Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:46])[N:14]([CH2:32][C:33]([NH:35][CH:36]([CH:43]([CH3:45])[CH3:44])[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[O:34])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C(=O)C(C)(C)C)=[CH:21][CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:46])[N:14]([CH2:32][C:33]([NH:35][CH:36]([CH:43]([CH3:44])[CH3:45])[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[O:34])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1cc(Cc2ccc(OC(=O)C(C)(C)C)cc2)cc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(NC(=O)Cn1cc(Cc2ccc(O)cc2)cc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 3 h

Procedure:
2-[3-Benzyloxycarbonylamino-2-oxo-5-(4-pivaloyloxybenzyl)-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl]acetamide was dissolved in methanol and excess 2N sodium hydroxide was added. The mixture was allowed to stir for 3 h, was evaporated, and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed (brine), dried, evaporated and purified by chromatography, using dichloromethane:methanol (gradient, 99:1, 95:5) as the eluent, to give the title compound; NMR: 0.78-0.91 (m,6), 2.20 (m,1), 4.09 (m, NHCH hydrate), 4.50-4.77 (m,3, CH2CO, NHCH keto), 5.13 (s,2), 6.68 (d,2, J=8), 6.95 (m, OH hydrate), 6.96 (d,2, J=8), 7.20 (m,1) 7.29-7.42 (m,5), 7.70 (m,1), 7.73 (d, J=10), 8.33 (s, NH hydrate), 8.37 (S, NH keto), 8.93 (d, J=6.5, NH keto), 9.24 (s,1, OH).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:38])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]4)=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)(C)(C)C>C(O)C.Cl>[O:37]=[S:33]1(=[O:36])[CH2:34][CH2:35][N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=4[CH3:14])=[CH:16][CH:17]=3)=[O:38])=[CH:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1

Procedure:
A solution of {4′-[4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-carbamic acid tert-butyl ester (685 mg) in ethanol (25 ml) and 6M HCl (25 ml) was stirred at 20 C for 18 h. The mixture was then basified and the ethanol evaporated. The colourless solid thus formed was collected by filtration and dried (434 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
In a round-bottomed flask 6-bromo-1H-indazole (0.70 g, 3.55 mmol) was dissolved in DMF (7.5 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 172 mg, 4.3 mmol) was added). The reaction mixture was warmed to room temperature and stirred for 30 min then cooled back to 0° C. and SEM-Cl (0.76 ml, 4.28 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was warmed to room temperature. After 1.5 h the reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-10% EtOAc) to give 802 mg (69%) of 6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:3]=1.Cl>C(O)C>[NH2:18][C:5]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:3][C:2]([Cl:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccc(OC)cc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Cl)nc(-c2ccc(OC)cc2)c(N)c1C(=O)OCC
Temperature: 60 °C

Procedure:
In 4 ml of ethanol was dissolved 280 mg of 2-chloro-3,4-diethyoxycarbonyl-6-(4-methoxyphenyl)-5nitropyridine, whereto 340 mg(8.9 eq.) of reduced iron was added. After the mixture was heated to 60° C., 1.5 ml of conc. hydrochloric acid was added dropwise and the mixture was refluxed. After heating for 20 minutes, the solvent was distilled off. The residue was neutralized with an aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. After the precipitate was filtered off, the obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Thereafter, the solvent was distilled off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[NH:12][N:13]=[C:14]([NH:15][CH3:16])[C:10]=2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([N:13]1[C:14]([NH:15][CH3:16])=[C:10]2[C:11]([N:6]([CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:21])[N:8]([CH2:18][CH2:19][CH3:20])[C:9]2=[O:17])=[N:12]1)(=[O:27])[CH3:26]
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCn1c(=O)c2c(NC)n(C(C)=O)nc2n(Cc2cccc(Cl)c2)c1=O
Yield: 85 %

