Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([CH2:8][S:9][C:10](=[O:12])[CH3:11])[C:5]([OH:7])=O.[O:14]=[C:15]1[CH2:32][CH2:31][C:30]2=[CH:33][N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.C1C=CC2N(O)N=[N:40]C=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[C:10]([S:9][CH2:8][CH:4]([CH2:3][CH:2]([CH3:1])[CH3:13])[C:5]([NH:40][C@H:32]1[CH2:31][C:30]2=[CH:33][N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:14])=[O:7])(=[O:12])[CH3:11]
Reactant: O=C1CCc2cn(c3ccccc23)CCCCCCN1
Reactant: On1nnc2ccccc21
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)SCC(CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 4-methyl-2-acetylthiomethylpentanoic acid (612 mg, 3 mmol), (10S)-10-amino-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (427 mg, 1.5 mmol), and HOBt.H2O (230 mg, 1.5 mmol) in dry DMF (30 mL) under argon at room temperature was added EDCI (863 mg, 4.5 mmol) in one portion. After stirring overnight, DMF was removed at 30° C. under high vacuum to give a yellowish semi-solid. It was dissolved in ethyl acetate (50 mL), washed with 1N HCl (30 mL), 5% NaHCO3 solution (30 mL) and finally brine (30 mL). The organic layer was dried (MgSO4) and evaporated to dryness. The resulting pale yellow-oil was stirred in 50% ether-pet. ether (40 mL) to yield 600 mg (85%) of (10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide as 1:1 stereoisomeric mixture. The stereoisomeric mixture was separated in flash column chromatography (LPS-2), eluted with 20% ethyl acetate in pet. ether to give the less polar stereoisomer, m.p. 226° C., and the more polar stereoisomer, m.p. 220° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[C:27]1([C:33]2([OH:41])[CH2:39][CH:38]3[NH:40][CH:35]([CH2:36][CH2:37]3)[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.C(OCC)(=O)C>[CH3:24][C:21]1[O:22][C:23]2[C:15]3[O:14][CH:13]([CH2:12][N:40]4[CH:38]5[CH2:37][CH2:36][CH:35]4[CH2:34][C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([OH:41])[CH2:39]5)[CH2:26][O:25][C:16]=3[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1C2CCC1CC(O)(c1ccccc1)C2)CO3
Temperature: 77.5 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.375 g, 1.00 mmole) and 3-phenyl-8-aza-bicyclo[3.2.1]-octan-3-ol (0.25 g, 1.2 mmole) were combined in 8 mL of DMSO. This solution was heated to 75-80° C. under nitrogen for 8 hours. After completion, the reaction was cooled to room temperature and diluted to 500 mL with ethyl acetate. The mixture was washed twice with 400 mL portions of saturated aqueous sodium bicarbonate, with 300 mL of water and twice with 400 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 0.5% methanol/methylene chloride to give, after concentration of the product fractions in vacuum, 0.12 g of the (S)-enantiomer of the title compound as an off-white solid, m.p. 203-205° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([C:35]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([S:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH2:5][CH2:4]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1)C1CCCCC1
Yield: 95.6 %

Procedure:
To a solution of 4-aminomethyl-1-(1-naphthylsulfonyl)piperidine (608 mg, 2.0 mmol) and triethylamine (303 mg, 3.0 mmol) in dichloromethane (30 mL) stirring at room temperature under argon, was added cyclohexanecarbonyl chloride (325 mg, 2.2 mmol) in a single portion. After 2 h the solvent was evaporated under vacuum, and the residue was slurried with diethyl ether and filtered. The filtrate was evaporated, and purification by column chromatography (silica gel, ethyl acetate in hexane) provided 4-(N-cyclohexylcarbonylaminomethyl)-1-(1-naphthylsulfonyl)piperidine (793 mg, 96% yield) as a gum.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Yield: 33 %

