Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][C:17](=O)OC(C)(C)C)=[N:13][CH:12]=3)[CH:9]=2)[CH:4]=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl.[C:33](O)([C:35]([F:38])([F:37])[F:36])=O>CN(C=O)C.CCOC(C)=O.Cl>[NH2:1][C@@H:10]([CH2:9][C:8]1[CH:11]=[CH:12][C:33]([C:35]([F:38])([F:37])[F:36])=[CH:6][CH:7]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[N:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[CH:12][N:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3cncnc3c2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@H](CNc1ncc(-c2ccc3cncnc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a stirred orange mixture of tert-butyl 5-(quinazolin-7-yl)thiazol-2-ylcarbamate (22 mg, 67 μmol) and Cs2CO3 (44 mg, 134 μmol) in DMF (1.0 mL), was slowly added a solution of the cyclic sulfamidate (38 mg, 100 μmol) in DMF (0.5 mL) at 50° C. The resulting light yellow mixture was stirred at 50° C. for 30 minutes. The mixture was then cooled to 0° C. and was then diluted with EtOAc and 1N HCl(aq) and the entire mixture was stirred at room temperature for 30 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (5 mL×3), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue, which was taken up in a solution of DCM (1.5 mL), and TFA (1.5 mL) was slowly added. The overall solution was stirred at room temperature for 30 minutes and concentrated. The crude residue was dissolved in DCM and mixed with silica. The solvent was evaporated, and the residue was purified with flash column chromatography (pure DCM→10% MeOH in DCM) to obtain N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(quinazolin-7-yl)thiazol-2-amine (12 mg, 42%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=C[NH:13]3)=[C:9]([NH2:16])[N:8]=2)[CH:2]=1.C(N)(=N)C1C=CC=NC=1.C(N)=[O:27]>>[NH2:16][C:9]1[C:10]([N:11]=[O:27])=[C:14]([NH2:13])[N:15]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: NC=O
Reactant: Nc1nc(-c2cccnc2)nc2[nH]cnc12
Agent: N=C(N)c1cccnc1
Product: Nc1nc(-c2cccnc2)nc(N)c1N=O

Procedure:
Taylor et al [J. Am. Chem. Soc. 81, 2442-8 (1959)] show, inter alia, the preparation of 2-(3-pyridinyl)-9H-purin-6-amine by heating the nicotinamidine salt of isonitrosomalonitrile in formamide to produce 4,6-diamino-5-nitroso-2-(3-pyridinyl)pyrimidine and heating the reaction mixture containing said 5-nitroso compound and formamide with a mixture of formic acid and sodium dithionite dihydrate to produce said 2-(3-pyridinyl)-9H-purin-6-amine, for which no use is indicated.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[N:38]([CH3:40])C)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[CH2:42](OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.C(N)C>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[NH:38][CH2:40][CH3:42])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Agent: CCN
Product: CCNC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:21]([C:20]3[CH:19]=[N:18][N:12]4[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:22])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:27][CH2:26]1
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: CN1CCN(S(=O)(=O)c2cccc(NC(=O)c3cnn4c(C(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)c2)CC1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 595.3 [(M+H)+]; mp 229° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+].Cl>>[C:1]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccccc1CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CCc1ccccc1C(=O)O
Temperature: 40 °C

Procedure:
A mixture of methyl 2-cyanomethylbenzoate (10.5 g, 60.0 mmol) in aq. NaOH (66 mL, 66 mmol, 1N solution) was heated at 40° C. for 5 h and it became a clear solution. The mixture was cooled to 0° C. and acidified to pH 1 using 6N aq. HCl. The resulting white solid was collected by filtration. 1H NMR (CD3OD): δ=4.27 (s, 2H), 7.46 (td, J=7.8, 1.0 Hz, 1H), 7.54-7.60 (m, 2H), 8.09 (dd, J=7.8, 1.3 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25]Br)[CH3:22]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([O:18][CH2:25][CH:24]([O:27][CH2:28][CH3:29])[O:23][CH2:21][CH3:22])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)C(=O)Oc1ccc(O)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1)OCC
Reaction time: 0.5 h
Yield: 21 %

