Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:25]([O:29][C:30](=[O:49])[NH:31][C@H:32]([CH:47]=O)[CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:49])[NH:31][C@H:32]([CH2:47][NH:1][C@@H:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4])[CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCCNC(=O)OCc1ccccc1
Reactant: CC(C)[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](NC[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H -quinazolin-4-one (a compound of Formula 107, 366 mg, 1.07 mmol) and ((S)-4-benzyloxycarbonylamino-1-formyl-butyl)-carbamic acid tert-butyl ester (prepared as previously described: Hamada, Y.; Shioro, T. Chem. Pharm. Bull. 1982, 30, 1921) (452 mg, 1.29 mmol) in CH2Cl2 (25 mL) was added sodium triacetoxyborohydride (341 mg, 1.61 mmol). The resultant cloudy mixture was stirred overnight and quenched with saturated brine (50 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2:1 hexanes:ethyl acetate) to provide 550 mg (76%) of the title compound as a yellow oil. MS(ES+) m/e 676.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:27]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:20])[CH:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)C(=O)c1cc(CCCC(=O)O)ccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(CCCC(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
To a solution of 4-(3-dimethylcarbamoyl-4-nitrophenyl)butanoic acid (1.37 g) in DMF (10 mL) were added potassium carbonate (880 mg) and benzyl bromide (922 mg). The mixture was stirred at 60° C. for 3.5 hours under heating and then allowed to stand for cooling down to room temperature. After addition of water thereto, the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1, v/v) to give the title compound (1.39 g).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([C:6]([CH2:8][CH2:9][CH2:10]Cl)=[O:7])[S:3][CH:2]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:10][CH2:9][CH2:8][C:6]([C:4]1[S:3][CH:2]=[CH:1][CH:5]=1)=[O:7])=[N+:13]=[N-:14]
Reactant: O=C(CCCCl)c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCC(=O)c1cccs1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
A mixture of 4-chloro-2′-butyrothienone (3.0 g, 15.9 mmol) and sodium azide (2.07 g, 31.8 mmol) in DMF (50 mL) was stirred at 70° C. for 1.5 h. The reaction mixture was then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. Removal of the solvent in vacuum provided the title compound (2.58 g, 83% yield). MS m/e 218; HPLC retention time 0.85 min (Method B).
Reaction SMILES: [N:1]1([C@@H:6]([CH2:11][C:12](OC)=[O:13])[C:7](OC)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.O>C1COCC1.CCOC(C)=O>[N:1]1([C@@H:6]([CH2:11][CH2:12][OH:13])[CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COC(=O)C[C@@H](C(=O)OC)n1cccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC[C@@H](CO)n1cccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
In a two necked flask cooled in an ice bath and under argon atmosphere, dimethyl(2S)-2-(1H-pyrrol-1-yl)butanedioate (20.3 mmol, 4.3 g) was dissolved in 50 ml of dry THF. LiAlH4 (42 ml, 1 M in THF) was cautiously added and the reaction was let warm up at room temperature. When the reaction was completed, it was cooled again to 0° C. and acidified with 2M HCl. Water and AcOEt were added to the quenched reaction and the organic layer was extracted with brine. The crude residue was purified by chromatography on silica gel (eluent: DCM/MeOH:95/5) to give the product as a colourless oil (2.0 g, 63% yield).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl.C(N(CCCC)CCCC)CCC>C(OCCOCC)C>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([O:32][CH3:33])[C:24]=3[O:23][CH3:22])[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1ccc(CCl)c(OC)c1OC
Agent: CCOCCOCC
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Yield: 91.2 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 1.4 g (0.005 mole), 1.1 g (0.005 mole) of 2,3,4-trimethoxybenzyl chloride, and 0.93 g (0.005 mole) of tributylamine were dissolved in 10 ml of ethylene glycol diethyl ether, and the resulting solution was heated at the refluxing temperature for 2.5 hours. The reaction liquid was left to cool, and filtered, and concentration of the filtrate under reduced pressure produced 2.1 g of oily 1-(3,3-diphenylpropyl)-4-(2,3,4-trimethoxybenzyl)piperazine (91.2% yield).
Reaction SMILES: [C:1]([S:5][C:6]1[C:7]([C:12](O)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[BH4-].[Li+].[OH-].[Na+]>O1CCCC1.O.C(OCC)(=O)C.CO>[C:1]([S:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1cccnc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)Sc1cccnc1CO
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-t-butylthio-2-carboxypyridine (10.0 g, 47.4 mmol) in tetrahydrofuran (200 mL) cooled to −5° C. was added trethylamine (8.25 mL, 47.4 mmol) followed by addition of ethyl chloroformate (4.38 g, 47.4 mmol) and reaction was stirred for 30 min at 0° C. Lithium borohydride (2.58 g, 118 mmol) was added in portions, maintaining the temperature below 5° C. After the addition was complete the reaction was allowed to warm to room temperature and stirred for 1 hour. Temperature was lowered to −5° C. and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10%). After addition of ethyl acetate (50 mL) and water (40 mL) dilute hydrochloric acid was added to pH=5.0.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[C:8]([C:16]([F:19])([F:17])[F:18])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(N2CCCC2)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(N2CCCC2)cc1C(F)(F)F

