Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([O:10][C:11]([CH:13]([CH3:23])[CH2:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[CH3:9].[OH-].[Na+]>C(O)C>[CH2:6]([O:5][C:3]([CH2:2][N:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:14][CH:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH3:23])=[O:4])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(C)CNCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN(Cc1ccccc1)CC(C)C(=O)OCC
Temperature: 0 °C
Yield: 61.4 %

Procedure:
88.4 g (0.53 mole) of ethyl bromoacetate were added to a solution of 98.0 g (0.44 mole) of N-(2-ethoxycarbonylpropyl)benzylamine [prepared as described in Step (1) above] dissolved in 200 ml of ethanol, and the mixture was heated under reflux for 2 hours. The reaction mixture was then poured into 500 ml of ice-water and made alkaline by the addition of a 50% w/v aqueous solution of sodium hydroxide. It was then extracted with ethyl acetate. The ethyl acetate extract was washed, in turn, with a 1N aqueous solution of sodium hydroxide and with water and dried. It was then freed from the solvent by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 1:9 by volume mixture of ethyl acetate and toluene, to give 83.0 g of N-ethoxycarbonylmethyl-N-(2-ethoxycarbonylpropyl)benzylamine as a pale yellow oil.
Reaction SMILES: [C:1](NC1C=C(B(O)O)C=CC=1)(=O)C=C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[NH:24]N=1>C(O)C.C(Cl)Cl>[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[NH:24][CH:1]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 19 (50 mg, 0.2369 mmol) and 2 (50 mg, 0.2369 mmol) in ethanol and toluene (1:4 mL) was added sodium carbonate (49.74 mg, 0.4738 mmol). The reaction was degassed and purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (9.06 mg, 0.0114 mmol), and again degassed for 15 min. The reaction mixture was stirred for 2 h at 90° C. and the reaction mixture allowed to cool to rt and diluted with DCM (25 mL). The organic layer was filtered through Celite and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using a gradient of 30% ethyl acetate:hexane to afford Compound 20. MS-ES+277 1H NMR (400 MHz, DMSO-D6) 20: 11.37 (d, 1H), 10.24 (d, 1H), 8.45 (d, 1H), 8.09 (d, 2H), 7.68 (d, 1H), 7.43 (d, 2H), 7.28 (d, 1H), 6.46 (d, 1H), 6.44 (d, 1H), 5.79 (d, 1H), 2.30 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.[CH3:28]C1N=C(CO)C=CC=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cc1cccc(CO)n1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cccc(C)n4)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120, step a, and 6-methyl-2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 2.48 (3H, s, CH3), 2.64 (3H, s, CH3), 5.74 (2H, s, CH2), 7.07 (1H, s, Ar—H), 7.18 (1H, d, J=7.7 Hz, Ar—H), 7.44 (1H, d, J=7.6 Hz, Ar—H), 7.69 (1H, t, J=7.7 Hz, Ar—H), 7.85 (1H, m, Ar—H), 7.99 (1H, m, Ar—H), 8.35 (1H, d, J=8.6 Hz, Ar—H), 8.71 (1H, d, Ar—H); MS (ES30) m/e 373 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[C:4]([F:13])[CH:3]=1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:12])[CH:9]([OH:10])[C:16]([F:19])([F:18])[F:17])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)(C=O)c1ccc(Br)cc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cc1F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanal (2.4 g, 9.8 mmol) and trimethyl(trifluoromethyl)silane (2.8 g, 20 mmol) in THF (20 mL) under nitrogen was added a solution of TBAF (1.3 g, 4.8 mmol) in THF (5 mL) dropwise at −30° C. The resulting solution was stirred at −30° C. for 1 hour and at ambient temperature for an additional 1 hour before 1 N aqueous HCl (10 mL) was added. The mixture was vigorously stirred at ambient temperature for 10 minutes, and then extracted with EtOAc (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-3% EtOAc/hexane) to the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 4.53 (q, J=7.5 Hz, 1H), 2.30 (br, 1H), 1.41 (s, 6H). MS ESI: [M+H]+ m/z 315.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH:9]([NH:17][C:18](=[O:24])[CH2:19][O:20]C(=O)C)[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([O:8][CH:9]([NH:17][C:18](=[O:24])[CH2:19][OH:20])[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OCC(=O)NC(Oc1cccnc1N)c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(NC(=O)CO)Oc1cccnc1N

