Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:34]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:34])[NH2:2]
Reactant: O
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D1, 220 mg) in ethanol (4 mL) and dimethyl sulfoxide (4 mL), 1.0 mol/L aqueous sodium hydroxide (2.4 mL) and 35% aqueous hydrogen peroxide (750 μL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain tert-butyl (3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D2, 195 mg) as white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:22])([F:23])[F:9])=[CH:17][CH:16]=2)[C:19]([OH:21])=[O:20])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethoxy-phenyl)-acetic acid (0.74 g, 3.39 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (0.78 g, 3.73 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo to remove the excess solvent. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethoxy-phenyl)-propionic acid (0.31 g, 30.6%) as a tan solid: mp 62-64° C.; EI-HRMS m/e calcd for C15H17F3 O3 (M+) 302.1129 found 302.1131.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([Br:19])=[C:16](Br)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][CH:16]=[C:15]([Br:19])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c(Br)[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c[nH]1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of intermediate 47 (75.93 mmol) in dry tetrahydrofuran (300 mL) at −78° C. under nitrogen was added n-butyllithium 2.5M solution in hexane (275 mmol). After completion of addition, the mixture was stirred under nitrogen between −70° C. and −80° C. for 30 min, and then allowed to warm up to −60° C. The reaction was carefully quenched with methanol (20 mL), maintaining the temperature below −40° C. The reaction mixture was then allowed to reach to 0° C., and water (100 mL) and ethyl acetate (100 mL) were added. The layers were separated and the organic was washed sequentially with a diluted HCl solution and brine. After evaporation in vacuo of the organic layer, the residue was purified by silica gel chromatography (eluent: DCM to DCM/methanol (1%)) to give compound 48 as a white foam in 52% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.16-1.37 (2s, 9H), 1.78-1.94 (m, 3H), 2.08-2.21 (m, 1H), 3.26-3.34 (m, 1H), 3.42-3.50 (m, 1H), 4.63-4.74 (m, 1H), 7.07-7.10 (m, 1H), 12.09-12.13 (m, 1H); MS (ESI, EI+) m/z=316.23-318.24 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+].O>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cnc2ccccc2c1
Yield: 89 %

Procedure:
3-Quinolinecarbaldehyde (2.00 g, 12.7 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.24 g, 6.4 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 1.8 g of quinolin-3-yl-methanol in 90% yield; 1H NMR (DMSO-d6) δ 4.89 (s, 2H), 7.53 (t, J=7.1 Hz, 1H), 7.64-7.71 (m, 1H), 7.77 (d, J=8.2 Hz, 1H), 8.04-8.12 (m, 2H), 8.83 (d, J=2.0 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C-:8]#[N:9].[K+].[OH-].[NH4+:12].[Cl-].[NH4+]>CO>[NH2:12][C:4]1([C:8]#[N:9])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOCC1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(N)CCOCC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of tetrahydropyran-4-one (150 g, 1.50 mol) in methanol (1500 mL) was added potassium cyanide (6.0 M in water, 400 mL, 2.4 mol), ammonium hydroxide (25% solution in water, 1000 mL, 7.4 mol), and ammonium chloride (161 g, 3.00 mol). The reaction mixture was heated to 70° C. After 16 hours, the reaction mixture was cooled, quenched with cold brine (2000 mL), and extracted with dichloromethane (4×1500 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4-amino-tetrahydro-2H-pyran-4-carbonitrile. The material was used without further purification.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2.[CH:17]([N:20]([CH:23]([CH3:25])[CH3:24])CC)([CH3:19])C.N1C=CC=C1C=O.N1CCCC1>C(O)C>[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]2=[CH:25][C:23]1[NH:20][CH:17]=[CH:19][CH:24]=1
Reactant: NCc1ccc2c(c1)CC(=O)N2
Reactant: CCN(C(C)C)C(C)C
Agent: O=Cc1ccc[nH]1
Solvent: CCO
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: NCc1ccc2c(c1)C(=Cc1ccc[nH]1)C(=O)N2
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Alternatively, a solution of 5-aminomethylindolin-2-one acetate salt (220 mg, 1 mmol) in ethanol (10 mL) was treated with diisopropylethylamine (DIEA) (3 mL). After 20 minutes, 2-pyrrolecarboxaldehyde (95 mg, 1 mmol) and pyrrolidine (0.05 mL) were added and the reaction mixture was stirred at 60° C. for 3 hours. Concentration of the solvent gave an oil which was purified by reverse phase HPLC (acetonitrile/water) to afford 5-aminomethyl-3-[(pyrrol-2-yl)methylene]indolin-2-one; as a trifluoroacetate salt (70 mg); 1H NMR (400 MHz, DMSO-d6) δ 3.98 (m, 2H), 6.36 (m, 1H), 6.84 (brs, 1H), 6.88 (d, 1H), 7.22 (d, 1H), 7.34 (s, 1H), 7.62 (s, 1H), 7.68 (s, 1H), 8.20 (brs, 2H), 11.00 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:33])[C:30](I)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:34])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:35]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:33])[C:30]([C:38]4[CH:37]=[CH:36][C:35]([CH:41]5[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:40][CH:39]=4)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:34])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccccc2)ccc1C
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(-c4ccc(C5CCCCC5)cc4)c(Cl)cc3n2Cc2ccccc2)ccc1C
Temperature: 130 °C