Procedure:
0.70 g of 3-t-butyl-4-trimethylacetoxyphenol was dissolved in 7 ml of dimethylformamide and the solution was added dropwise into a suspension of 0.13 g of oily sodium hydride in 7 ml of dimethylformamide at 0° C. under a nitrogen stream. After stirring for 30 minutes, 0.50 ml of bromoacetaldehyde diethylacetal was added dropwise and the solution was stirred overnight and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the reaction mixture was extracted with water and ethyl acetate and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% -5% ethyl acetate) to give 0.21 g of 3-t-butyl-1-(2,2-diethoxyethoxy)-4-trimethylacetoxybenzene as a white solid (yield 21%).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=1)(OCC)=O)C.[H-].[Na+].[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35]([CH:36]=O)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.O>O1CCCC1>[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35](/[CH:36]=[CH:9]/[C:10]2[N:11]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=2)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(-c2ccccc2C(=O)OC)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(-c2ccccc2C(=O)OC)n1
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
To a solution of methyl {4-[(diethoxyphosphoryl)methyl]-1,3-thiazol-2-yl}benzoate (4.7 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 1.1 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.8 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (30:70-60:40, v/v) to give methyl (4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazol-2-yl)benzoate as pale-yellow crystals (1.1 g, yield 20%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 134-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[Cl:30].C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH:44]1([NH2:48])[CH2:47][CH2:46][CH2:45]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:48][CH:44]4[CH2:47][CH2:46][CH2:45]4)=[O:42])=[C:3]([Cl:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NC1CCC1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)c1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(Cl)c3)CC2)c1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
3-((4-(4-Amino-3-chlorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (200 mg, 0.466 mmol) and 4-nitrophenylchloroformate (94 mg, 0.466 mmol) were heated to reflux in dichloromethane (10 ml) for 2 hours. Cyclobutylamine (99 mg, 1.398 mmol) was added and the reaction stirred overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC to afford the title compound (20 mg).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([N+]([O-])=O)[CH3:21])=[CH:15][CH:14]=1.N1CCCCC1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][C:20]=2[CH3:21])=[CH:15][CH:14]=1
Reactant: CC(=Cc1ccc(F)cc1)[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)oc(C)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl isobutyrylacetate (20.06 g, 126.8 mmol) and 1-fluoro-4-(2-nitro-1-propenyl)benzene (23.0 g, 127 mmol) in ethanol (100 ml) was added piperidine (12.5 ml, 127 mmol) at room temperature, and the mixture was stirred overnight at room temperature and at 80° C. for 1 hr. The solvent of the reaction solution was evaporated under-reduced pressure, water (50 ml) and conc. hydrochloric acid (30 ml) were added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction solution was extracted twice with ethyl acetate and the collected organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to give the objective substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]([OH:16])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[CH3:18][N+:19]([CH3:22])([CH3:21])[CH3:20]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:13][C:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:18][N+:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)CS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])CS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
Into a 100 ml flask equipped with magnetic stirrer were placed 2.45 g (0.01 mol) of 4-nitrophenylsulfonylacetic acid and 50 ml of acetone. Stirring was begun and upon dissolution of the acid, 4.0 g of a 25% methanolic solution (i.e., 1.00 g, 0.011 mol) of tetramethylammonium hydroxide was slowly added, dropwise over a 15 min period. A precipitate formed in the dark red solution. Filtration, washing with acetone (10 ml) and drying in air afforded 2.9 g (91%) of tetramethylammonium 4-nitrophenylsulfonylacetate (Compound C1-A1). 1H and 13C NMR were in agreement with the proposed structure.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:7]=1[C:8](O)=[O:9].C[N:21](C)C=O>>[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:7]=1[C:8]([NH2:21])=[O:9]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(C(F)(F)F)cc(F)c1F
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(C(F)(F)F)cc(F)c1F
Temperature: 75 °C
Yield: 86 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a solution of 3.50 g (15 mmol) 2,3-difluoro-5-(trifluoromethyl) benzoic acid in 10 mL dimethylformamide. The reaction mixture was heated to 75° C. for 2 hours, cooled to room temperature and carefully added to 25 mL of ice cold ammonium hydroxide. The mixture was cooled to 0° C. and the solid product filtered, washed with water and dried to yield 3.00 g (86%) of 2,3-difluoro-5-(trifluoromethyl)benzamide m.p. 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:17]2[S:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[C:20]([CH3:21])[C:16]=2[CH:15]=1.Cl>N1C=CC=CC=1>[Cl:13][C:14]1[CH:27]=[CH:26][C:17]2[S:18][C:19]([S:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)(=[O:23])=[O:24])=[C:20]([CH3:21])[C:16]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
Into 3 mL of pyridine was dissolved 60 mg of ethyl 4-aminobenzoate, and 123 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 2 hours of stirring at room temperature. After confirmation of disappearance of the starting material, 2 mol/L hydrochloric acid was added, followed by extraction with ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 80 mg of the title compound as light pink powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([OH:26])=[O:25])=[CH:18]4)=[O:13])=[CH:9][C:8]=2[CH:27]=1)([O-])=O.[N+](C1C=C2C(=CC=1)NC(C(O)=O)=C2)([O-])=O>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([OH:26])=[O:25])=[CH:18]4)=[O:13])=[CH:9][C:8]=2[CH:27]=1
Reactant: O=C(O)c1cc2cc(NC(=O)c3cc4cc([N+](=O)[O-])ccc4o3)ccc2[nH]1
Agent: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1