Procedure:
A solution of 2-amino-3-(2-acetoxyacetamido-6-methylbenzyloxy)pyridine (0.63 g) and 1N sodium hydroxide solution (2 ml) in methanol (20 ml) was stirred at room temperature for 1 hour. The resulting precipitates were collected by filtration to give 2-amino-3-(2-hydroxyacetamido-6-methylbenzyloxy)pyridine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC#N>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:5]2[C:6](=[NH:7])[N:2]([CH3:1])[N:3]=[C:4]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:17]([CH3:23])[CH:16]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: Cn1nc(-c2ccccn2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)ccc1C=C1C(=N)N(C)N=C1c1ccccn1
Temperature: 45 °C
Yield: 64.1 %

Procedure:
A suspension of 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (4.50 g, 25.8 mmol, Example #2 step B), 4-bromo-2-methylbenzaldehyde (5.14 g, 25.8 mmol, Astatech) and 4-methylbenzenesulfonic acid hydrate (0.491 g, 2.58 mmol) in MeCN (36 ml) was warmed up to about 45° C. for about 15 min to give a solution then the reaction was allowed to cool to rt. The precipitate was filtered and washed with MeCN to give 4-(4-bromo-2-methylbenzylidene)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5(4H)-imine (5.88 g, 16.55 mmol, 64%) as a beige solid: LC-MS (Table 1, Method g) Rt=2.55 min, m/z 355/357 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.07 (s, 1H), 8.60-8.57 (m, 1H), 8.02-7.95 (m, 2H), 7.91-7.86 (m, 1H), 7.61-7.50 (m, 2H), 7.40-7.31 (m, 1H), 7.19 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:24]([F:27])([F:26])[F:25])([O:19][Si](C)(C)C)[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:24]([F:25])([F:27])[F:26])([OH:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)(C)c1ccc(Cl)c(OC)c1)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(Cl)c(OC)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
8.9 g (20.18 mmol) of contaminated ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate is dissolved in 116 ml of tetrahydrofuran and mixed at room temperature with 6.37 g (20.18 mmol) of tetrabutylammonium fluoride trihydrate and stirred for one hour at room temperature. The reaction mixture is mixed with water and extracted twice with 250 ml each of diethyl ether. The combined organic extracts are washed with water and with brine. After drying on sodium sulfate, the dessicant is filtered off, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.03 g (54.2%) of the desired compound is isolated. Other batches are implemented analogously.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:19](=[O:21])[CH3:20])[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(C2CCCN2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 132 %

Procedure:
To a solution of 3-bromo-5-(2-pyrrolidinyl)pyridine (200 mg, 0.881 mmol) and pyridine (0.2 mL, 1.96 mmol) in DCM (1 mL) in a 8-mL vial is added acetic anhydride (0.093 mL, 0.969 mmol) dropwise. The mixture is stirred at room temperature for 2.5 h. The mixture is concentrated. The resulting crude product is purified by normal phase chromatography using 0-4.5% MeOH in DCM as the gradient to afford 1-[2-(5-bromo-pyridin-3-yl)-pyrrolidin-1-yl]-ethanone (313 mg, 83% yield).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:29])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[O:16]2)=[C:11]([O:30][CH3:31])[C:10]=1[O:32][CH3:33])C1C=CC=CC=1>C(Cl)(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:29])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[O:16]2)=[C:11]([O:30][CH3:31])[C:10]=1[O:32][CH3:33]
Reactant: COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(OCc4ccccc4)cc3o2)cc1OC
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(O)cc3o2)cc1OC
Temperature: 25 °C
Yield: 99.1 %

Procedure:
7-benzyloxy-3',4',5,6-tetramethoxy flavone (5.62 g, 12.5 mmol) was dissolved in chloroform, hereto was added 10% Pd/C (1.06 g, 0.08 equivalents) and the mixture was stirred under hydrogen atmosphere at room temperature. After the reaction was completed, the reaction mixture was filtered through celite pad and the solvent was removed by evaporation to give 4.44 g of the titled product (98%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([O:26]CC4C=CC=CC=4)=[C:21]([F:34])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>CO.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[C:21]([F:34])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3cc(F)c(O)c(F)c3)cc3ccccc23)CC1
Yield: 64.9 %

