Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([N:5]=[C:6]=[S:7])=[O:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:8][CH2:9][CH3:10])=[S:7])=[CH:28][CH:27]=1
Reactant: CCCC(C)C(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2-Methylpentanoyl isothiocyanate prepared according to the method 2 was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 57%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][C:16]([CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=O)[CH3:12].[CH2:31]([O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])[CH3:32]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[S:2][CH3:1])[C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:39])=[C:36]([CH3:37])[NH:38][C:16]=1[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:30])[CH3:12]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CSc1ccccc1C=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1SC

Procedure:
A solution of 10 g of 2-methylmercapto-benzaldehyde (77% pure), 14 g of phthalimidoacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 100 ccs of ethanol is heated under reflux for 2×24 hours and, after subsequent cooling, the precipitate is filtered off.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].CCN(CC)CC.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of 2-(3-hydroxypropyl) isoindoline-1,3-dione (1.8 g, 8.77 mmol) in CH2Cl2 (30 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol). After stirring for 10 min at 0° C., tosylchloride (2 g, 10.5 mmol) was added and the reaction was stirred for 12 h at RT. The reaction was quenched with water and extracted with CH2Cl2 (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-(1,3-dioxoisoindolin-2-yl)propyl 4-methylbenzenesulfonate (3 mg, 96%). Observed mass (M+1): 360.1.
Reaction SMILES: C(O)(=O)C.C([CH2:7][C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1)([CH3:12])[C:9]([OH:11])=[O:10])C.[NH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[SH:30].C([O-])(=O)C.[Na+]>O.C(OCC)(=O)C>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]2[S:30][C:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][C:8]([CH3:7])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:19][CH:18]=3)=[N:22][C:23]=2[CH:28]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ccc(-c2nc3cc(Cl)ccc3s2)cc1)C(=O)O
Yield: 35.3 %

Procedure:
In an acetic acid (0.37 mL) solvent, a mixture including Compound 97c (78.2 mg, 0.38 mmol), 2-amino-4-chlorobenzenethiol (60.0 mg, 0.38 mmol), and sodium acetate (NaOAc) (93.6 mg, 1.13 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was evaporated under reduced pressure. The produced precipitate was filtered, and washed with methylene chloride to obtain Compound 99 (46.6 mg, 39.6%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH2:24][CH2:25][N:26]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:27]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=4)=[CH:30][C:28]=3[CH:29]=2)=[O:22])=[CH:16][CH:15]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH2:24][CH2:25][N:26]([CH2:48][CH:49]([CH3:50])[CH3:51])[C:27]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=4)=[CH:30][C:28]=3[CH:29]=2)=[O:22])=[CH:18][CH:19]=1)=[O:60])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of [2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]thio]methyl]-1H-imidazol-1-yl]ethyl acetate (350 mg) in dichloromethane (10 ml) was added dropwise 3-chloroperbenzoic acid (70%, 146 mg) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica get, ethyl acetate:hexane 1:1→ethyl acetate→ethanol:ethyl acetate 1:19), to give [2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]ethyl acetate (Preparation of Compound 411) (278.7 mg) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: OCC1CC(c2ccc(I)c(F)c2)=NO1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCC1CC(c2ccc(I)c(F)c2)=NO1

Procedure:
(5RS)-3-(3-Fluoro-4-iodophenyl)-5-hydroxymethyl-4,5-dihydroisoxazole (2 g, 6.2 mM) was treated with methanesulfonyl chloride under essentially the conditions of the equivalent intermediate of Example 4. Product was obtained as a white solid (2.18 g) without chromatography. MS (EI): 399 (M+) for C11H11FINO4S
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:25]([Mg]Br)[CH3:26].[BH4-].[Na+].O>O1CCCC1.CC(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:24])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 132.4 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (1.496 g, 3.096 mmol) in tetrahydrofuran (40 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 13.2 mL, 39.6 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 4 hr, then the mixture was cooled to room temperature. A suspension of sodium tetrahydroborate (3.0 g, 79.3 mmol) in 2-propanol (40 mL) was added to the reaction mixture at room temperature. After the mixture was stirred at room temperature for 18 hr, water was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine; dried over anhydrous magnesium sulfate, concentrated in vacuo to give title compound (1.68 g) as a pale yellow amorphous.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.Cl>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]3[C:14]4[C:19]([CH2:11][C:12]=3[C:5]=2[CH:4]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: Fc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Reaction time: 5 h