Procedure:
A solution of 7-(3-chlorobenzyl)-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.0 g, 2.9 mM) and acetic anhydride (1.0 ml, 9.8 mM) in pyridine (15 ml) was stirred at 80° C. for 5 hours. The solution was concentrated to dryness and the residue was triturated with water (10 ml). Recrystallization from chloroform/ether gave colorless needles (0.95 g, 85%), m.p. 169°-171° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[BH4-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCN=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCNCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Ethyl 3-[(furan-2-ylmethylene)amino]propionate (19.2 g) prepared in the step 1 was dissolved in 200 mL of dry ethanol, 4.46 g of sodium borohydride was slowly added thereto little by little at room temperature and the mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo from the reaction and the residue was poured over 300 mL of 10% aqueous solution of acetic acid. The resulting aqueous solution was washed with diethyl ether, neutralized with 10% aqueous ammonia and subjected to extraction with diethyl ether. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo therefrom to give 10.8 g of the objective compound as yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:14]([C:19](OC)=[O:20])[C:15]([F:18])([F:17])[F:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([C:15]([F:17])([F:16])[F:18])[CH2:19][OH:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Methyl N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-3,3,3-trifluoroalaninate (1.08 g, 2.70 mmol), prepared in the previous step, was dissolved in 50 mL of tetrahydrofuran and cooled to 0° C. Lithium aluminum hydride (1M solution in tetrahydrofuran, 5.5 mL, 5.5 mmol) was added slowly and the mixture was stirred for 30 min. The reaction was then quenched by careful addition of 0.2 mL H2O, followed by 0.2 mL of 15% aqueous KOH, then an additional 0.6 mL of H2O and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate and filtered through the Celite™ reagent. The filtrate was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (15% acetone/hexane) provided 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-3,3,3-trifluoropropan-1-ol (0.67 g, 68%) as a white solid, mp 133-134° C.; MS (ESI) m/z 367. HRMS: calcd for C12H10BrF3N2OS+H, 366.97275; found (ESI, [M+H]+), 366.9712. Analytical HPLC: retention time 10.0 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH:15]([CH3:21])[C:16](OCC)=[O:17])[CH2:10]1.CO>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH:15]([CH3:21])[CH2:16][OH:17])[CH2:10]1
Reactant: CCOC(=O)C(C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
0.4 g of lithium borohydride was added, whilst ice-cooling, to a solution of 2.95 g of ethyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propionate (prepared as described in Preparation 4) in 25 ml of tetrahydrofuran, and then a mixture of 0.37 ml of methanol and 5 ml of tetrahydrofuran was added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 2 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and an aqueous solution of sodium chloride was added to the resulting residue, which was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The ethyl acetate was then removed from the extract by evaporation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 0.93 g of the title compound, melting at 114° C. to 115° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])C)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[O-].[Na+].S(=O)(O)[O-:17].[Na+].Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:17])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 1-(2,3-dihydrobenzofuran-5-yl)ethanone (4.0 g, 25 mmol) and sodium hypochlorite [160 mL of a 6.0% aqueous solution, (Clorox brand of bleach)] at 55° C. is stirred for 1 h. The mixture (now homogeneous) is cooled to rt and solid sodium bisulfite is added until a clear color persists. Hydrochloric acid (80 mL of a 1.0 N aqueous solution) is added, followed by extraction with EtOAc. The organic layer is washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3.93 g (97%) of 2,3-dihydrobenzofuran-5-carboxylic acid as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.0-10.3, 8.00, 6.87, 4.72, 3.31.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:29][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=4[C:7]=3[CH:6]=2)(=[O:4])=[O:3])[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]cc(C(=O)O)c4c3c2)CC1

Procedure:
8-(1-tert-Butoxycarbonyl-piperidin-4-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 178, from 2.1 g (6.45 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 1.8 mL (12.9 mmol) of triethylamine and 1.29 g (6.45 mmol) of 4-amino-1-tert-butoxycarbonyl-piperidine to give, after purification by precipitation and trituration in water, 1.86 g (59%) of 8-(1-tert-butoxycarbonyl-piperidin-4-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=O)[C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1.ClCCCl.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH:10]=[C:20]([C:15]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=2)[C:21]([F:24])([F:23])[F:22])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Yield: 88.5 %

Procedure:
3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane, 2.46 g of potassium carbonate and 0.18 g of triethylamine were fed and the mixture was refluxed by heating for 16 hours. The reaction solution was cooled to room temperature, and separated by adding 200 ml of ethyl acetate and iced water. The organic phase was washed with diluted hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as brown liquid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2)cc1C#N

Procedure:
A mixture of 4-nitrophthalonitrile (5.0 g), 4-chlorophenol (3.13 ml) and potassium carbonate (7.99 g) in acetone (87 ml) was refluxed for 3 h. After filtration and concentration, the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1N, 50 ml×3) and brine. The organic layer was dried, filtered, concentrated and diluted with dichloromethane. Filtration and rinse through a pad of silica gel gave 5.7 g of the title compound. 1H NMR (200 MHz, DMSO) δ 8.09 (d, J=9 Hz, 1H), 7.83 (d, J=2.6, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.42 (dd, J=2.8, 8.6 Hz, 1H), 7.24 (d, J=8.6, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[OH:20])C1C=CC=CC=1>[Pd].C(O)C>[CH2:30]([S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:19]([OH:20])[C:10]2[CH:11]=[C:12]([C:15]([F:17])([F:18])[F:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:26][CH:25]=1)(=[O:28])=[O:29])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(C(O)c2cc(C(F)(F)F)ccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(C(O)c2cc(C(F)(F)F)ccc2O)cc1
Reaction time: 0.75 h