Procedure:
A mixture of 2.5 g (9.12 mmol) of methyl 6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylate, obtained in step 11.1, and of 0.76 g (13.67 mmol) of potassium hydroxide in 50 ml of methanol and 2 ml of water is stirred for 24 hours at 20° C. The mixture is subsequently concentrated under reduced pressure. 100 ml of water are subsequently added and the solution is washed with 100 ml of dichloromethane and then acidified to pH 4 by the addition of concentrated hydrochloric acid. A precipitate is recovered by filtration and is washed with 50 ml of water. After drying under reduced pressure, 2.2 g of the expected compound are isolated.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28]C)=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([OH:28])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH3:33])(=[O:32])=[O:31])[CH3:3]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1S(C)(=O)=O
Reaction time: 8 h
Yield: 91 %

Procedure:
Iodoethane (1.10 mL, 13.65 mL) was slowly added to a mixture of methyl 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.0 g, 6.83 mmol) and Cs2CO3 (6.67 g, 20.48 mmol) in N,N-dimethylformamide (30 mL) at room temperature. The reaction mixture was stirred overnight, quenched with saturated NH4Cl, and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 120 g silica, 0-20% ethyl acetate/methylene chloride) to afford 7-(ethyloxy)-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.92 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ8.25 (s, 1H), 7.98-8.06 (m, 2H), 7.92 (d, J=8.03 Hz, 1H), 7.76-7.83 (m, 2H), 4.40 (q, J=6.94 Hz, 2H), 4.09 (s, 3H), 2.37 (s, 3H), 1.47 (t, J=6.90 Hz, 3H); MS (m/z) 468.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:15]=3)[CH:9]=2)[N:4]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:3]=1.[NH2:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[O:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]1[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]3[N:12]=[N:13][N:14]([C:16]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:15]=3)=[CH:7][CH:6]=2)[C:2]([C:46]2[CH:47]=[C:42]([NH2:41])[CH:43]=[CH:44][CH:45]=2)=[N:3]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1