Procedure:
A mixture of 4-fluorophenylhydrazine hydrochloride (1.83 g, 11.25 mM) and 1-indanone (1.49 g) in ethanol (20 cm3) was heated to reflux, and conc. hydrochloric acid was (1 cm3) added. Heating was continued for 5 hours, and the reaction mixture was cooled. The product which crystallised out from the cold solution as coloured platelets, was collected by filtration and dried (1.90 g, 75%). M.p. 225°-227° C. (from ethyl acetate/petrol [60°-80 ]). 1H NMR (CDCl3) δ: 8.3 (1H, br, s), 7.6-6.9 (7H, m), 3.70 (2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[N:39](CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:39][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Yield: 93 %

Procedure:
5-Benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1d employing 5-benzyloxy-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 5a) instead of preparation 1c.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:6]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:19])[N:22]3[CH2:21][CH2:20][NH:23][C:8]3([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[CH2:7][N:5]2[CH:6]=1
Reactant: NCCN
Reactant: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Solvent: CCO
Product: O=C1c2cc(Br)cn2CC2(c3ccc(Cl)cc3)NCCN12
Yield: 68.7 %

Procedure:
To a solution of crude 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, 0.29 mmol) dissolved in a mixture of xylenes (10 mL) and ethanol (3 mL) was added ethane-1,2-diamine (100 μL, 1.5 mmol). The reaction mixture was heated at reflux. After 90 minutes (monitored by LCMS) the mixture was concentrated in vacuo and the resultant residue purified flash chromatography (Biotage SP4, 40 g cartridge, 0-5% MeOH gradient in CH2Cl2) to give 7-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a light yellow solid (73 mg, yield: 68%). 1H NMR (400 MHz, d6-acetone): δ 2.74-2.82 (m, 1H), 3.30-3.38 (m, 1H), 3.44 (ddd, 1H, J 7.7, 3.4, 1.3 Hz), 3.67-3.75 (m, 1H), 4.39 (d, 1H, J 12.5 Hz), 4.69 (d, 1H, J 12.5 Hz), 6.68 (d, 1H, 1.8 Hz), 6.79 (d, 1H, J 1.7 Hz), 7.32-7.40 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][NH:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[NH2:44][CH2:43][CH2:42][N:41]([CH3:40])[C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[C:13]2[CH:12]=[CH:11][C:10](=[O:39])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CNCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 15.9 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in THF (5 mL) was added N-methyl-1,2-ethanediamine (0.044 mL, 0.5 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (8.0 mg, 16%). LC-MS (ES) m/z 559 (M+H)+; 1H-NMR (MeOD) δ 2.35 (s, 3H), 2.65 (m, 1H), 2.86 (m, 1H), 2.92 (m, 1H), 3.26 (m, 1H), 3.35 (m, 1H), 3.40 (m, 1H), 3.77 (m, 1H), 6.36 (d, 1H), 7.14 (m, 2H), 7.25 (m, 2H), 7.52 (d, 1H), 7.59 (d, 1H), 7.62 (m, 1H), 7.71 (m, 2H), 7.92 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH:27][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:11]=[CH:10]2
Reactant: COc1cccc(CN)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Product: COc1cccc(CNc2ccc3nc(NCc4ccc(C)o4)ccc3c2)c1

Procedure:
The title compound, MS: m/e=374.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-methoxybenzylamine.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[C@H:20]([C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[OH:22])[CH2:19][S:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1)=[O:4].I([O-])(=O)(=O)=[O:34].[Na+]>CO.O>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]2[C@H:20]([C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[OH:22])[CH2:19][S:18](=[O:34])[CH2:17]2)=[O:15])=[CH:11][CH:12]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)C(=O)NCc1ccc(NC(=O)N2CSC[C@H]2[C@@H](O)c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(NC(=O)N2CS(=O)C[C@H]2[C@@H](O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4(R)-[(3,4-dichlorophenyl)-(S)hydroxymethyl]-thiazolidine-3-carboxylic acid {4-[(2,2-dimethyl-propionylamino)-methyl]-phenyl}-amide (11 mg, 0.022 mmol) in MeOH (2 ml) is added sodium periodate (4.9 mg, 0.023 mmol) in water (0.5 ml). The reaction mixture is stirred at 25° C. for 18 hrs. More aqueous sodium periodate is added by portions until almost complete conversion of the starting material. The reaction mixture is filtered on cellite and concentrated in vacuo. The residue is taken into methylene chloride, washed with water and brine, concentrated and purified by preparative reverse phase HPLC and flash chromatography (silica gel, 2% to 5% MeOH/NH3 in methylene chloride) sequentially to give the following two products isomeric at the sulfoxide center:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].C([O:44][C:45]([NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=O)(C)(C)C.[C:54](OC(=O)C)(=O)C>>[C:45]([NH:47][CH:48]1[CH2:53][CH2:52][N:51]([C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:30])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:39])([F:1])[F:38])[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:50][CH2:49]1)(=[O:44])[CH3:54]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 75 %

