Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH:10]=1)[CH2:44][C:40]1[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=1
Reactant: CCCN(CCC)CCCCc1ccc2cc(CNCc3ncc[nH]3)ccc2c1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCc1ccc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (39.0 mg) obtained in Example 124-5 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (9.40 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazole carboxaldehyde (12.0 mg), followed by stirring at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. The solution was added with a saturated aqueous sodium bicarbonate solution and stirred. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.7 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=C=O)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>ClCCl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (880 mg, 3.6 mmol), benzyl chloroformate (575 uL, 4.0 mmol) and Hunig's base (935 uL, 5.4 mmol) in dichloromethane (9.0 mL) was stirred at rt for 16 h. Saturated ammonium chloride was added and the separated aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried (anh. Magnesium sulfate), filtered and evaporated to yield a residue which was purified by reverse phase preparative HPLC. LC-MS m/z 377.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[C:11](=[S:21])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O-].[Na+].CI>CO>[CH2:1]([C:8]1[N:12]([CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[C:11]([S:21][CH3:22])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CCOC(Cn1c(Cc2ccccc2)n[nH]c1=S)OCC
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CCOC(Cn1c(Cc2ccccc2)nnc1SC)OCC

Procedure:
In 3 ml of methanol was dissolved 0.307 g of the 3-benzyl-4-(2,2-diethoxyethyl)-4H-1,2,4-triazole-5-thione prepared in Reference Example 2, followed by addition of 0.6 ml of a 2N solution of sodium methoxide in methanol. Under stirring, 0.07 ml of methyl iodide was added dropwise and, after 30 minutes, the methanol was evaporated off. The residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried over Na2SO4. Evaporation of the solvent gave 3-benzyl-4-(2,2-diethoxyethyl)-5-methylthio-4H-1,2,4-triazole as an oil (quantitative yield).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (221 mg, 2.79 mmol) and then Tf2O (395 mg, 1.40 mmol) dropwise with stifling at 0° C. The resulting solution was stirred overnight at room temperature, then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([N:13]2[CH2:17][C@H:16]([OH:18])[C@H:15]([NH:19][C:20](=[O:29])[O:21]CC3C=CC=CC=3)[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.I[Si](C)(C)C.Cl.[NH2:36][NH2:37]>C(#N)C.C(O)C(C)C>[OH:18][C@H:16]1[CH2:17][N:13]([C@H:8]([C:5]2[CH:6]=[N:7][C:2]([NH:36][NH2:37])=[CH:3][CH:4]=2)[C:9]([F:12])([F:10])[F:11])[CH2:14][C@H:15]1[NH:19][C:20](=[O:29])[O:21][C:5]([CH3:8])([CH3:6])[CH3:4]
Reactant: O=C(N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@@H]1O)OCc1ccccc1
Reactant: NN
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC#N
Solvent: CC(C)CO
Product: CC(C)(C)OC(=O)N[C@@H]1CN([C@H](c2ccc(NN)nc2)C(F)(F)F)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
To a solution of benzyl (3R,4S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-4-hydroxypyrrolidin-3-ylcarbamate (1.16 g, 2.7 mmol) in acetonitrile (2 mL) cooled to 0° C. in an ice bath was added iodotrimethylsilane (1.22 mL, 8.10 mmol) and the mixture allowed to warm to ambient temperature for 1 hour. The reaction mixture was poured into aqueous 1N HCl (15 mL) and stirred for 10 minutes and extracted with diethyl ether. The aqueous layer was pH adjusted to 10 with a 5N sodium hydroxide solution and extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated under reduced pressure. The residue (0.512 g, 1.29 mmol) was combined with anhydrous hydrazine (0.81 mL, 25.87 mmol) in i-BuOH (3 mL) in a sealed tube and heated with stirring at 100° C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford tert-butyl (3R,4S)-4-hydroxy-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.44 g, 86%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(CCc2ccccn2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(CCc3ccccn3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (39 mg, 0.33 mmol) described in Manufacturing Example 1-2-3 was added (4-(2-pyridin-2-yl-ethyl)-phenyl)-acetohydroximoyl chloride hydrochloride (310 mg, 1.0 mmol) described in Manufacturing Example 93-1-8 under nitrogen atmosphere at room temperature. Triethylamine (0.42 mL, 3.0 mmol) was then added dropwise, and stirred for 2 hours at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:7 then 4:6), and the resulting crude product was further purified by silica gel thin-layer chromatography (ethyl acetate) to obtain the title compound (21.2 mg, 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][S:18]2(=[O:24])=[O:23])=[N:11][C:10]=1[C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].ClC=[N+](C)C.[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl>[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:25]([C:10]2[N:11]=[C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][S:18]3(=[O:24])=[O:23])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])=[CH:37][CH:36]=1
Reactant: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)O)c(OCc2ccccc2)c1=O
Reactant: Nc1ccc(F)cc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)Nc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Reaction time: 0.25 h
Yield: 108.8 %