Procedure:
The title compound was prepared according to the procedure described in example 209A using 2-{3-bromo-5-[2-(triphenylmethyl)(1,2,3,4-tetrazol-5-yl)]-1H-indazolyl}perhydro-2H-pyran (0.754 g, 1.27 mmol) in ethylene glycol dimethyl ether (12 mL), 3-aminophenyl boronic acid (0.296 g, 1.91 mmol), [1,1′-bis(diphenylphosphino)ferrocene] complex with dichloromethane (1:1) (0.147 g, 0.127 mmol), and potassium phosphate (1.35 g, 6.35 mmol). It was isolated after chromatographic purification using 25% ethyl acetate in hexanes (0.246 g, 32% yield): ES-MS (m/z) 604 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:18][C:19]([O:21]CC)=[O:20])([CH3:17])[C:13]2[C:3]=1[CH:4]=[C:5]1[NH:10][C:9](=[O:11])[C:8](=[O:12])[NH:7][C:6]1=2.O1CCOCC1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:18][C:19]([OH:21])=[O:20])([CH3:17])[C:13]2[C:3]=1[CH:4]=[C:5]1[NH:10][C:9](=[O:11])[C:8](=[O:12])[NH:7][C:6]1=2
Reactant: CCOC(=O)CC1(C)C=CC(Cl)=C2C=c3[nH]c(=O)c(=O)[nH]c3=C21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(CC(=O)O)C=CC(Cl)=C2C=c3[nH]c(=O)c(=O)[nH]c3=C21
Temperature: 80 °C
Yield: 19.7 %

Procedure:
A mixture of 2.27 g of ethyl (8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno [1,2-b]pyrazin-5-yl)acetate, 120 ml of dioxane and 25 ml of 8N aqueous hydrochloric acid solution is heated to a temperature in the region of 80° C. for 4 hours. The reaction mixture is then evaporated under reduced pressure, and the evaporation residue is triturated in 35 ml of an ethanol/water (85:15 by volume) mixture, filtered and washed with distilled water (2 times 10 ml). The product obtained is taken up in 68 ml of 0.1N aqueous sodium hydroxide solution. The insoluble matter is separated by filtration, and the filtrate is neutralized by adding 6.8 ml of 1N aqueous hydrochloric acid solution. The solid obtained is separated by filtration, washed with distilled water (2 times 5 ml) and dried in the air. 0.41 g of (8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno[1,2-b]pyrazin-5-yl) acetic acid is thereby obtained in the form of an ochre-coloured solid melting above 300° C. (1H NMR spectrum [200 MHz, (CD3)2SO-d6, δ in ppm]: 1.39 (3H, s, CH3); 2.93 (2H, m, --CH2 --CO); 7.19 (lH, dd, J=8 and 2 Hz, arom H); 7.48 (1H, d, J=8 Hz, arom H); 7.56 (1H, d, 2=2 Hz, arom H); 12.18 (1H, s, --NH--); 12.24, s, --NH); Analysis, % calculated C: 54.83; H: 3.61; Cl: 11.56; N: 9.13; 0: 20.87; % found C: 55.2; H: 3.4; Cl: 11.2; N: 9.0; O: 18.6).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([O:18][CH3:19])[C:8]([CH3:20])=[CH:7][C:5]=2[N:6]=1.[CH3:21][C:22]1([CH3:33])[C:26](C)(C)OB(C=C(C)C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:4]3[S:3][C:2]([CH:21]=[C:22]([CH3:33])[CH3:26])=[N:6][C:5]=3[CH:7]=[C:8]([CH3:20])[C:9]=2[O:18][CH3:19])=[CH:12][CH:13]=1
Reactant: COc1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1c(C)cc2nc(C=C(C)C)sc2c1-c1ccc(Cl)cc1

Procedure:
The mixture of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (0.153 g, 0.417 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (0.256 ml, 1.24 mmol), K3PO4 (0.35 g, 1.66 mmol), PdCl2(dppf) (45 mg, 0.062 mmol) in DME (1 ml) and H2O (0.5 ml) was reacted in microwave at 120° C. for 0.5 h. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C19H18ClNOS: 344.1 (M+H+). Found: 344.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[N:5]=1.Br[CH2:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:19]2=[C:20]([CH:23]=1)[O:21][CH2:22][C:16]1[CH:15]=[C:14]([CH2:13][N:5]3[C:6]4=[CH:11][S:10][CH:9]=[C:7]4[N:8]=[C:4]3[CH2:3][O:2][CH3:1])[CH:33]=[CH:32][C:17]=1/[C:18]/2=[C:28](/[CH3:31])\[C:29]#[N:30]
Reactant: COCc1nc2cscc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: COCc1nc2cscc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 96.1 %