Procedure:
In a similar manner to Example 24, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg), 4-(t-butoxycarbonylamino)piperidine (36.1 mg) and acetic anhydride (0.05 mL) were reacted to obtain 2-[4-(acetylamino)piperidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(71.2 mg, 75%).
Reaction SMILES: C(O)(=O)C.[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13])(=[O:8])=[O:7].Cl[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[N:19]=1.CCN(CC)CC>O1CCOCC1>[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:13][C:22]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:18][N:19]=[C:20]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[N:21]=1)(=[O:7])=[O:8]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: O=C1Cc2c(cccc2Nc2ncc(C(F)(F)F)c(Cl)n2)N1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(CNc2nc(Nc3cccc4c3CC(=O)N4)ncc2C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3-methanesulfonyl-benzylamine mono-acetate (150 mg, 0.61 mmol) and 4-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one (200 mg, 1 eq) were combined with Et3N (136 mg, 2.2 eq) in dioxane (3 mL) at 100° C. for 3 hours. The reaction was cooled to RT and product crystallized by the addition of water to the crude reaction. The product was filtered of as a tan solid, 139 mg (48%). 1H NMR (DMSO-d6, 400 MHz) δ 3.11 (s, 3H), 3.39 (s, 2H), 4.62 (d, J=5.8 Hz, 2H), 6.48 (d, J=7.5 Hz, 1H), 6.96 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.53 (m, 2H), 7.75 (d, J=7.5 Hz, 1H), 7.83 (m, 2H), 8.19 (s, 1H), 9.08 (s, 1H), 10.31 (s, 1H); HPLC ret. time: 5.314 min. LRMS (M+) 478.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](I)=[N:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:24]([C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:14]=1)#[N:25]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(F)cc3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(F)cc3)noc2c1O
Temperature: 110 °C
Yield: 45.5 %

Procedure:
Ethyl 3-(4-fluorophenyl)-7-hydroxy-4-iodoisoxazolo[4,5-c]pyridine-6-carboxylate (290 mg, 0.678 mmol) and CuCN (182 mg, 2.03 mmol) were added to 4.5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 101 mg of the title compound. MS: (+) m/z 328.32 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[NH:14][C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1.C([O-])([O-])=O.[K+].[K+].CS([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])(=O)=O.CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])[C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1
Reactant: C=CCC(CC=C)S(C)(=O)=O
Reactant: CCc1nc2c([nH]1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCC(CC=C)n1c(CC)nc2c1C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
Prepared by the method described in example 8 using the appropriate starting materials except for part “B” to give the desired product. Part “B” was replaced with the following procedure. A solution of 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (65 mg, 0.20 mmol) in anhydrous DMF (1.2 mL) was treated with finely ground K2CO3 (83 mg, 0.60 mmol). After stirring 5 min at rt, 4-methanesulfonyl-1,6-heptadiene (203 μL, 1.11 mmol) was added via syringe and the reaction mixture was heated at 90° C. for 4 h. The mixture was cooled to rt and transferred to a separatory funnel containing ether (50 mL). The organic layer was washed with water (4×15 mL), brine (15 mL), dried over MgSO4, filtered, and concentrated. Purification of the residue by prep plate (1000 μM silica gel plate, 25% ethyl acetate in hexanes) followed by further purification by reverse phase HPLC afforded the title compound (15 mg, 18% yield) as a colorless oil; HRMS (ESI) m/e 419.1435 [(M+H)+, calcd for C21H25N4OCl2 419.1405].
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25](=[O:27])[CH3:26])[CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(OCC)(=O)C.O>C(O)C>[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:27])[CH3:26])[CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 87.8 %

Procedure:
Sodium borohydride (0.03 g) was added to a solution (5 ml) of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetylindoline (0.17 g) in ethanol and the resultant mixture was stirred at room temperature overnight. Then ethyl acetate and water were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Then the residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (150 mg) as a colorless oil (yield: 89%).