Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc3ccccc3cn2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(CC2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
2.21 g of 3-benzylisoquinoline and 2.88 g of nickel dichloride.hexahydrate were dissolved in 50 mL of methanol at room temperature, and 4.58 g of sodium borohydride was added thereto over 30 minutes, followed by further stirring at room temperature for 4 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=100:1→50:1) to obtain 1.85 g (yield 82%) of a title compound as a light yellow oily substance.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:33])[C:25]([NH:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:29]([O:28][NH:27][C:25]([C@:20]1([CH3:33])[C@H:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:24][CH2:23][O:22][CH2:21]1)=[O:26])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)ONC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)ONC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
(3R,4R)-4-(4-(Benzyloxy)phenylsulfonamido)-N-tert-butoxy-3-methyl-tetrahydro-2H-pyran-3-carboxamide was dissolved in ethyl acetate (25 mL), 10% palladium on carbon (90 mg) was added, and the resulting reaction mixture was stirred under a hydrogen balloon overnight. The reaction mixture was then filtered and concentrated to provide (3R,4R)-N-tert-butoxy-4-(4-hydroxyphenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxamide as a white solid that was used in the next step without purification. MS: (M+Na)+=409.0; (M−H)−=385.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: OCc1cc(Br)ccn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Br)ccn1
Temperature: 25 °C

Procedure:
Manganese(IV) oxide (22.19 g, 255.29 mmol) was added to a solution of (4-bromopyridin-2-yl)methanol (4.00 g, 21.27 mmol) in chloroform (80 mL) and the reaction mixture was stirred under reflux for 45 min. After the mixture had cooled to room temperature the solids were removed by filtration through a pad of Celite®. The solvent was removed in vacuo and the residue (3.96 g, quant.) was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:21]2[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])=[O:15])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(C(=O)Oc2cc(Cl)c(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a solution of 4-octyloxybenzoic acid (13.8 g) in diethyl ether (552 ml) were added 2,4,5-trichlorophenol (10.87 g) and N,N'-dicyclohexylcarbodiimide (11.37 g). The solution was stirred under a nitrogen atmosphere for 18 hours at room temperature. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in petroleum ether and was allowed to stand on ice-water. The resulting crystals (15.2 g) were filtered and dissolved in warm n-hexane (150 ml). After standing overnight at room temperature, the resulting crystal was removed by filtration. The filtrate was concentrated to an oil which was purified by a column chromatography over silica gel using a mixture of ethyl acetate and n-hexane to give 2,4,5-trichlorophenyl 4-octyloxybenzoate (7.58 g) (MP 53° C., Anal Calcd. for C21H23O3Cl3 : Cl 24.75, Found: Cl 24.05).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[C:5]([F:13])=[CH:4][N:3]=1.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:26].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.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:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH:25][C:2]2[CH:7]=[C:6]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)[C:5]([F:13])=[CH:4][N:3]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:26]
Reactant: Fc1cnc(Br)cc1C1OCCO1
Reactant: CC[C@@H](N)c1ccc(Cl)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@@H](Nc1cc(C2OCCO2)c(F)cn1)c1ccc(Cl)c(C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of INT 44 (370 mg, 1.492 mmol), (R)-1-(4-chloro-3-methyl-phenyl)-propylamine hydrochloride (394 mg, 1.790 mmol) and sodium tert-butoxide (344 mg, 3.58 mmol) in degassed toluene (5.8 mL) was added Pd2(dba)3 (68.3 mg, 0.075 mmol) and BINAP (93 mg, 0.149 mmol) and the resulting mixture was stirred at 80° C. for 5 hours. The mixture was diluted in EtOAc, washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (cyclohexane/EtOAc) to give INT 46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:32]([CH3:34])[CH3:33])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:31])[CH2:23][C@@H:24]([OH:30])[CH2:25][C:26]([O:28]C)=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+:36]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:32]([CH3:34])[CH3:33])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:31])[CH2:23][C@@H:24]([OH:30])[CH2:25][C:26]([O-:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[Na+:36]
Reactant: COC(=O)C[C@H](O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Reaction time: 0.08 h