Procedure:
A mixture of the product from step (iii) (0.225 g), 10% palladium on carbon (0.05 g) in ethanol (20 ml) was hydrogenated at 1 Bar for 45 min. After filtration the solvent was evaporated under reduced pressure. Yield 0.22 g
Reaction SMILES: CC[O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)Cn1c(-c2cccnc2)c(C)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(CCO)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 11.77 g of 1-(2-ethoxycarbonylmethyl)-2-(3-pyridyl)-3-methylindole in 400 ml of dry tetrahydrofuran at 0° is added 60 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran. This is allowed to stir at room temperature for 1 hour, then cooled by an ice bath and quenched successively with 2.26 ml of water, 2.26 ml of a 15% sodium hydroxide solution, and 6.78 ml of water. The mixture is filtered, concentrated in vacuo, and the residue dissolved in ether, washed with a saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. There is obtained the semi-solid 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methylindole which is used directly in the next step.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[N:31]=[C:30]([CH2:32][N:1]3[CH:2]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=4[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]3=[O:9])[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 407.07 g/mol.
Reaction SMILES: B(Br)(Br)Br.Cl[C:6]1[N:7]([C:15]2[CH:20]=[C:19]([O:21]C(C)C)[C:18]([Cl:25])=[CH:17][C:16]=2[Cl:26])[N:8]=[C:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2.O.CCOCC>ClCCl>[Cl:26][C:16]1[CH:17]=[C:18]([Cl:25])[C:19]([OH:21])=[CH:20][C:15]=1[N:7]1[CH:6]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)=[N:8]1
Reactant: CC(C)Oc1cc(-n2nc3c(c2Cl)CCCC3)c(Cl)cc1Cl
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: Oc1cc(-n2cc3c(n2)CCCC3)c(Cl)cc1Cl
Temperature: -78 °C
Yield: 97.9 %

Procedure:
To a solution of 2.78 g boron tribromide in 5 ml of dichloromethane was added a solution of 3.10 g of 3-chloro-2-(2,4-dichloro-5-isopropoxyphenyl)-4,5,6,7-tetrahydro-2H-indazole VII-1 in 35 ml of dichloromethane under cooling at -78° C. in 15 minutes. The resultant mixture was stirred at -78° C. for 0.5 hours and at room temperature for 1.5 hours and mixed with water and ether at 0° C. The mixture was basified, and the aqueous layer was separated and acidified and shaken with ether. The extract was dried, concentrated and the residue was purified by silica gel chromatography, whereby 2.39 g of the titled compound II-1 was obtained.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].CC(O)=O>C1COCC1.[Zn]>[NH2:19][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:22]=[CH:23][CH:24]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Temperature: 20 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-nitrophenyl)benzamide 4 (27 g, 84 mmol) and CH3COOH (72 mL, 1.3 mol) in THF (300 mL) at rt was added zinc (1.68 mol, 109 g). The temperature was maintained at 20° C. by cooling with an ice bath. The reaction was stirred at 20° C. for 1 hour. After dilution with ether the organic layer was extracted with 1N NaOH solution, water, brine, dried and evaporated to give crude N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (24.7 g, 100%). 1H-NMR (400 MHz, CDCl3) 1.77 (s, 6H), 2.15 (s, 3H), 3.68 (br s, 2H). 6.77 (dd, J=7.1 and 1.9 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.27 (br s, 1H), 7.50 (t, J=8, 1H), 7.69 (m, 1H), 7.75 (m, 2H), 7.96 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1B1OC(C)(C)C(C)(C)O1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: COc1cc(OC)c(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: Clc1ncc2cnn(C3CCCCO3)c2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(OC)c(F)c(-c2ncc3cnn(C4CCCCO4)c3n2)c1F
Temperature: 125 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (477 mg, 2.00 mmol), 2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600. mg, 2.00 mmol), bis(tri-t-butylphosphine)palladium (150.0 mg, 0.300 mmol) and diisopropylethylamine (0.700 mL, 4.02 mmol) in 1,4-dioxane (20 mL) was degassed and recharged with nitrogen for three times. The mixture was stirred at 125° C. overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.30 g, 40%). LCMS (M+H)+=377.2.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)[NH2:29].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]([CH3:23])[C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:12]=[C:11]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([N:33]3[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]3)=[C:26]([O:25][CH3:24])[CH:27]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CN(Cc1ccccc1)c1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(N(C)Cc3ccccc3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 66.4 %

Procedure:
A mixture of N-benzyl-2-chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (197 mg, 0.57 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (116 mg, 0.57 mmol), cesium carbonate (371 mg, 1.14 mmol), palladium (II) acetate (19 mg, 0.09 mmol) and 2-(dicyclohexylphosphino)biphenyl (30 mg, 0.09 mmol) in dioxane (4 mL) was heated under argon at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica gel plug which was washed with 10% solution of methanol in ethyl acetate (75 mL). The eluate was concentrated in vacuum and the residue was purified by preparative HPLC to give the title compound as a solid 194 mg (66%).