Procedure:
A solution of methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate (0.52 g, 0.0016 mole), t-butylamine (20 ml) and methanol (10 ml) was heated under reflux for 16 hours. Evaporation of the reaction mixture left an oil which was dissolved in ethanol and treated with ether to give crystalline methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 33%; m.p. 127°-128°).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([SnH](CCCC)CCCC)CCC.O>O1CCCC1.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>[Cl:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:7][C:8]([Cl:11])=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 34.4 %

Procedure:
To a solution of 2,5-Dichloro-nicotinoyl chloride (15 g, 0.071 mol) in tetrahydrofuran was added tributyl-stannane (24.9 g, 0.086 mol) portionwise over 45 minutes. The resulting mixture was stirred at ambient temperature for 50 minutes, and then treated with tetrakis(triphenylphosphine)palladium(0) (0.82 g, 0.00071 mol). The reaction mixture was stirred at ambient temperature for 4 hours, poured into water; the product was extracted with ethylacetate, the combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (10% ethyl acetate/hexanes) followed by recrystallization from hexanes/ethylacetate gave the title compound (4.3 g).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2].S(OC)(O[CH3:16])(=O)=O>C(O)=O>[CH3:16][N:5]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][N:8]=[C:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)c1ncc([N+](=O)[O-])[nH]1
Solvent: O=CO
Product: CC(C)c1ncc([N+](=O)[O-])n1C
Temperature: 5 °C
Yield: 72 %

Procedure:
155 parts of 2-isopropyl-5-nitroimidazole, 350 parts of formic acid and 126 parts of dimethyl sulfate are heated under reflux for 2 hours. The formic acid is distilled off in vacuo and the residue which remains is dissolved in 500 parts of water. A pH of 1.8 is set up with dilute aqueous ammonia solution and the solution is cooled for 2 hours at +5° C. The unreacted 2-isopropyl-5-nitroimidazole (15 parts) is suction filtered and the filtrate is adjusted to pH 10 by adding aqueous ammonia solution. After cooling for 2 hours at 5° C. the mixture is suction filtered and the end product is dried. 110 parts of 1-methyl-2-isopropyl-5-nitroimidazole having a melting point of 56° C. is obtained and this is equivalent to a yield of 72% of theory based on reacted 2-isopropyl-5-nitroimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O-:38][C:39]#[N:40].[Na+]>CC(O)=O.O>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:39]([NH2:40])=[O:38])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To a solution of compound 126 (3.0 g, 5.72 mmol) in AcOH (13.6 mL) at 0° C. was added a solution of sodium cyanate (0.743 g, 11.44 mmol, 2 eq.) in water (5.2 mL). The mixture was stirred at r.t. for 20 h. Water (100 mL) was added and the reaction mixture turned into a suspension. After 30 min, the solid was collected by filtration and the product cake was washed with water (2×20 mL), dried in vacuum and purified by Biotage SPI Flash Purification System (eluent a gradient EA/MeOH, 100/0 to 90/10) to afford 288 as a white solid (2.0 g, 3.52 mmol, 62% yield). MS (m/z): 568.4 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([OH:24])=O)[C:7]=2[C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36]>>[CH3:37][C:31]1[NH:30][C:29](=[O:38])[C:28]([CH2:27][NH:26][C:22]([C:8]2[C:7]3[C:6]([CH3:25])=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=3[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=2)=[O:24])=[C:33]([CH2:34][CH2:35][CH3:36])[CH:32]=1
Reactant: Cc1nn(C(C)C)c2cc(-c3cnc4[nH]ccc4c3)cc(C(=O)O)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1c(C)nn2C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in the same manner as described for example 80 (step c) from 1-isopropyl-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-4-carboxylic acid (50 mg, 0.149 mmol) and 3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one (26 mg, 0.149 mmol) wherein the contents were stirred at RT for 5 h. The crude product was washed with DCM, filtered, and dried to afford the title compound as an off-white solid. (48 mg, 64%). 1H NMR (DMSO-d6, 400 MHz): 0.930 (t, J=7.6 Hz, 3H), 1.468 (d, J=6.4 Hz, 6H), 1.544-1.601 (m, 2H), 2.123 (s, 3H), 2.452 (s, 3H), 2.501 (s, 2H), 4.394 (d, J=4 Hz, 2H), 5.060-5.093 (m, 1H), 5.902 (s, 1H), 6.526 (s, 1H), 7.420 (s, 1H), 7.528 (s, 1H), 7.996 (s, 1H), 8.348 (s, 1H), 8.445 (s, 1H), 8.656 (s, 1H), 11.490 (brs, 1H), 11.735 (brs, 1H). LCMS (ES+) m/z: 497.49
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15].[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[C:14]([F:15])([F:16])[F:17]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 60.8 %