Procedure:
Compound 129 was reduced as described for Compound 126 in Example 115, to give 130 which was used immediately as described in Example 118.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([OH:21])[CH:9]=[CH:10][C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][C:3]1=[O:4].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>N1CCCCC1>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:21][CH2:22][CH:24]3[O:26][CH2:25]3)[CH:9]=[CH:10][C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: ClCC1CO1
Reactant: CN1C(=O)CCc2c(O)ccc(OCc3ccccc3)c21
Solvent: C1CCNCC1
Product: CN1C(=O)CCc2c(OCC3CO3)ccc(OCc3ccccc3)c21
Reaction time: 3 h
Yield: 53.1 %

Procedure:
5.5 g of 1-methyl-5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril was added to 15 g of epichlorohydrin, and 12 drops of piperidine were then added thereto followed by stirring at 90° to 100° C. for 3 hours. The unreacted epichlorohydrin and piperidine were evaporated under reduced pressure, and the residue was dissolved in chloroform, washed successively with a 5% aqueous solution of sodium hydroxide and water and dried over anhydrous potassium carbonate. The chloroform was evaporated under reduced pressure, and the residue was purified by silica gel chromatography and then recrystallized from ethanol to afford 3.5 g of 1-methyl-5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril as yellow needle-like crystals having a melting point of 111°-112.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([OH:12])[CH2:7]2.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O1C2C(=CC=CC=2)CCC1O.C(OC(=O)C)(=O)C>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][C:8](=[O:12])[CH2:7]2
Reactant: OC1COc2c(Br)cccc2C1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: OC1CCc2ccccc2O1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C1COc2c(Br)cccc2C1
Reaction time: 0.17 h

Procedure:
The 8-bromo-3-chromanol was oxidized in small portions (400 mg, 1.7 mmol) in order to achieve better total yields. Dry pyridine (1.1 ml) was added to CH2Cl2 (60 ml), dried over P2O5 and CrO3 (0.69 g, 6.9 mmol) and molecular sieves were added to that solution. After 15 min the chromanol was added together with acetic anhydride (0.66 ml). The mixture was stirred for 10 min and then passed with suction through a column containing SiO2 (10 g), eluting with CH2Cl2. The collected eluate was evaporated and toluene was added after each evaporation (2-3 times), leaving the pure 8-bromo-3-chromanone (200 mg). GC/MS showed M+ /M+2 at m/e=226.25(89%)/228.25(82%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=O)=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Sn].C(Cl)Cl>CO.Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([SH:14])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(S(=O)(=O)Cl)cc2)CC1
Agent: Cl
Agent: [Sn]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(S)cc2)CC1
Reaction time: 3 h

