Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1.[CH:22]([C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=2)=[CH:26][CH:25]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:24]3[CH:39]=[CH:38][C:27]([O:28][C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=4)=[CH:26][CH:25]=3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccc(C2CCCNC2)c1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4cccc(Cl)c4)C3)cc2)nc1
Yield: 74 %

Procedure:
Using a method similar to Example 345, using 3-(3-chloro-phenyl)-piperidine fumaric acid salt (0.129 g, 0.414 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.413 mmol) sodium triacetoxyborohydride (0.132 g, 0.623 mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0 mL) provides, after reverse-phase HPLC, 0.129 g (70%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C24H25ClN3O2 422.1635, found 422.1664; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.6 Hz), 8.30 (dd, 1H, J=2.6, 8.8 Hz), 7.47 (d, 2H, J=8.8 Hz), 7.34-7.27 (m, 2H), 7.26-7.19 (m, 2H), 7.16 (d, 2H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 3.70 (s, 2H), 3.07 (d, 2H, J=11.4 Hz), 2.89 (tt, 1H, J=4.0, 11.9 Hz), 2.29-2.16 (m, 2H), 2.00-1.72 (m, 3H), 1.56 (dq, 1H, J=4.0, 12.3 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:3]=1.[NH2:20][CH:21]1[CH2:24][CH:23]([NH:25]C(=O)OC(C)(C)C)[C:22]1([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:20][C@H:21]1[CH2:24][C@H:23]([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:3]=2)[C:22]1([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1CC(N)C1(C)C
Reactant: N#Cc1cnc(NCCc2cccc(Cl)c2)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C[C@@H]1N
Temperature: 125 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
To a mixture of 4-chloro-2-((3-chlorophenethyl)amino)pyrimidine-5-carbonitrile (600 mg, 2.04 mmol) and tert-butyl (3-amino-2,2-dimethylcyclobutyl)carbamate (490 mg, 2.29 mmol) in dioxane (20 mL) was added DIEA (738 mg, 5.73 mmol). The resulting mixture was stirred at 125° C. under microwave irradiation for 5 h. After removal of the organic solvent under reduced pressure, the residue was diluted with ethyl acetate and the organic layer ws washed with aqueous solution of ammonia chloride. The organic layer was separated and dried over sodium sulfate and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (10% to 33% ethyl acetate in petroleum) to afford the title compound (610 mg, 1.30 mmol, 63% yield) as a pale yellow solid. The racemic product (500 mg, 1.06 mmol) was separated by chiral preparative supercritical fluid chromatography (chiral column: OJ, Column size: 0.46 cm I.D.×25 cm L, 5 um; Mobile phase: CO2:MeOH:DEA=60:40:0.1, Flow: 2.5 mL/min, 220 nm T=35° C.) to give four isomers: tert-butyl ((1S,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 1, 100 mg, 0.21 mmol, 20% yield, RT=7.88 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 3, 102 mg, 0.22 mmol, 20% yield, RT=9.37 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 2, 85 mg, 0.18 mmol, 17% yield, RT=8.29 min, d.e.=100%, e.e. =100%) and tert-butyl ((1S,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 4, 82 mg, 0.17 mmol, 17% yield, RT=10.96 min, d.e.=100%, e.e. =100%). MS (ESI) m/z 471.2 [M+H]+
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([F:23])([F:19])([F:20])([F:21])[F:22])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC=C(c2ccc(S(F)(F)(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(S(F)(F)(F)(F)F)cc2)CC1

Procedure:
A mixture of 6.5 g of 4-(4-pentylcyclohex-1-enyl)-phenyl-sulfur pentafluoride, 0.5 g of palladium-on-active charcoal (1%) and 40 ml of toluene is hydrogenated at room temperature under normal pressure until saturation is reached. Removing the solvent by distillation and working up in the customary manner gives 4-(trans-4-pentylcyclohexyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:21]=4[N:22]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:21]=4[N:22]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1

Procedure:
To 3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 44, 0.30 g, 0.58 mmol), methanol saturated with hydrogen chloride gas (15 mL) is added at 0° C. with stirring. The reaction mixture is allowed to reach rt and stirred there for 12 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (15 mL) and ammonium carbonate (0.540 g, 3.48 mmol) is added. After stirring at rt for 24 h, the reaction mixture is concentrated and the residue obtained is purified by preparative HPLC to afford 3-[2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 8.28 (s, 1H), 8.22 (m, 1H), 8.15 (br, 2H), 7.96-8.03 (m, 2H), 7.67 (m, 2H), 7.59 (s, 1H), 7.45-7.50 (m, 9H), 6.47 (d, 1H), 6.15 (br, 1H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 534.0.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH2:34][OH:35])=[CH:4]1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:33])[C:5]([CH:34]=[O:35])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(CO)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1cc(C=O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 62.9 %