Procedure:
A solution of methyl (3R,5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoate (34.4 mg) in dry THF (2 ml) was treated with aqueous sodium hydroxide solution (0.1M 0.660 ml). After 5 minutes, the solution was concentrated and the aqueous residue was diluted with water (9 ml) and the solution washed with ethyl acetate (4×). The solution was briefly evaporated and then freeze-dried to give the title compound (29.2 mg) as a white fluffy solid, [α]D20 +16.7° (c 0.4, H2O); δ(D2O) 1.20-1.55, 1.55-1.85 (m, 2H, CH(OH)CH2CH(OH)), 1.34 (d, J 7 Hz, 6H, CH(CH3)2), 2.26 (d, J 7 Hz, 2H, CH2CO2Na), 3.30 (septet, J 7 Hz, 1H, CH(CH3)2), 3.67 (m, 1H, =CHCH(OH)CH2CH(OH)), 4.35 (m, 1H, CH=CHCH(OH)), 5.61 (dd, J 14 and 7 Hz, 1H, NCH=CH), 6.75 (d, J 14 Hz, 1H, NCH=CH), 7.01 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-(4-fluorophenyl)), 7.1-7.4 (m, 6H, aromatics).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:7]([C:8]([Cl:17])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: COc1nc(SC)nc(Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1nc(SC)nc(Cl)c1C(=O)Cl
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-chloro-5-carboxy-6-methoxy-2-methylthiopyrimidine (prepared in the above (3)) 2.00 g and thionyl chloride 5 ml is stirred at 40° C. for 15 minutes. Thionyl chloride, etc. is distilled off and the solvent is removed with azeotrope with methylene chloride to give 4-chloro-5-chloroformyl-6-methoxy-2-methylthiopyrimidine.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1\[C:6](=[O:24])[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:8]=[C:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)C.[N:25]1([C:30]2[CH:35]=[CH:34][C:33](CN)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:7]1[C:6](=[O:24])[C:5]2=[CH:4][N:2]([CH2:1][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:35][CH:34]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[N:8]1
Reactant: NCc1ccc(-n2cccn2)cc1
Reactant: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
(4Z)-4-[(Dimethylamino)methylidene]-2,5-bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (241 mg, 0.735 mmol) and 1-[4-(1H-pyrazol-1-yl)phenyl]methanamine (127 mg, 0.735 mmol, 1 equiv) were combined in dimethylsulfoxide (10 mL) and placed into a preheated oil bath at 100° C. for 1.5 hours. To the mixture was added potassium carbonate (102 mg, 0.735 mmol, 1 equiv) and the mixture was heated for an additional 1 hour at 140° C. Additional 1-[4-(1H-pyrazol-1-yl)phenyl]methanamine (127 mg, 0.735 mmol, 1 equiv) and potassium carbonate (102 mg, 0.735 mmol, 1 equiv) were added and the mixture was heated for an additional 1 hour at 140° C. The mixture was cooled to ambient temperature, poured into water (75 mL) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol; then 100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.16 (1H, s), 8.46 (1H, d, J=2.4 Hz), 8.20 (1H, dd, J=7.8, 1.4 Hz), 7.82 (2H, d, J=8.7 Hz), 7.77 (1H, d, J=8.7 Hz), 7.72 (1H, d, J=14.6 Hz), 7.64-7.59 (2H, m), 7.55-7.52 (1H, m), 7.47 (2H, d, J=8.4 Hz), 7.47-7.38 (2H, m), 7.36-7.32 (1H, m), 6.53 (1H, dd, J=2.4, 1.7 Hz), 5.78 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 436.1560 [(M+H)+; calculated for C26H19FN5O: 436.1568].
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:12].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[C:11]([C:13]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:14][CH2:15][N:16]([CH:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1)#[N:12]
Reactant: CCOC(=O)N1CCCC(N2CCC(C#N)CC2)CC1
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N2CCC(C#N)(C(=O)OCC)CC2)CC1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 13.3 %

Procedure:
LCMS (Method A): m/z 280 (M+H)+ (ES+), at 1.67 min, UV inactive 1.0 M Lithium bis(trimethylsilyl)amide (4.48 mL, 7.17 mmol) was added to anhydrous THF (20 mL) under nitrogen and cooled to −78° C. The solution was treated drop wise with ethyl 4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate (0.400 g, 1.43 mmol) as a solution in anhydrous THF (2 mL). The solution was stirred at −78° C. under nitrogen for 1 h, ethyl chloroformate (0.17 g, 1.57 mmol) was added drop wise. The solution was stirred at −78° C. for a further 2 h and then allowed to warm to rt overnight. The reaction mixture was quenched with the addition of water and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol. The organic layer was washed with sat. NaCl sol. and dried by passing through a Biotage Phase Separator cartridge. The solvents were removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 50 mL per min, gradient 2% to 4% MeOH in DCM]) to give ethyl 4-[4-cyano-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.067 g, 12.7%) as an amber oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][OH:25]>C[O-].[Na+].CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Agent: C[O-]
Agent: [Na+]
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Reaction time: 5 h
Yield: 43 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-methoxyethoxy)purine (69 mg, 0.18 mmol) in methanol (50 ml) was dissolved in 28% sodium methoxide/methanol (1 ml) and the mixture was refluxed on heating under stirring for 5 hours. The reaction mixture was concentrated in vacuo to dryness, and to the residue was added water. The solution was extracted with chloroform and the organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (26 mg, yield 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:22]([C:21]([OH:24])=[O:23])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(C(=O)O)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To 450 mg of 3-(3-fluorophenyl)-7-methoxy-1H-indazole-5-carbonitrile were sequentially added 6 ml of glacial acetic acid, 2 ml of water and 2 ml of concentrated sulfuric acid, followed by stirring at 100° C. for one day. After standing to cool, water was added to the reaction mixture and the resulting crystals were collected by filtration. The crystals were sequentially washed with isopropanol and diethyl ether, to give 428 mg of the title compound as colorless crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O.[Pd]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C@@H:10]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:36])=[O:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:24])=[O:25])=[C:14]([OH:26])[CH:13]=1
Reactant: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3nc4ccccc4[nH]3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3nc4ccccc4[nH]3)cc2O)S(=O)(=O)N1