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3,5-difluorophenyl)isoquinoline (6.44 g) was converted into a hydrochloride in a conventional manner. The hydrochloride was dissolved in methanol (200 ml), followed by the addition of 10% palladium/carbon catalyst (0.48 g), and then the catalytic reduction was conducted at atmospheric pressure overnight. The catalyst was filtered off, while the solvent was evaporated. Water was added to the resulting residue, followed by the addition of an aqueous solution of saturated sodium bicarbonate, and the mixture was extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated, to give obtain 1-(4-ethylpiperazin-1-yl)-3-(3,5-difluoro-4-hydroxyphenyl)isoquinoline (3.36 g) as a pale brown amorphous.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Li][CH3:14]>C(OCC)C>[CH3:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([CH3:14])([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Reactant: [Li]C
Solvent: CCOCC
Product: CN1C(C)(C)CC(C)(O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of 1,2,2,6,6-pentamethylpiperidin-4-one (1.5 g, 8.88 mmol) in diethyl ether (25 mL) at rt was added MeLi (1.6 M, 5.5 mL, 8.88 mmol) slowly. The resulting mixture was stirred at rt for 30 min before it was quenched with sat. NH4Cl (15 mL). The mixture was then partitioned between EtOAc (35 mL) and sat. NaHCO3 (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 1,2,2,4,6,6-hexamethylpiperidin-4-ol (1.51 g) as an oil. LC-MS (ESI) m/z 186 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:7][C:6]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39])[NH:34][CH2:33][CH2:32]2>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:34]2[C:35]3[C:31](=[CH:30][C:29]([O:28][CH3:27])=[C:37]([C:38]([F:40])([F:41])[F:39])[CH:36]=3)[CH2:32][CH2:33]2)=[O:20])=[CH:7][C:6]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)Oc2ccccc2)cc1-c1cccnc1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(C(C)(C)C)c(-c3cccnc3)c1)CC2
Yield: 23 %

Procedure:
The title compound (0.055 g, 23%) was prepared from phenyl N-[4-t-butyl-3-(pyrid-3-yl)phenyl]carbamate (D22) (0.18 g, 0.00052 mole) and 5-methoxy-6-trifluoromethylindoline (D11) using the method of Example 28.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:14]#[C:15][NH2:16].[Na]>C1COCC1>[C:1]12([C:11]([NH:16][C:15]#[N:14])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N#CN
Agent: [Na]
Solvent: C1CCOC1
Product: N#CNC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 85.2 %

Procedure:
1-Adamantanecarbonyl chloride (1.99 g, 0.010 mol) in 50 ml of THF was added drop-wise to a suspension of sodium cyanamide (1.92 g, 0.030 mol) in 100 ml of THF with stirring at ice bath temperature. The reaction was allowed to proceed at 25° C. for 15 hours. The reaction mixture was then extracted with ethyl acetate (100 ml). The separated aqueous portion (pH 10.5) was acidified to pH 1.5 with 10% HCl and extracted with ethyl acetate (3×60 ml). The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo to dryness. The resulting white solid residue was triturated in a minimal amount of distilled water, filtered, and air-dried to give 1.74 g (85.2% yield) of crude 4 as white solid. This was recrystallized from ethyl acetate and petroleum ether to give 0.55 g (crop 1) of white crystalline powder. The filtrate was concentrated when further crystallization occurred to give 0.49 g (crop 2) of additional product giving a total yield of 50.9%, mp 168°-170° C. TLC: Rf =0.58 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching (weak) and reddish orange color with ferricyanide spray reagent; IR (Nujol, cm-1), 3210 (NH), 2230 (C≡N), 1710 (C=O); NMR (Silanor C, δfrom TMS) 1.62-2.2 (m, aliphatic CH's). Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.59; H, 8.04; N, 13.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>[Ni].CO>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)cc(C(F)(F)F)c1