Procedure:
5.4 g of 2,4-bis(trifluoromethyl)benzoic acid methyl ester and 2.5 g of 2-aminomethylpyridine were heated to 160°-180° C for 6 hours. After cooling, the product was recrystallized from toluene. 4.2 g (64% of theory) of N-(pyrid-2-ylmethyl)-2,4-bis(trifluoromethyl)benzoic acid amide of melting point 112°-113° C were thus obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:22])([CH3:21])[CH2:5]1.[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[CH2:25]([O:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:21])([CH3:22])[CH2:5]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Temperature: 35 °C
Yield: 69.9 %

Procedure:
Sodium hydride (2.65 grams, 110 mmol) is added to a solution of 30.0 grams (105 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine in 150 ml of tetrahydrofuran under nitrogen. The reaction mixture is heated at reflux for three hours, cooled to 35° C., and treated with 12.7 grams (110 mmol) of allyl bromide. The reaction mixture is heated at reflux for one hour, then partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer is washed with saturated sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in heptane (50 ml) and passed through a pad of silica gel (eluent 5:1 heptane:ethyl acetate). The crude product is purified by flash chromatography (silica gel; 9:1 heptane:ethyl acetate) to afford 23.9 grams (70% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]([C:33]([O:35]C)=[O:34])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[OH-].[Li+].Cl>O1CCOCC1.O.C(Cl)Cl>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:19]=2)[CH2:21][CH:22]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CN(c2ccnc(Nc3cc(OC)c(OC)c(OC)c3)n2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(N3CCN(C(=O)OC(C)(C)C)C(C(=O)O)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.2 (0.05 g, 0.099 mmol) in dioxane (0.331 mL) was added lithium hydroxide monohydrate (6.25 mg, 0.149 mmol) in water (0.331 mL). The reaction was stirred at room temperature for 1 hour. The reaction was then acidified with 1N HCl and diluted with DCM. The organic layer was extracted, dried over Na2SO4, filtered and concentrated to provide 2.3 as a light yellow solid. ESI-MS M+H 490.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]#N)[C:10]1=[O:18].BrC1C=C(F)C=CC=1N1C=CC(C)=C(C#N)C1=[O:36].S(=O)(=O)(O)O.[OH-:42].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([OH:36])=[O:42])[C:10]1=[O:18]
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1Br
Reactant: Cc1ccn(-c2ccc(F)cc2Br)c(=O)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a mixture of 1-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile, 1-(2-bromo-4-fluorophenyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (2.00 g, 6.51 mmol) and water (10 mL) was added conc. sulfuric acid (10 mL) at 0° C., and the mixture was stirred at 100° C. for 16 hr. After cooling to 0° C., the mixture was basified (pH 11) with 8N aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified (pH 4) with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (1.12 g, 53%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][OH:24])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([O:24][CH2:23][C:8]1[N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)=[CH:13][CH:14]=2)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cn2c(CO)cc3cc(-c4cccc(C)c4)ccc32)cc1
Product: CC(=O)OCc1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from [1-(4-methylbenzyl)-5-(3-methylphenyl)-1H-indol-2-yl]methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a brown oil. Mass spectrum (ESI, [M+H]+) m/z 384. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.47 (s, 1H), 7.45–7.40 (m, 3H), 7.31 (t, 1H, J=7.74 Hz), 7.13–7.08 (m, 3H), 6.90 (d, 2H, J=8.09 Hz), 6.68 (s, 1H), 5.43 (s, 2H), 5.22 (s, 2H), 2.36 (s, 3H), 2.23 (s, 3H), and 1.85 ppm (s, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[Si:22]([O:5][CH2:4][CH2:3][C@H:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCC[C@@H](O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of diol compound 9 (2.28 g, 10 mmol) in N,N-dimethyl formamide (50 mL) at 0° C. was added sequentially imidazole (1.63 g, 24 mmol), and t-butyldimethylsilyl chloride (1.65 g, 11 mmol), and the reaction mixture was stirred for 2 h. After completion of the reaction (TLC). The mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), dried and concentrated to give a colorless oil, which after purification by flash chromatography, afforded the pure monosilyl compound 10 as an oil (Rf 0.71, silica, ethyl acetate and hexane, 1:10, 2.80 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:55][OH:56])([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:54][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][CH:51]=1)[O:47][C:43]1([CH2:55][OH:56])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(CO)(Oc2cccc(F)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(CO)(Oc5cccc(F)c5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.2 mmol, 100 mg), HCl salt of (3-amino-1-(3-fluorophenoxy)cyclohexyl)methanol (0.2 mmol, 55 mg), HATU (0.2 mmol, 76 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(3-fluorophenoxy)-3-(hydroxymethyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]=[O:20])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:21]([O-])([O-])[O:22]C.O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]([O:22][CH3:21])[O:20][CH3:27])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(C=O)cc(-c2cccc(C#N)c2)c1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C#N)c2)cc(C(OC)OC)c1