Procedure:
[step 2] Using 2-(methoxymethyl)-1H-thieno[3,4-d]imidazole (65 mg, 0.39 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (141 mg, 0.39 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (167 mg, 97%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:22][CH:21]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(F)c(C(F)(F)F)c3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(F)c(C(F)(F)F)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 74A. mp 116-117° C.; IR (KBr) cm−1: 3028, 1741, 1704, 1511, 1235, 1110; 400 MHz 1H NMR (DMSO-d6): δ 12.96 (br(s), 1H), 7.74-7.85 (m, 2H) 7.45-7.54 (m, 1H), 7.08-7.15 (m, 2H), 7.04 (d, 1H, J=8.5 Hz), 6.84-6.91 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.09 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.66 (t, 2H, J=7.5 Hz), 1.88 (pentet, 2H); MS m/z 505 (M−1). Anal. Calc'd for C26H22F4O4S: C, 61.65H, 4.38. found: C, 61.50; H, 4.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=O)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.Cl.[NH2:36][OH:37].O>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](/[CH:12]=[N:36]\[OH:37])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2
Reactant: NO
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C=N\O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5 (270 mg, 0.57 mmol, 1.0 eq) and hydroxylamine hydrochloride (495 mg, 7.1 mmol, 13 eq) in pyridine (4 mL) and MeOH (20 mL) was stirred at RT overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product, (S,Z)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde oxime (240).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>CC(C)=O>[CH3:13][O:12][C:10]([CH:9]([C:8]([O:15][CH3:16])=[O:14])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:11]
Reactant: O=C1C=CCCC1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)OC)[C@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 194 μL (2.0 mmol) of 2-cyclohexenone, 229 μL (2.0 mmol) of dimethyl malonate, and 2 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 316 mg (69% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=85:15, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 73% ee.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10](O)[CH2:11][CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:25]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([C@@H](O)CC[C@H](O)c2cccc([N+](=O)[O-])c2)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=[N+]([O-])c1cccc([C@H]2CC[C@H](c3cccc([N+](=O)[O-])c3)N2c2ccc(C(F)(F)F)cc2)c1
Yield: 19 %

Procedure:
The product from Example 205A and 4-aminobenzotrifluoride were processed using the method described in Examples 55C and 55D to afford the title compound (0.27 g, 19%). MS (ESI) m/z 858 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:9]CC)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si](C)(C)[O-].[K+:17]>O1CCCC1>[CH2:1]([O:3][P:4]([O-:9])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[K+:17]
Reactant: CCOP(=O)(OCC)OCC
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)([O-])OCC
Reaction time: 40 h
Yield: 92.4 %

Procedure:
The procedure of Example 1 was followed except that triethylphosphate (3.4 mL, 20 mmol) was added by syringe to a slurry of potassium trimethylsilanolate (2.56 g, 20 mmol) in dry tetrahydrofuran (50 mL), and a 2 h reaction time at room temperature was used, followed by 40 h of heating at reflux. Potassium diethylphosphate (3.55 g, 92% yield) was isolated as a white solid: 1H NMR (D2O, DSS) δ 1.1 (t, J=6.9 Hz, 6H), 3.75 (q, J=6.9 Hz, 4H). Anal. Calcd. for C4H10KO4P: C, 25.00; H, 5.24; K, 20.34. Found: C, 25.83, 25.88; H, 5.40, 5.29; K, 20.37, 20.10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc([N+](=O)[O-])cc2)c1=O
Yield: 92.6 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-nitrobenzyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 92.6%.