Procedure:
To a yellow solution of 1-ethyl-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (16 g, 33.6 mmol) in Dichloromethane (DCM) (200 mL) was added manganese dioxide (29.3 g, 336 mmol), and the mixture was stirred at rt for 6.5 h. The mixture was filtered through Celite and washed with DCM, the filtrate was concentrated to afford 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (10 g, 21.12 mmol, 62.8% yield) as a brown solid, which was used in the next step without further purification. LCMS: (M+H)+: 474.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=O)[CH3:2].Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:23]=[C:17]1[CH:16]([N:15]2[C:9](=[O:10])[C:4]3[C:5](=[CH:11][CH:12]=[CH:13][C:3]=3[CH2:1][CH3:2])[C:6]2=[O:8])[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1
Reactant: NC1CCC(=O)NC1=O
Reactant: CCc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
2-(2,6-Dioxo(3-piperidyl))-4-ethylisoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-ethylphthalic anhydride (0.860 g, 4.89 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (0.803 g, 4.88 mmol) and sodium acetate (0.420 g, 5.12 mmol) in acetic acid (10 mL). The product was a white solid (1.06 g, 76% yield); mp, 235.0-236.5° C.; 1H NMR (DMSO-d6) δ1.22 (t, J=7.4 Hz, 3H, CH3), 2.04-2.10 (m, 1H, CHH), 2.47-2.63 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 3.07 (q, J=7.5 Hz, 2H, CH2), 5.13 (dd, J=5.4, 12.5 Hz, 1H, NCH), 7.70-7.82 (m, 3H, Ar), 11.13 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.84, 21.95, 23.69, 30.90, 48.77, 121.09, 127.26, 131.76, 134.63, 135.39, 143.87, 166.99, 167.58, 169.85, 172.72; Anal Calcd for C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found: C, 62.74; H, 4.84; N, 9.54.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20]CC)[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.Cl.[OH-].[Na+]>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(N4CCCC4=O)cnc3c2n1CC(C)C
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cn1c(CO)nc2c(N)nc3cc(N4CCCC4=O)cnc3c21
Reaction time: 16 h

Procedure:
1-[4-Amino-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]-1,5-naphthyridin-7-yl]pyrrolidin-2-one (0.150 g, 0.39 mmol) from Example 13 was dissolved in dichloromethane (5 mL) and cooled with an ice bath. Boron tribromide (0.5 mL of a 1.0 M solution in dichloromethane) was added dropwise over 1 minute. The resulting slurry was stirred for 16 hours. The reaction mixture was acidified with 6 N hydrochloric acid (3 mL). The mixture was stirred until all of the solids dissolved. The biphasic mixture was made basic with 50% aqueous sodium hydroxide (˜6 mL). The layers were separated and the aqueous fraction was extracted with dichloromethane, followed by extraction with a 10% methanol in dichloromethane solution. The organic fractions were combined and concentrated under vacuum. The residue was purified by HPFC eluting with a linear gradient of 2-30% CMA in chloroform. Recrystallization from acetonitrile afforded 1-[4-amino-2-(hydroxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-7-yl]pyrrolidin-2-one as 0.034 g of a white powder, m.p. 233-235° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-hydroxy-7-trifluoromethylquinoline-3-carboxylate (370.5 g), anhydrous potassium carbonate (179.4 g), iodomethane (202.4 g) and anhydrous dimethylformamide (2 liters) was stirred at room temperature overnight. More dimethylformamide (500 ml) was added and stirring was continued for 24 hours. The dimethylformamide was distilled off in vacuo and water (2 litres) was added to the residue. The resulting solid was collected, washed with water, dried and recrystallised from IMS to give the novel compound ethyl 1-methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylate, m.p. 222°-224°.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:26]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([C:22]([F:24])([F:25])[F:23])[CH2:19][CH2:20][CH2:21]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:28][CH2:27]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCC2)cc1F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoate (2.11 g, 5.5 mmol), cyclopropylboronic acid (0.94 g, 11.0 mmol), potassium phosphate (5.25 g, 24.8 mmol) and tricyclohexylphosphine tetrafluoroborate (0.4 g, 1.10 mmol) in toluene (60 mL) and water (3 mL) under a nitrogen atmosphere was added palladium acetate (0.25 g, 1.10 mmol). The reaction mixture was heated to 110° C. for 18 hours and then cooled to ambient temperature. Water (20 mL) was added and the mixture extracted with ethyl acetate, the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo., the crude product tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoate was dissolved in dichloromethane (30 mL) and added trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was purified by column chromatography (5% to 60% ethyl acetate contains 0.2% acetic acid in hexanes) afforded the title compound was obtained as colorless solid (0.50, 27%): MS (ES+) m/z 333.1 (M+1); MS (ES−) m/z 331.2 (M−1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15]2[C:16]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].O>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:16]2[C:15]([N:14]([CH3:35])[CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:25]([OH:27])=[O:26])[CH:22]=3)[N:17]=2)=[CH:29][CH:30]=1
Reactant: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (90.0 mg, 0.23 mmol) in MeOH (20 mL) was added sodium hydroxide (50 mg, 1.25 mol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (1N) and concentrated in vacuo. The crude product was purified by Prep-HPLC with the following conditions (3#-Agilent 1200 prep HPLC): Column, X-Bridge Prep C18,19*150 mm; mobile phase, water with 0.5% TFA:CH3CN=(25%-37% CH3CN in 9.0 min); Detector, 5 μm to afford 2-(4-fluorophenyl)-3-(methyl(piperidin-4-yl)amino)quinoxaline-6-carboxylic acid as a yellow solid (22 mg, 25%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH3:26])[C:12](=[O:25])[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:24].CN(C=O)C.Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Si:36]([O:35][CH2:34][CH2:33][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH3:26])[C:12](=[O:25])[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:24])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CN(Cc1nc2ccccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1nc2ccccc2n1CCO[Si](C)(C)C(C)(C)C)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a mixture of N-(1H-benzimidazol-2-ylmethyl)-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (500 mg) and DMF (15 mL) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (555 μL) and K2CO3 (358 mg), followed by heating and stirring at 95° C. for 24 hours. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. To the resulting solid was added EtOAc, followed by suspending. An equivalent amount of Hex was added thereto, followed by collecting by filtration and washing with a Hex-EtOAc mixed solvent to obtain N-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-benzimidazol-2-yl]methyl}-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (523 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][CH3:20])[CH:11]=1>[Pd].CO.O1CCCC1>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=2[O:2][CH3:1])=[O:21])=[CH:11][C:12]=1[NH:19][CH3:20]
Reactant: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1N
Reaction time: 2.5 h
Yield: 103.7 %