Procedure:
In 200 ml of methanol, were dissolved 2.00 g of the compound obtained in Example 11, 0.86 ml of methyl orthoformate and 0.004 g of p-toluenesulfonic acid monohydrate. The resulting solution was refluxed for 12 hours. After completing the reaction, 0.03 ml of triethylamine was added to the reaction solution, and the solvent was then removed under reduced pressure. Ethyl acetate was added to the residue, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure to provide 2.35 g (quantitatively) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[C:16]([O-])(=O)C.[Na+].C=O.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH:25]=[CH:24]1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:16][C:25]3[C:26]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[NH:23][CH:24]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)[O-]
Reactant: c1cnc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Reaction time: 0.08 h
Yield: 41 %

Procedure:
1-Phenylpiperazine (1.63 g, 10.0 mmol), and sodium acetate trihydrate (1.36 g, 10 mmol) were dissolved in acetic acid (4 ml) and water (2 ml). 37% Aqueous formaldehyde (0.9 ml, 12 mmol) was added and the reaction mixture stirred for five minutes. 1H-Pyrrolo[2,3-b]pyridine (1.18 g, 10 mmol) was added, and the resulting solution stirred at room temperature overnight. The reaction mixture was poured into 2M sodium hydroxide solution (50 ml) and extracted with ethyl acetate (2×50 ml). The extracts were washed with brine (50 ml), combined and dried (MgSO4). The ethyl acetate solution was concentrated in vacuo to about one quarter of the original volume and the precipitated yellow solid was collected by filtration and recrystallised from toluene to yield the title compound (1.20 g), as pale lemon crystals. This material was further recrystallised from methanol to give pale lemon needles, m.p. 207°-209° C; (Found: C, 73.91; H, 7.09; N, 19.31. C18H20N4 requires C, 73.94; H, 6.90; N, 19.16%); δH (DMSO-d6) 2.53 (4H, t, J 5Hz, 2×CH2N), 3.10 (4H, t, J 5Hz, 2×CH2N), 3.68 (2H, s, indole-CH2N), 6.75 (1H, t, J 7Hz, 4'-H), 6.89 (2H, d, J 8 Hz, 2'-H, 6'-H), 7.04 (1H, dd, J 8, 4.5 Hz, 5-H), 7.18 (2H, t, J 8Hz, 3'-H, 5'-H), 8.05 (1H, dd, J 8, 1.5 Hz, 4-H), 8.19 (1H, dd, J 4.5, 1.5 Hz, 6-H), and 11.45 (1H, br s, NH); m/z (CI+, NH3) 293 (M+ 1)+.