Procedure:
A solution of 5-benzyloxy-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid (0.200 g, 0.51 mmol) in dichloromethane (20 ml) was treated at 25° C. with (chloromethylene)dimethylammonium chloride (0.080 g, 0.62 mmol) and the resulting mixture was stirred for 15 min. Then a solution of 4-fluoroaniline (0.117 g, 1.06 mmol) and pyridine (0.1 ml, 1.2 mmol) in dichloromethane (2 ml) was added and the reaction mixture was stirred for another 45 min. The mixture was quenched by addition of ethyl acetate and pH 6 phosphate buffer. The organic phase was then washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 7:3) gave 0.270 g (88% yield) of the title amide as white crystals; mp 201–202° C.(ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65–1.69 and 2.35–2.7 (1H and 3H, 2 m, 2×CH2), 3.2–3.25 (1H, m, CH), 3.59–3.73 (2H, m, CH2), 3.68 (3H, s, NCH3), 3.99–4.07 (1H, m, CH), 5.47 (2H, AB system, JAB=10.8 Hz, Δν=49.8 Hz, OCH2), 6.93 (2H, m, aromatics), 7.22 (2H, m, aromatics), 7.39–7.52 (5H, m, aromatics) Anal. Calcd for C23H23FN4O5S: C, 56.78; H, 4.77; N, 11.52. Found: C, 56.83; H, 4.58; N, 11.53.
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]([CH3:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])C.[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24]>>[CH:17]([N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[N:25]([CH2:22][CH2:23][CH3:24])[C:26]1=[O:27])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Reactant: CCCN=C=O
Product: CCCn1c(=O)c2cnc3c(OC)cccc3c2n(C(C)C)c1=O
Yield: 35.1 %

Procedure:
1-Isopropyl-7-methoxy-3-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (23 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (60 mg, 0.20 mmol) and n-propyl isocyanate (1.0 mmol) following general procedure C. LCMS: m/z 328 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:19]=[C:20]1[C:25]2[S:26][CH:27]=[C:28]([S:29](Cl)(=[O:31])=[O:30])[C:24]=2[CH2:23][CH2:22][CH2:21]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH3:11])[S:29]([C:28]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20](=[O:19])[C:25]=3[S:26][CH:27]=2)(=[O:30])=[O:31])=[CH:6][CH:7]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a solution of [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (520 mg) and triethylamine (474 μL) in tetrahydrofuran was added a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (800 mg) in tetrahydrofuran. The solution was stirred on an ice bath for 30 minutes, and at room temperature for 30 minutes. The residue resulting from the removal of the solvent by evaporation was purified by NH silica gel column chromatography (hexane/ethyl acetate), and the title compound (834 mg) was obtained as a colorless candy-like substance.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 59.2 %

Procedure:
To a solution of 3-[3-(1-hydroxyethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.99 g, 0.0107 mol) in dry methylene chloride under a nitrogen atmosphere is added powdered 4 Å molecular sieves followed by pyridinium dichromate (4.85 g, 0.0129 mol). The resultant mixture is stirred 22 hours at room temperature, diluted with ether, filtered through silica gel and diatomaceous earth, and concentrated in vacuo to a solid. The solid is recrystallized from ethyl acetate:hexanes to afford he title compound as a white crystalline solid (2.34 g, 59.2%, mp 149° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][NH2:13]>>[CH3:12][NH:13][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: CN
Reactant: NS(=O)(=O)c1cnccc1Cl
Product: CNc1ccncc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
10 g of 4-chloropyridine-3-sulfonamide are dissolved in 100 cm3 of 40% aqueous methylamine solution and the solution is introduced into a sealed tube. The tube is placed at 150° C. for 18 hours. After cooling, the reaction mixture is concentrated under vacuum (rotary evaporator) to a volume of 30 cm3. The crystalline precipitate corresponding to the title compound is collected on a filter, washed with water and dried.
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[C:1]1([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[N:23][OH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Yield: 100.9 %

Procedure:
A solution of phenyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (60 mg, 0.19 mmol) and hydroxylamine hydrochloride (0.04 g, 0.58 mmol) in pyridine (2 mL) was refluxed for 1 h, concentrated in vacuo, treated with toluene (2 mL), concentrated in vacuo and the resulting solid dissolved in EtOAc (5 mL), washed with water (3 mL) and concentrated in vacuo to give the title compound (62 mg, 98%), a mixture of geometrical isomers, as an oily solid.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:25])[CH:16]([Br:33])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(OC)c1