Procedure:
The above product 36B (1.0 g, 3.64 mmol) was refluxed with tin powder (2.2 g, 18.8 mmol) in MeOH (10 mL) and 4M HCl/dioxane (10 mL). After 3 h, the reaction mixture was poured into ice with CH2Cl2 (100 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried with magnesium sulfate, filtered and evaporated to give the thiol compound 36C as a yellow oil (650 mg, 86%). MS: 207 (M−1)+
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:14]([O:9][C@@H:3]([CH2:2][Cl:1])[CH2:4][C:5]([O:7][CH3:8])=[O:6])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: COC(=O)C[C@@H](O)CCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@H](CCl)O[Si](C)(C)C(C)(C)C
Yield: 113.9 %

Procedure:
A solution of (R)-methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 mL) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol) at room temperature under N2. The reaction mixture was poured into water (150 mL) and acidified to pH 6-7 by dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3×60 mL). The combined organic phases were washed with sat. Na2CO3 solution, brine, dried over anhydrous Na2SO4 and concentrated to give (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (30 g, crude).
Reaction SMILES: [Na].Cl.[NH:3]=[C:4]([NH:14][CH:15]1[CH2:17][CH2:16]1)[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[NH:7].[CH3:18][C:19]1([C:22](OCC)=O)[CH2:21][CH2:20]1>C(O)C>[CH:15]1([NH:14][C:4]2[N:3]=[C:18]([C:19]3([CH3:22])[CH2:21][CH2:20]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[CH2:17][CH2:16]1
Reactant: N=C(NC(=N)N1CCOCC1)NC1CC1
Reactant: CCOC(=O)C1(C)CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC1(c2nc(NC3CC3)nc(N3CCOCC3)n2)CC1
Yield: 17.8 %

Procedure:
0.48 g (20 mmoles) of sodium is dissolved in 20 ml of anhydrous ethanol. This solution is added to an ethanol solution containing 2.48 g (10 mmoles) of N-[imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride, and 2.82 g (22 mmoles) of ethyl 1-methylcyclopropane-carboxylate are then also added to the mixture. The mixture is then heated under reflux under nitrogen for 88 hours. It is cooled, the alcohol is evaporated under reduced pressure and the residue is redissolved in 50 ml of water and 200 ml of dichloromethane. The aqueous phase is separated off and the organic phase is washed twice with 50 ml of water and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is recrystallized from a 1:1 (v/v) mixture of petroleum ether-dichloromethane. 0.49 g of 2-cyclopropylamino-4-(1-methylcyclopropyl)-6-morpholino-1,3,5-triazine is obtained. Yield: 17%. M.P.: 94°-95°% C.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:26])[CH3:2].B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:26])[CH3:2]
Reactant: CC[C@H]1C(=O)N(C)c2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC[C@H]1C(=O)N(C)c2cc(F)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of (3S)-3-ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (0.27 g, 0.7 mmol)) and tetrabutylamonium iodide (0.77 g, 2.09 mmol) in methylene chloride (20 mL) was cooled to −78° C. and treated with a 1M solution of boron trichloride in methylene chloride (3.5 mL, 3.5 mmol) via syringe. The cooling bath was removed and the solution was stirred at 25° C. for 3 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude oil was purified via flash column chromatography (SiO2, 40% ethyl acetate:hexane) to afford 0.2 g (78%) of (3S)-3-ethyl-7-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one as white solid. MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. Calcd for C17H17FN2O4S: C, 56.03; H, 4.70; N, 7.69. Found: C, 56.12; H, 4.03; N, 7.45.