Procedure:
In the presence of 10.17 g of Raney nickel, 92 g (0.408 mol) of 5-chloro-3-trifluoromethyl-nitrobenzene are hydrogenated in 1 liter of methanol. The reaction mixture is filtered over Celite/activated carbon and the residue is washed with methanol. Concentration of the filtrate by evaporation yields the oily title compound: 1H-NMR (DMSO-d6) 6.80 (m, 3H), 5.92 (s, H2N); FAB-MS (M+H)+=196.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:21]([OH:23])=O)=[C:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].O>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:7]2[N:8]=[C:9]3[C:21](=[O:23])[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH2:14][CH2:13][C:10]3=[C:11]([OH:12])[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(CCc3ccccc3)c(C(=O)O)nc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCn1ncc2c(O)c3c(nc21)C(=O)c1ccccc1CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12.4 g. of 1-ethyl-4-hydroxy-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (0.04 mol.) and 150 g. of polyphosphoric acid are heated at 200°-210° (bath temperature) with stirring for 30 minutes. After the mixture has cooled to room temperature 300 ml. of water are added slowly with stirring until the polyphosphoric acid is completely dissolved. The remaining 1-ethyl-5,6-dihydro-4-hydroxybenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-b]pyridin-11(1H)-one is dissolved in chloroform, the extract is washed twice with water, dried with Na2SO4 and then evaporated in vacuo, yield: 9 g. (77%); m.p. 190°-192°. Recrystallization from ethanol raises the m.p. to 195°-197°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[O:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:48][C:47]3[CH:49]=[CH:50][CH:51]=[C:45]([O:44][C:32]4[C:31]5[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=5)[N:35]=[CH:34][N:33]=4)[CH:46]=3)=[O:22])=[CH:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 68 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.166 g, 68%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.55 (d, 1H), 7.67 (m, 2H), 7.54 (m, 2H), 7.44 (m, 4H), 7.20 (d, 1H), 6.97 (d, 1H), 6.86 (s, 1H), 4.35 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 613 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5](=[O:14])[C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][OH:22].CC([O-])(C)C.[K+]>CS(C)=O>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][C:3]1[NH:4][C:5](=[O:14])[C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1
Reactant: Cc1ccnc2nc(Cl)[nH]c(=O)c12
Reactant: OCCCOc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc2nc(OCCCOc3ccccc3Cl)[nH]c(=O)c12

Procedure:
In analogy to the procedure described in example 97.3, 2-chloro-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride was reacted with 3-(2-chloro-phenoxy)-propan-1-ol [60222-56-2] in DMSO in the presence of molecular sieves and potassium tert-butylate to give the title compound as off-white crystals. MS: m/e=346.1 [M+H+].
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](OC(C)(C)C)=[O:14])[C:8]([C:20]1C(Cl)=[N:22][C:23]3[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7]2)(=O)C.[C:31](O)(=[O:33])[CH3:32]>O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:20]([C:8]1[C:13](=[O:14])[NH:9][C:10]3[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:12][CH:11]=3)=[CH:29]2)(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Solvent: O
Product: CC(=O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1

Procedure:
A solution of tert-butyl 5-acetyl-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (8-3, 400 mg, 0.95 mmol) was heated in a 3:1 mixture of acetic acid and water at reflux for 20 hours. The reaction mixture was cooled, then concentrated to dryness. The residue was suspended in ethyl ether (50 mL) with the aid of sonication, then filtered and air dried to give 3-(5-acetyl-1H-indol-2-yl)-2(1H)-quinolinone (8-4) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 11.94 (s, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 7.76 (d, 2H, J=7.9 Hz), 7.60 (d, 1H, J=8.6 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.49 (s, 1H), 7.39 (d, 1H, J=7.9 Hz), 7.26 (t, 1H, J=7.5 Hz), 2.62 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccccc1CO
Yield: 90.6 %

Procedure:
To a solution of 2-nitrobenzyl alcohol (500 g, 3.2 mol) in MeOH (2.5 L) was added Pd/C (40 g) under N2 and refluxed for 30 min. Hydrazine hydrate (500 mL) was added slowly with stirring. The resulting mixture was stirred under reflux for another 2 h. The solid formed was filtered, concentrated and the crude residue was extracted with ethyl acetate (2×500 mL). The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvents, 2-aminobenzyl alcohol (357 g, 89% yield) was isolated as pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][O:28][CH2:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Yield: 67.9 %

Procedure:
To a 150-mL sealed tube containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.72 g, 2.0 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.33 g, 2.2 mmol) in ethanol (20 mL) was added triethylamine (1.0 mL, 2.2 mmol). The mixture was heated with a heat gun until all solid material was dissolved, then mixture was allowed to cool, at which time a precipitate was formed. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a pale yellow solid (0.59 g, 68%). MS (ES+): 435.0 (M+H)+