Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1S(N)(=O)=O.[Cl:15]C1C=CC(O)=CC=1.C1(=O)OCCO1.OCCOC1C=CC(Cl)=CC=1.C(Cl)(Cl)=O.S(Cl)(Cl)=O>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:15])=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Agent: O=C(Cl)Cl
Agent: OCCOc1ccc(Cl)cc1
Solvent: O=C1OCCO1
Solvent: O=S(Cl)Cl
Product: ClCCOc1ccc(Cl)cc1

Procedure:
A process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide of formula I ##STR15## which process comprises the etherification of 4-chlorophenol of formula II ##STR16## with ethylene carbonate at a temperature between +130° C. and +150° C. and chlorination of the resulting 4-(2-hydroxyethoxy)-chlorobenzene of formula III ##STR17## with phosgene or thionyl chloride at a temperature between +70° C. and +90° C. to give 4-(2-chloroethoxy)-chlorobenzene of formula IV ##STR18## which is converted with chlorosulfonic acid, at a temperature between -20° C. and +60° C. and subsequent neutralizaion with sodium hydroxide to the sulfonic acid sodium salt of formula V ##STR19## which is hydrogenated at a temperature between +20° C. and +70° C. to the compound of formula VI ##STR20## which is subsequently reacted with phosgene at a temperature between +60° C. and +120° C. to the sulfonic acid chloride of formula VII ##STR21## which is reacted with ammonia at a temperature between 0° C. and +100° C. to the sulfonamide of formula I.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=[O:26]>CCOCC>[Br:21][C:22]1[CH:23]=[C:24]([CH:25]([C:7]2[CH:2]=[CH:3][C:4]([F:15])=[CH:5][C:6]=2[O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[OH:26])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccc(F)c(Br)c1)c1ccc(F)cc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.0 g, 17 mmol) in ether (40 mL) at −78° C. was added a solution of n-butyllithium (6.9 mL, 2.5 M, 17 mmol). The reaction mixture was stirred for 15 minutes and was added a solution of 3-bromo-4-fluorobenzaldehyde (3.5 g, 17 mmol) in ether (10 mL). The reaction was stirred at −78° C. for 2 h, then quenched with sat. NH4Cl and warmed to room temperature. The ether layer was separated and dried over magnesium sulfate, filtered and concentrated to yield (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol as an amber oil (6.5 g, 92% yield). The product was used in the next step without further purification. To a solution of (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (29.5 g, 71.3 mmol) in dichloromethane (600 mL) was added MnO2 (30 g, 345 mmol). The reaction mixture was stirred for 6 h, then another 30 g of MnO2 was added and the reaction continued to stir overnight. The MnO2 addition was repeated twice and the reaction was stirred for a total of 48 h when the reaction was complete. The suspension was filtered through a pad of celite, the filtrate vas concentrated and the residue was purified by ISCO flash chromatography to yield (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone as a yellow oil (60% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, d, J=6.59 Hz), 7.76 (1H, ddd, J=6.48, 4.50, 2.20 Hz), 7.38-7.44 (2H, m), 7.21-7.29 (2H, m), 6.09-5.83 (1 H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Reaction time: 2 h