Procedure:
A solution of N-{(S)-1-(1H-benzoimidazol-2-yl)-2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-benzenesulfonamide and K2CO3 (50 mg) in 10 mL of EtOH/water (1:1) is hydrogenated over 10% Pd/C (100 mg) at 1 atm for 18 h. The catalyst is filtered and the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC followed by lyophilization to give the title compound as a pink solid. (M−1)−: 526. HPLC retention time: 0.98 min. (Method A).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:11]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCNC1
Yield: 48 %

Procedure:
Prepared according to Example 53, using tert-butyl (3R)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (Ex. 52) and (2.5:1) DCM:TFA. Purification by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) provided 2-(2-methyl-3-((3R)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (115 mg, 48%) as the free base after washing with saturated aq. NaHCO3, extracting with 10% MeOH/DCM, drying over Na2SO4, and concentrating under reduced pressure. 1H NMR (DMSO-d6) δ: 7.90-7.95 (m, 1H), 7.62-7.70 (m, 1H), 7.30-7.42 (m, 1H), 7.09 (s, 1H), 5.83 (s, 1H), 4.06 (br. s., 1H), 3.61-3.69 (m, 2H), 3.21-3.31 (m, 1H), 2.89-3.09 (m, 5H), 2.66 (s, 3H), 2.15-2.33 (m, 2H), 2.10 (m, 2H), 1.77-1.89 (m, 2H), 1.55-1.70 (m, 1H). m/z (ESI, +ve) 377.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.B(F)(F)F.CCOCC>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[N:16][S:13]([CH2:12][CH2:11][Si:10]([CH3:18])([CH3:17])[CH3:9])(=[O:15])=[O:14])[CH:4]=1
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Reactant: O=Cc1cccnc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[Si](C)(C)CCS(=O)(=O)N=Cc1cccnc1
Yield: 102.2 %

Procedure:
To a solution of 3-formylpyridine (0.228 mL, 2.42 mmol) and 2-(trimethylsilyl)ethanesulfonamide (0.438 g, 2.42 mmol) in toluene (30 mL) was added boron trifluoride etherate (0.02 mL, 0.15 mmol) under Ar. The mixture was heated at reflux for 20 hours using a Dean-Stark trap. After cooling, 10% aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness to under reduced pressure obtain crude 2-trimethylsilyl-ethanesulfonic acid pyridin-3-ylmethyleneamide (669 mg), which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:13]1[CH:14]=[CH:15][C:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-(3-nitrophenyl)pyridine 34.1.B. (500 mg, 2.9 mole) in 5 ml of methanol was added 1 g of 10% Pd on carbon by weight. The air was evacuated from the reaction flask and was replaced with hydrogen. The resulting slurry was stirred overnight at room temperature, at which time the reaction mixture was filtered over a bed of celite and the mother liquor concentrated to afford 3-(pyridin-4-yl)benzenamine 34.1.C (500 mg, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([O:19][CH3:20])=[O:18])=[N:12][CH:11]=[C:10]([OH:21])[C:9]=3[C:8]2=[O:22])=[CH:4][CH:3]=1.[OH:25]O>C(O)(=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:21])[CH:11]=[N+:12]([O-:25])[C:13]=3[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: OO
Reactant: COC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Solvent: CC(=O)O
Product: COC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 100 °C

Procedure:
To a solution of methyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (0.509 g, 1.541 mmol) in acetic acid (2 mL) was added hydrogen peroxide (35% wt % in H2O, 0.262 g, 7.705 mmol). The reaction mixture was heated to 100° C. for 1 hour. The product mixture was concentrated under vacuum and purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCCCCC>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:27]([C:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:28]=[N:29][N:30]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: Cc1nc(C)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(=O)CC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(=O)CC2
Reaction time: 60 h
Yield: 83.1 %

Procedure:
To a solution of 2,4-dimethyl-8-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 4.86 mmol) (prepared according to J. W. Ellingboe, et al. U.S. Pat. No. 5,149,699) in CHCl3 (50 mL) was added triethylamine (0.49 g, 4.86 mmol) and triphenylmethyl chloride (1.36 g, 4.86 mmol). After 2.5 days, the mixture was washed with 0.1N NaOH, brine, dried MgSO4), and concentrated to give a white foam. Trituration with hexane gave 2.64 g (85%) of product as a white solid, mp 160°-161° C.