Procedure:
To a solution of [5-(1-Benzyl-6-chloro-5-iodo-1H-benzoimidazol-2-yloxy)-2-methyl-phenyl]-phosphonic acid diethyl ester (5.2 g, 8.5 mmol) in toluene (30 ml) was added 4-cyclohexylbenzeneboronic acid (3.5 g, 17 mmol), tetrakis(triphenylphosphine)palladium(0) (983 mg, 0.9 mmol), and then potassium carbonate (4.7 g, 34 mmol) in a solution of H2O (15 ml). The resulting mixture was heated in a microwave reactor at 130° C. for 15 minutes, and then quenched with saturated ammonium chloride solution. The mixture was then partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, and then dried with MgSO4. The crude mixture was then purified by flash chromatography (SiO2, 80 g). The title compound was eluted with 60% EtOAc in Hexane.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:21])[C:3]1=[O:29].[C:30]([OH:40])(=[O:39])[C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32]>C(#N)C.ClC1C=C(Cl)C=C(C=O)C=1O>[NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:21])[C:3]1=[O:29].[C:30]([O-:40])(=[O:39])[C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32]
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CC#N
Product: Cc1ccccc1C(=O)CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Product: O=C([O-])[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 2.75 g 3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one in 55 ml acetonitrile, was added 0.98 g (S)(+)-mandelic acid, the mixture was stirred at room temperature for 30 minutes, 41 mg 3,5-dichlorosalicylaldehyde was then added, and stirring was further continued for 18 hours. The crystals which separated out were collected by filtration and washed with 15 ml acetonitrile, thus giving 2.94 g of (R)-3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one·(S)-mandelate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:11][NH:10][C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.O>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:11][N:10]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (4.0 g, 11.1 mmol) in THF (30 mL) at −78° C. is added KN(Si(CH3)3)2 (45.0 mL 1M THF, 45.0 mmol) slowly. The mixture is stirred at room temperature for 20 min, cooled to −78° C., and 3-chloromethyl-pyridine hydrochloride (2.75 g, 16.7 mmol) is added in portions. The reaction is warmed to room temperature and stirred for 16 h, H2O (20 mL) is added and the mixture is partitioned with H2O/ether, the organic layer is separated, dried with Na2SO4 and evaporated to give a white solid, 5.0 g (quantitative) of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-carbamic acid tert-butyl ester. MS (ESI) 899.3 (2M+H)+
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1ccc(F)cc1)C1(O)CCNCC1
Yield: 100 %

