulfate and evaporated to provide 2.76 g (76%) of Compound 9 as a sticky white solid. TLC analysis showed Rf=0.25 (30% ethyl acetate in hexane). The structure of this compound is given below:
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([O:7][C:8]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)=[CH:13][C:9]=1[C:10](N)=[O:11])[CH3:6].OC1C=CC([C@H]2CC[C@H](CCC)CC2)=CC=1.C(Cl)(Cl)Cl.[OH-].[K+]>>[CH2:5]([O:7][C:8]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]2)=[CH:13][C:9]=1[CH:10]=[O:11])[CH3:6]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C(N)=O)c2)CC1
Agent: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C=O)c2)CC1

Procedure:
18 g of SOCl2 is added, at 80°, to a suspension of 28.9 g of 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzamide [obtainable, for example, by reaction of trans-1-(4-hydroxyphenyl)-4-propyl-cyclohexane with chloroform/KOH to give 2-ethoxy-5-(trans-4-propylcyclohexyl)-benzaldehyde, oxidation to the acid, reaction with SOCl2 to give the chloride and reaction with NH3 ] in 100 ml of toluene. After the mixture has been stirred at 80° for 6 hours, cooled and poured into water, 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzonitrile of m.p. 32° is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([NH:14][C:9]2[C:8]3[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a suspension of 8-nitro-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine (500 mg, 1.49 mmol) and iron powder (834 mg, 14.9 mmol) in EtOH (10 mL) was added a solution of NH4Cl (649 mg, 11.92 mmol) in water (3 mL) and the reaction mixture was heated at reflux for 2 h. Then the reaction mixture was cooled to rt and filtered. The filtrate was concentrated and the concentrate was dissolved in CHCl3. The organic layer was washed with an aq. saturated solution of NaHCO3 and brine. The organic layer was dried, filtered and concentrated to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.74 (br s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.45-7.42 (d, J=7.5 Hz, 1H), 7.37-7.32 (t, J=8.0 Hz, 1H), 7.00-6.98 (d, J=7.8 Hz, 1H), 5.91 (br s, 2H); MS (m/z): 305.27 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.N1C=CC=CC=1.P(Br)(Br)[Br:26]>C1(C)C=CC=CC=1>[Br:26][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(Br)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Bis(4-methoxyphenyl)methanol (2.0 g, 8.2 mmol) was dissolved in toluene (60 mL) and pyridine (661 μL, 8.2 mmol)) was added. The solution was cooled to 0° C. PBr3 (768 μL, 8.2 mmol) was added dropwise over 15 min. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give the crude product 4,4′-(bromomethylene)bis(methoxybenzene) (780 mg, 31%), as a colourless oil. This was used in the next reaction step without further purification. Sodium ethoxide (133 mg, 1.96 mmol) was added to DMF (5 mL) at 0° C., and the suspension was stirred for 10 min. 7-hydroxy-4-methylcoumarin (345 mg, 1.96 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h. To this mixture 4,4′-(bromomethylene)bis(methoxybenzene (500 mg, 1.63 mmol) was added portionwise. Resulting reaction mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue was taken up in EtOAc, and washed with brine, water and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and product was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 49 (100 mg, 15%) as a white solid. Mpt=142-145° C. m/z=403 (M+H). H1 NMR (500 MHz, acetone-d6): δ=7.60 (1H, d, ArH), 7.45 (4H, d, ArH), 7.04 (1H, d, ArH), 6.94 (5H, d, ArH), 6.56 (1H, s ArH), 6.10 (1H, s, qCH), 3.78 (6H, s, 2×CH3O), 2.39 (3H, s, CH3). 13C NMR (500 MHz, acetone-d6, DEPT 135): δ=206.3 (qC), 134.1 (2×qC), 129.3 (2×CH), 129.2 (2×CH), 129.0, (2×CH), 126.9 (Ar CH), 114.4 (Ar CH), 114.7 (Ar CH), 115.1 (Ar CH), 112.5 (Ar CH), 104.0 (Ar CH), 81.7 (CH), 55.6 (2×CH3), 18.2 (CH3).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[N:11]2)[CH:5]=1.S(Cl)([Cl:29])(=O)=O>ClCCl>[Cl:29][C:5]1[C:6]([N:10]2[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[N:11]2)=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:25]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2NC(=O)C(F)(F)F)cc1OC(F)F
Solvent: ClCCl
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2NC(=O)C(F)(F)F)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.79 g (2.1 mmol) N-[1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-4-nitro-5-pyrazolyl]-2,2,2-trifluoroacetamide was suspended in 35 ml dichloromethane and treated with 0.17 ml sulfuryl chloride. The mixture was stirred for one hour at room temperature and concentrated.
Reaction SMILES: C(O[CH:4]1[CH2:12][C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5]1)C.C(OC(OCC)CC1C(=O)CCCC1=O)C.[NH3:30]>CO>[O:5]=[C:6]1[CH2:7][CH2:8][CH2:9][C:10]2[NH:30][CH:4]=[CH:12][C:11]1=2
Reactant: CCOC1CC2=C(CCCC2=O)O1
Reactant: N
Agent: CCOC(CC1C(=O)CCCC1=O)OCC
Solvent: CO
Product: O=C1CCCc2[nH]ccc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
The reactions of Examples 1 and 3 were respectively repeated and the reaction products were admixed in a molar (1)/(2) ratio of 87.6:12.4. Then, 1014 mg of this mixture of 2-ethoxy-4-oxo-2,3,4,5,6,7-hexahydrocoumarone and 2-(2',2'-diethoxyethyl)-1,3-cyclohexanedione, 1.7 ml of liquid ammonia and 5.5 ml of methanol were admixed in a glass tube which was sealed and heated at 100° C. for 1 hour and, then, at 150° C. for 16 hours. The above procedure provided 357.6 mg of 4-oxo-4,5,6,7-tetrahydroindole (yield 49%).