Procedure:
In a 250 ml 3-neck round bottom flask with mechanical stirrer, septum and drying tube was added 3,4-difluoronitrobenzene (1) (12.91 g, 81.1 mmol), methanol (60 ml) and morpholine (15.93 g, 16 ml, 183 mmol). The clear solution was heated at reflux with stirring for 2 hours. The reaction mixture containing yellow crystals was cooled in an ice bath for 1 hour with stirring. The crystals were collected by filtration and dried in vacuo (1 mm) at room temperature for 3 hours (16.99 g, 93%). Homogenous by TLC (silica gel, CHCl3) Rf=0.54 (yellow spot) 1H NMR (500 MHz, CDCl3) δ 8.00 (ddd, 1H, J=9 Hz, J=2.6 Hz, J=1 Hz), 7.92 (dd, 1H, J=13.1 Hz, J=2.5 Hz,), 6.92 (dd, 1H, J=8.8 Hz, J=8.8 Hz), 3.86 (dd, 4H, J=4.7 Hz, J=4.7 Hz), 3.28 (dd, 4H, J=4.7 Hz, J=4.7 Hz). LCMS (Method A) 0.79 min m/e 227.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(COc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A mixture of 3,5-difluorophenol (1 1.0 g, 84.6 mmol), 4-fluorobenzylbromide (16.5 g, 84.6 mmol) and potassium carbonate (12.7 g, 92.2 mmol) in acetone (50 mL) was heated under reflux for 6 h. After cooling to room temperature, the mixture was filtered and the filtrate evaporated. The residue was dissolved in diethyl ether, washed with sodium cabonate (saturated solution), dried over sodium sulfate, filtered and evaporated to leave the title compound (20.8 g, 96%) as a light yellow liquid. MS: m/e=238.1 (M+).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][C:28]([O:34]CC4C=CC(OC)=CC=4)=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=3)=[CH:21][C:20]=2[F:44])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28](=[O:34])[NH:27][CH:26]=3)=[CH:21][C:20]=2[F:44])[CH:9]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=1
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a mixture of N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.048 mmol) in DCM (5 mL) was added TFA (7.42 μL, 0.096 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The mixture was concentrated to give crude product, which was purified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mLl/min; Gradient Profile Description: 30-66 (B %)) to give N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (5.12 mg, 10.01 μmol, 20.8% yield): 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br. s., 1H), 11.33 (s, 1H), 10.85 (s, 1H), 8.69-8.57 (m, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.47 (d, J=11.7 Hz, 1H), 7.42-7.27 (m, 3H), 7.12 (br. s., 1H), 4.03 (d, J=6.8 Hz, 2H), 3.79 (s, 2H), 1.31 (t, J=6.8 Hz, 3H). ES-LCMS m/z 503 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11])([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:11][C:30]1=[O:32])([O-:3])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1CNCCC(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OC(c2ccccc2)CCN1Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.9 %

Procedure:
3-(2-Nitrobenzylamino)-1-phenylpropanol (3.00 g, 10.5 mmol), triethylamine (4.24 g, 42.0 mmol) were dissolved in toluene (50 ml). Under ice cooled condition, a solution in which triphosgene (1.24 g, 4.19 mmol) was dissolved in toluene (5 ml) was slowly added dropwise thereto and heated to reflux for six hours after stirred at room temperature for one hour. The reaction mixture was poured into water and, after standing to cool, extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid water and then dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was washed with a mixture of ether-ethyl acetate (1:2) to obtain 3-(2-nitrobenzyl)-6-phenyl-[1,3]-oxazinan-2-one (1.70 g).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:16]([C:20]1[N:21]=[CH:22][N:23]2[CH:27]=[CH:26][S:25][C:24]=12)(=[O:19])(=[O:18])[NH2:17].C(OCC)(=O)C>CN(C=O)C>[Si:1]([NH:17][S:16]([C:20]1[N:21]=[CH:22][N:23]2[CH:27]=[CH:26][S:25][C:24]=12)(=[O:19])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NS(=O)(=O)c1ncn2ccsc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyldimethylsilyl chloride (0.30 g) and 0.33 ml of triethylamine were added to a solution of 0.20 g of 7-sulfamoylimidazo[5,1-b]thiazole in 5 ml of DMF. The mixture was stirred at room temperature for one hr. Ethyl acetate was added to the reaction mixture, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 0.34 of 7-(t-butyldimethylsilylsulfamoyl)imidazo[5,1-b]thiazole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[O:15][CH2:16][CH2:17][OH:18].O>C(Cl)Cl>[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[O:15][CH2:16][CH:17]=[O:18]
Reactant: Cc1ccc(OCCO)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(OCC=O)cc1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of oxalyl chloride (0.76 ml; 9.000 mmol) in anhydrous DCM (40 ml) was treated dropwise with a solution of dimethyl sulfoxide (1.40 ml; 18.000 mmol) in anhydrous DCM (6 ml). After 10 min., a solution of 2-(3,4-dimethyl-phenoxy)-ethanol (0.997 g; 6.000 mmol) in DCM (12 ml) was added dropwise, and the reaction mixture was further stirred at −78° C. for 30 min. TEA (4.17 ml; 30.000 mmol) was then added dropwise, and after 10 min. the resulting mixture was allowed to warm-up to 0° C. before a mixture of water (4 ml) and DCM (40 ml) was added. The aq. layer was extracted with DCM (2×40 ml), and the mixed organic layers were then washed with aq. sat. NaHCO3 (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give (3,4-dimethyl-phenoxy)-acetaldehyde as a yellow oil (0.985 g; 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[NH:19][C:18](=[O:32])[N:17]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:41](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:41])[C:18](=[O:32])[N:17]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2CC(=O)OCC
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.9 %