Procedure:
(0.550 g, 1.76 mmol) of (1-Benzyl-4-hydroxy-piperidin-4-yl)-(4-fluoro-phenyl)-methanone was hydrogenated in 4 mL of ethyl acetate and 2 mL of methanol using 0.065 g, (0.61 mmol) of Palladium on charcoal. to yield 0.392 g of the title compound (1.76 mmol, 100% yield) as a off-white solid after filtration of the catalyst and removal of the solvent under vacuum. MS (m/e): 314.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:14]([CH3:22])=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=2)[CH:9]=[CH:8][N:7]=1)=[O:4].[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:19][C:16]1[N:15]=[C:14]([CH3:22])[C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:23])[CH3:1])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
A mixture of 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (0.500 g, 1.576 mmol) and NH4Cl (2.53 g, 47.3 mmol) in MeOH (10 mL) and THF (10 mL) was treated with zinc dust (1.030 g, 15.76 mmol) and stirred at RT for 0.5 h. The mixture was diluted with EtOAc, the solids removed via filtration, washed with EtOAc and the filtrate concentrated to dryness. The residue was treated with DCM, sonicated, the solids removed via filtration and the filtrate concentrated to dryness to afford 3-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea (510 mg, 113%). MS (ESI) m/z: 288.1 (M+H+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:15][CH2:16][C@:17]1([CH3:30])[C@H:21]([CH:22]=[CH2:23])[O:20][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18]1)[CH2:10][C:11]([O:13]C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO.O>[Si:1]([O:8][C@H:9]([CH2:15][CH2:16][C@:17]1([CH3:30])[C@H:21]([CH:22]=[CH2:23])[O:20][C@H:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:18]1)[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CC[C@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Methyl (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S,4R,5S)-4-methyl-2-phenyl-5-vinyl-1,3-dioxolan-4-yl]pentanoate (14.6 g, 33.6 mmol) was dissolved in a mixed solution of THF (140 ml)-methanol (140 ml)-water (70.0 ml) and anhydrous lithium hydroxide (4.02 g, 168 mmol) was added. The reaction solution was stirred at room temperature for four and a half hours. The reaction solution was poured into 0.5N hydrochloric acid, which was then extracted with ethyl acetate. After the organic layer was washed with water and brine sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=4:1→2:1) to obtain the title compound (14.1 g) as a colorless oil.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]1=O.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[BrH:1].[NH2:17][C:15]1[S:16][C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=2[N:14]=1
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: CCOC(=O)C1CCCc2sc(N)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethanol (50 mL) was added to ethyl 3-bromo-2-oxocyclohexane-carboxylate (50 g, 0.20 mol) and thiourea (15.3 g, 0.20 mol) and the reaction mixture was stirred for a period of 24 hours at room temperature under a blanket of nitrogen as inert gas. Following the removal of the solvent, ether (100 mL) was added to the residue. Following stirring for a period of 2 hours at room temperature, the suspension was filtered off and the solid matter was dried in vacuo. The product ethyl 2-amino-4,5,6,7-tetrahydrobenzthiazole-4-carboxyate hydrobromide was obtained in a yield of 58.6 g (corresponding to 95% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[F:15].[CH:16]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[C:4]([CH3:16])[C:3]=1[F:15]
Reactant: Fc1cc(OC2CCCCO2)ccc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(OC2CCCCO2)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-(4-bromo-3-fluorophenoxy)tetrahydro-2H-pyran (1200 mg, 4.4 mmol) was dissolved in tetrahydrofuran (22 mL, 0.2M) under nitrogen and cooled to −78° C. To this was added (600 mg, 5.6 mmol) lithium diisopropylamide in solution dropwise over 5 minutes. The reaction mixture was stirred for 1 h at −78° C. Methyl iodide (948 mg, 6.5 mmol) was then added dropwise. The reaction was stirred at −78° C. for 30 min and allowed to warm to RT overnight. The mixture was quenched with water and 10 mL of saturated aqueous ammonium chloride solution. The reaction was extracted with diethyl ether (3×). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 1.17 g (93%) of a light yellow mix of solid and oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.78 (m, 3H) 1.85-1.93 (m, 2H) 1.95-2.08 (m, 1H) 2.21 (d, J=2.34 Hz, 3H) 3.61 (m, J=11.27, 3.98, 3.98, 1.46 Hz, 1H) 3.78-3.88 (m, 1H) 5.41 (t, J=3.12 Hz, 1H) 6.81 (dd, J=8.98, 1.37 Hz, 1H) 7.27 (d, J=16.98 Hz, 1H)
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=1[CH3:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=3[CH3:34])[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1cccc(N=C=O)c1C
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C)c3C)c(=O)n(C3CCCC3)c12
Yield: 16.5 %

Procedure:
1-Cyclopentyl-3-(2,3-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (22 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-2,3-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C:13]([CH2:15][C@:16]4([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:14]>O1CCOCC1.Cl>[CH3:22][C@:16]12[CH2:15][C:13](=[O:14])[C@H:12]3[C@@H:11]([CH:10]=[CH:9][C:8]4[C@:2]3([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=4)[C@@H:17]1[CH2:18][CH2:19][C:20]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1.5 h

Procedure:
Adrenosterone (androst-4-ene-3,11,17-trione, A-1, 50 g, 166.7 mmol) was dissolved in dioxane (1200 mL, dry), which had been saturated with HCl gas at 10 ° C. under argon, and a chilled solution of 2,3-dichloro-5,6-dicyanoquionone (DDQ, 50 g, 220 mmol) in hydrogen chloride saturated dioxane (450 mL) was added slowly to the stirred solution. Solid dihydro-DDQ rapidly separated from the solution. After 1.5 h, the mixture was filtered through a sintered glass funnel, most of the dioxane was evaporated under reduced pressure and the residue was chromatographed over silica gel (1000 g) using chloroform as the eluting solvent. The light-yellowish material from evaporation of the eluate was 48.7 g of the dienone compound A-2: mp 237° C.; UV (MeOH) λmax 278 nm (ε24,600); IR (CHCl3) 1745 (17-C═0), 1705 (11-C═0) and 1650 (3conjugated C═0) cm−1; 1H NMR (CDCl3) δ0.92 (s, 3, 18-CH3), 1.32 (s, 3, 19-CH3), 5.63 (s, 1, 4-H) and 6.13 (s, 2, 6- and 7-H); m/z 298 (m+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23](OCC)(OCC)(OCC)[CH3:24]>>[CH3:23][C:24]1[N:11]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CO[C@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Product: CO[C@H]1C[C@@H](n2c(C)nc3cnc4ccsc4c32)CC[C@@H]1CC#N

Procedure:
This compound was prepared according to the procedure of Example 34, steps 12, using {(1R,2S,4S)-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-methoxycyclohexyl}acetonitrile (racemic) and triethyl orthoacetate as the starting material. LCMS calculated for C18H21N4OS (M+H)+: m/z=341.1. Found: 341.1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:28]
Reactant: Cc1cccc(C(=O)CBr)n1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cccc(C)n2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer, J. Jenni, and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).