Procedure:
AIBN (10 mg) was added to a solution of (3-Methoxy-phenyl)-acetic acid methyl ester (2 g, 11 mmol) in CCl4 (30 ml). The solution was then heated to reflux and NBS (2.3 g, 13 mmol) was added in portions. After complete addition the reaction mixture was refluxed for 4 h. After cooling, solid residue was filtered off and the filtrate concentrated to yield product Bromo-(3-methoxy-phenyl)-acetic acid methyl ester, that was washed repeatedly with pet ether.
Reaction SMILES: [F:1]/[C:2](/[S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])=[CH:3]\[CH2:4][OH:5].N1C=CC=CC=1.[CH:20](OC(=O)C)=[O:21]>O>[CH:20]([O:5][CH2:4]/[CH:3]=[C:2](\[F:1])/[S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])=[O:21]
Reactant: CCCCCCS(=O)/C(F)=C/CO
Reactant: CC(=O)OC=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCS(=O)/C(F)=C/COC=O

Procedure:
To a mixture of (E)-3-fluoro-3-hexylsulfinyl-2-propenol (0.21 g, 1.0 mmol) and 2 ml of pyridine cooled to -30° is added through syringe acetic-formic anhydride (0.4 ml). The mixture is allowed to warm to 10° over a period of 1 hour. It is then diluted with water, extracted with hexane, washed with aqueous 2N H2S04, then water, then aqueous NaHCO3, finally brine and is dried. The product is purified by prep. TLC to give (E)-3-fluoro-3-hexylsulfinyl-2-propenyl formate (cpd. 3, Table A).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][CH:27]=[C:26]([CH2:29][OH:30])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:26]5[CH:25]=[C:24]([C:23]([F:32])([F:22])[F:31])[S:28][CH:27]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Reactant: OCc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (800 mg), (5-(trifluoromethyl)-3-thienyl)methanol (972 mg), cesium carbonate (2.61 g) and DMF (8 ml) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH-water to give the title compound (258 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([CH:30]([CH2:29][CH2:28][NH2:27])[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:26])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(CCN)C(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OCc1ccccc1
Yield: 95 %

Procedure:
85 mmol of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan and 85 mmol of tert.-butyl γ-aminobutyrate are dissolved in 170 ml of acetone and 300 ml of pure chloroform. A solution of 17.7 g (86 mmol) of dicyclohexylcarbodiimide in 80 ml of chloroform is then added and the mixture is stirred at ordinary temperature until the condensation has ended. After evaporation, taking up with ethyl acetate and the customary treatment, 40 g of a crude product are obtained, which are purified by chromatography on a silica column, elution being carried out with a methylene chloride/acetone mixture. This gives 48% of a pure product showing a single spot in TLC on Kieselgel in the system chloroform 20/acetone 6, of Rf=0.45. The NMR spectrum is recorded in solution in CDCl3 : 8.4 ppm (s) (1H) --OH; 7.3 ppm (s) (5H) benzyl; 7.2 to 6.6 ppm (m) (4H) arom; 6.4 ppm (m) (1H) and 5.9 ppm (d) (1H) --NH; 5 ppm (s) (2H) CH2 --Ph; 4.4 ppm (m) (1H) CH(NH)--CO; 3.1 ppm (m) (4H) CH2 --CH(--NH)CO and NH CH2 ; 2.1 to 1.8 ppm (m) 4H: CH2 --CH2 ; 1.4 ppm (s) (9H) tert.-butyl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:21](=[S:24])[NH:22][NH2:23])[N:10]=1.[CH3:25][C:26](C)(C)C([O-])([O-])[O-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:21]2[S:24][C:25]([CH3:26])=[N:23][N:22]=2)[N:10]=1
Reactant: CC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Reactant: CC(C)(C)C([O-])([O-])[O-]
Product: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(C)c2ccccc2)s1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
5-(2,5-difluorophenyl)-2-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide (0.268 g, 0.735 mmol) was weighed into a 25 mL 1 neck flask, and suspended in 9.0 mL of trimethylorthoacetate (0.088 g, 0.74 mmol). P-toluenesulfonic acid hydrate (0.0028 g, 0.015 mmol) was then added, and the reaction heated to 80° C. for 1 hour. The reaction was then concentrated in vacuo, and then purified by flash column chromatography (20-50% ethyl acetate/hexanes) yielding 0.201 g, 70% of the desired product as a white solid. MS ESI (+) m/z 389 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.08 (m, 2H), 2.59 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:23]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:33])[C:3]1=[O:12]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 7 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 6 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether/THF mixture. m=9.4 g. M.p.=229° C.