Procedure:
4-[3-Ethoxycarbonylmethyl-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (60 mg) was dissolved in N,N-dimethylformamide (2 ml), methyl iodide (17 μl) and potassium carbonate (17 mg) were added to the solution, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 48 mg of the title compound.
Reaction SMILES: ClC1C(CO)=CC=CN=1.[Br:10][CH2:11][C:12]1[C:13]([Cl:20])=[N:14][C:15](Cl)=[C:16](F)[CH:17]=1>>[Br:10][CH2:11][C:12]1[C:13]([Cl:20])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Agent: OCc1cccnc1Cl
Product: Clc1ncccc1CBr
Yield: 78 %

Procedure:
Compound 12B (0.22 g, 78%) was prepared from 12A (0.20 g, 1.39 mmol) using a procedure similar to the synthesis of 1B. HPLC Rt=1.94 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]=[CH:16][NH:17][C:18](=O)[C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[Cl:24][C:18]1[C:19]2[N:20]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1OC
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1OC
Yield: 76.9 %

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (150 mg, 0.53 mmol) in toluene (30 ml) was added phosphorus oxychloride (148 μl, 1.59 mmol) and 2,6-lutidine (185 μl, 1.59 mmol). The reaction mixture was refluxed overnight until a black solution was obtained. After evaporation to dryness, the residue was redissolved in ethyl acetate and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography, the mobile phase being an ethyl acetate/hexane mixture, in a ratio gradually ranging from 2:8 to 3:7, resulting in the pure title compound (123 mg, yield 77%) which was characterised by its mass spectrum as follows: MS (m/z): 302, 304 ([M+H]+, 100).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:14]([CH3:13])[N:15]=[C:10]([NH2:11])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1cccc(Br)n1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(N)cc1-c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 3-(6-bromo-2-pyridyl)-3-oxo-propanenitrile (1.71 g, 7.6 mmol, Preparation A.1) in ethanol (50 mL) was added methyl hydrazine (1.20 mL, 22.8 mmol). The resulting mixture was stirred for about 30 min at rt and then heated under reflux for about 4 h. After cooling to rt the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:2) to give 3-(6-bromo-2-pyridyl)-2-methyl-pyrazol-5-amine (1.56 g, 6.2 mmol, 81%) as an off white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.57 (2 H, br s); 3.75 (3 H, s); 5.90 (1 H, s); 7.34 (1 H, d, J=8 Hz); 7.52 (1 H, t, J=8 Hz); 7.82 (1 H, d, J=8 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[CH2:17]([S:20]([NH-:23])(=[O:22])=[O:21])[CH2:18][CH3:19].Cl>CS(C)=O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: CCCS([NH-])(=O)=O
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Reaction time: 14 h
Yield: 78.3 %