Procedure:
A mixture comprising N-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), suspended palladium on carbon (10%, 0.5 g) in methanol (100 mL) and tetrahydrofuran (50 mL) was stirred under a hydrogen atmosphere at ambient pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to provide 4-amino-N-[2-(2-methoxyphenoxy)ethyl]-3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PB-PCI) C17H21N3O3 m/e calc 315.37; found 316 (MH+).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:26][C:24]3[CH:23]=[C:22]([CH3:27])[N:21]=[C:20]([CH3:19])[N:25]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Cc1cc(N)nc(C)n1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cccc4Cl)sc23)nc(C)n1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 2,6-dimethylpyrimidin-4-amine (0.027 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos ((0.017 g, 0.034 mmol) and Cs2CO3 (0.111 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (14 mg, 21% yield). 1H NMR (500 MHz, CH3OH-d4): δ 8.44 (d, J=5.5 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.56-7.51 (m, 4H), 7.31 (s, 1H), 2.44 (s, 3H), 2.35 (s, 3H). LCMS (Method A): RT=5.75 min, m/z: 402.0 [M+H+].
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[N:24][OH:25])[CH2:6]1)(=O)C.[OH-].[K+]>>[N:24](=[C:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@:20]1([CH3:23])[C:7]([CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]1)=[CH:8][CH2:9]3)[OH:25]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12

Procedure:
17-Oximino-5-androsten-3β-yl acetate (8) was hydrolyzed with methanolic potassium hydroxide to get 17-oximino-5-androsten-3β-ol (9). In 1H-NMR spectrum signals for 3α and 6-vinylic protons appeared at δ 4.54 and δ 5.22, respectively. IR spectrum showed disappearance of the stretching due to acetate carbonyl at 1740 cm−1. 17-Oximino-5-androsten-3β-ol (9) was reacted with respective acid and dicyclohexylcarbodiimide (DCC) in anhydrous dichloromethane. The reaction mixture was stirred for 48 hr at room temperature and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered, solvent removed under vacuum and the residue was crystallized from ethyl acetate:petroleum ether (60:80) to obtain the desired product.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:24]3[CH:25]=[CH:20][N:21]=[C:22]([NH:26][CH:27]4[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]4)[N:23]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2ccn([Si](C)(C)C(C)(C)C)c2c1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-methoxy-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 535 mg (84%).