Procedure:
To a solution of 4,6-dichloro-5-(p-tolyl)pyrimidine (Example 1b; 717 mg) in DMSO (5 ml) and n-propanesulfonamide potassium salt (1016 mg) was added. Stirring was continued for 14 h at rt. The solution was poured onto ice/water and acidified by 2 N HCl to pH 3-4. The precipitate was filtered off and washed with water and diethylether to give n-propanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (765 mg) as a white powder. LC-MS: tR: 4.44, [M+H]+: 326.13.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@@H:29]3[CH2:32][C@H:31]([C:33](N(OC)C)=[O:34])[CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:40])[CH:10]=1)#[N:2].[CH3:41][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[C:33]([C@@H:31]1[CH2:32][C@H:29]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:40])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:30]1)(=[O:34])[CH3:41]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](C(=O)N(C)OC)C2)c2nc(C)nn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](C(C)=O)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}-N-methoxy-N-methylcyclobutanecarboxamide (3.65 g) in tetrahydrofuran (10 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (10 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50 (volume ratio)] to give the title compound as a colorless amorphous compound (2.83 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.[Br:16][CH2:17][C:18]1C=CC=C2C=1CC(C)=C2.CC1C(CC2C=CC=C3C=2CC(C)=C3)C2C(C=1)=CC=CC=2>CCOCC.C1COCC1.O>[Br:16][CH2:17][CH2:18][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][C:2]([CH3:1])=[CH:10]2
Reactant: CC1=Cc2cccc(CBr)c2C1
Reactant: CC1=Cc2ccccc2C1
Agent: CC1=Cc2cccc(CC3C(C)=Cc4ccccc43)c2C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=Cc2cccc(CCBr)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.30 g (10 mmol) of 2-methyl-1H-indene in 90 ml of ether 4.0 ml of 2.5 M (10 mmol) n-BuLi in hexanes was added at 0° C. This mixture was stirred for 2 h at room temperature, and then a solution of 2.23 g (10 mmol) of 7-(bromomethyl)-2-methyl-1H-indene in 15 ml of THF was added dropwise at vigorous stirring for 10 min at −80° C. The resulting mixture was stirred for 12 h at room temperature, and then 1 ml of water was added. This mixture was evaporated to dryness, and 100 ml of water was added. The crude product was extracted with 3×50 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using a short column with Silica Gel 60 (40-63 um, d 60 mm, l 70 mm; eluent: hexanes. Yield 2.50 g (92%) of 2-methyl-1-[(2-methyl-1H-inden-7-yl)methyl]-1H-indene.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CBr
Reactant: SCCc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CSCCc1ccc2c(c1)OCO2
Yield: 93.2 %

Procedure:
100 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75.1 g of bromoacetic acid were dissolved in 1 l of ethanol. A solution of 44 g of sodium hydroxide in 125 ml of water and then 2 l of ethanol were added thereto. The mixture was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure. 2.5 l of water was added thereto. The mixture was made alkaline with a 1N sodium hydroxide solution, washed with 35% hydrochloric acid, extracted with ethyl acetate, washed with water four times and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 121 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in the form of a faint yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:23][C:24]1[C:25](I)=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([CH:30]=1)[NH2:29]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[C:25]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[Cl:1])=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([CH:30]=1)[NH2:29]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of [2-chloro-4-(trifluoromethyl)phenyl]boronic acid (4.5 g, 20.06 mmol) in water (30 mL) and dioxane (200 mL) was added K3PO4 (5.7 g, 26.85 mmol), 5-chloro-4-iodo-2-nitroaniline (4 g, 13.40 mmol) and Pd(PPh3)4 (800 mg, 0.69 mmol) maintained with an inert atmosphere of nitrogen and stirred overnight at 95° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-4-[2-chloro-4-(trifluoromethyl)phenyl]-2-nitroaniline as a yellow solid (3 g, 32%). Next, to a solution of 5-chloro-4-[2-chloro-4-(trifluoromethyl)phenyl]-2-nitroaniline (3 g, 8.54 mmol) in ethanol (80 mL) was added hydrochloric acid (2 mL) and Zn powder (3.4 g, 52.3 mmol) in portions. The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum and dissolved in water (100 ml) adjusted to pH 8 with sodium carbonate and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was purified by a silica gel column with 20% ethyl acetate in petroleum ether to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (1 g, 36%). Finally, the solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in TFA (5 mL) and hydrochloric acid (conc, 1 mL) was stirred overnight at 80° C. and quenched with water (100 ml), adjusted pH to 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (107.8 mg, 87%).