Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]1>>[CH:1]1([C:8]2([OH:14])[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: Br[Mg]C1CCCC1
Product: OC1(C2CCCC2)C=CCCC1
Yield: 92 %

Procedure:
According to Example 2, cyclopentylmagnesium bromide (1.00 M in THF, 2.10 mL; 2.10 mmol; 1.05 equiv) was reacted with cyclohexenone (192 mg; 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). Gel filtration (silica; pentane:Et2O 9:1, 0.5 vol-% NEt3) afforded 1-Cyclopentyl-cyclohex-2-enol (7) as colorless oil (306 mg, 93%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[OH-].[Na+].C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCC2(CC1)OCCO2
Yield: 87.2 %

Procedure:
A solution of ethyl 1,4-dioxaspiro[4,5]decane-8-acetate (50.0 g) in 50 mL of 4.8N sodium hydroxide solution and 400 mL of ethanol is refluxed under nitrogen for 2 hours. The mixture is concentrated in vacuo to remove the ethanol. The residue is acidified with a saturated sodium biphosphate solution and the mixture is extracted with ethyl acetate (2×300 mL). The organic extract is dried over magnesium sulfate, and evaporated in vacuo to give an oily solid which is triturated with hexane and filtered to give 38.25 g of the title compound as a white solid; mp 110°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([C:18]([O:20][CH3:21])=[O:19])[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30]Br>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[NH:10][C:9]1([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C1(c2c(F)cccc2F)N=c2ccccc2=N1
Reactant: Fc1cccc(F)c1CBr
Product: COC(=O)C1(c2c(F)cccc2F)Nc2ccccc2N1Cc1c(F)cccc1F
Yield: 76 %

Procedure:
Methyl 2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4004) (16.15 g, 56.0 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (14.67 g, 70.86 mmol, 125 M %). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2, and recrystallization from diethylether, yielding white crystals of methyl 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4005) (17.63 g, 42.55 mmol, 76% yield). M.p. 185-186° C. 1H-NMR (200 MHz, CD2Cl2) δ 7.94 (dd, J=1.1, 7.6 Hz, 1H, H5), 7.72 (dd, J=1.1, 8.2 Hz, 1H, H7), 7.56 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.2 Hz, 1H, H6), 7.26 (m, 1H, H4″),7.09 (m,2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.39 (s, 2H, CH2PhF2), 3.95 (s, 3H, CO2CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([O:30][C:31](=O)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[CH3:48])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH:12][C:31]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=1[NH:40][C:41]1[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=1[CH3:48])=[O:30])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc(F)c1F
Reactant: CN(CCON)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCN(C)C(=O)OC(C)(C)C)ccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
To a solution of (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (0.63 g, 3.31 mmol) and diisopropylethylamine (0.6 mL, 3.44 mmol) in dimethylformamide (10 mL) was added 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.66 g, 2.99 mmol). The resultant reaction mixture was stirred 5 h at ambient temperature and concentrated under reduced pressure. The residue was diluted with ether (100 mL), washed with water (2×25 mL) and brine (2×25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with dichloromethane afforded [2-({1-[3,4-difluoro-2-(4iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.05 g, 62%) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.85 and 11.80 (br s, 1H), 8.49 (br s, 1H), 7.50 (s, 1H), 7.39 (m, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.14 (m, 1H), 6.46 (dd, J=7.8, 5.9 Hz, 1H), 3.85 (br s, 2H), 3.35 (br s, 2H), 2.79 (br s, 3H), 2.21 (s, 3H), 1.36 and 1.33 (s, 9H); 19F NMR (376 MHz, DMSO-d6) δ −132.9, −143.3 (d, J=17.7 Hz); MS (APCI+)=562.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[NH:14]2)=[CH:9][CH:8]=1.O.Cl>C(S)C>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[NH:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(O)cc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution of aluminum chloride (2.40 g, 18.0 mmol) in ethanethiol (20 mL) was cooled to 0° C. and (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 2.00 g, 6.7 mmol) was added. The flask was capped and the reaction mixture was stirred at 0° C. for about 20 min and then at room temperature for 2 h. The solution was added to water (100 mL) with vigorous stirring and the resulting mixture was acidified to pH 1-2 with 1 M HCl. The resulting solid was filtered off, washed with water and then hexanes, air-dried and then dried under vacuum to give (4S,7R)-2-(4-hydroxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.63 g, 85%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:11]2[C:12](=O)[NH:13][CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([C:7]1[C:11]2[C:12](=[S:19])[NH:13][CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCOC(=O)c1c[nH]c2c1C(=O)NCCC2
Solvent: c1ccncc1
Product: CCCOC(=O)c1c[nH]c2c1C(=S)NCCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of compound (500 mg) from Step 1 and P4S10 (2.0 g) in 20 mL of pyridine is heated at 80° C. with stirring overnight. It is cooled and evaporated under vacuum, then diluted with water and stirred. The insoluble material is filtered and the mother liquid is extracted with CH2Cl2/EtOAc (1:4). The combined extract is washed with brine, dried and concentrated to give 120 mg of 4-thioxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acid propyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccnc(C)c1
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(C)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
2,4-Dimethylpyridine (40 g, 0.37 mol) was stirred with 30% hydrogen peroxide (170 ml) in glacial acetic acid (400 ml) in an oil bath (80-90° C.) for 24 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, 1) ether, 2) methanol:chloroform (8:92)) to afford 45 g (98%) of 2,4-dimethyl-pyridine 1-oxide as an oil. 1H NMR (200 MHz, DMSO-d6) δ 2.02 (3H, s), 2.18 (3H, s), 6.69 (1H, d, J=6.5 Hz), 6.82 (1H, s), 7.84 (1H, d, J=6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)O.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([Cl:23])[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2oc(C(O)C3CCCCC3)c(Br)c2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2oc(C(Cl)C3CCCCC3)c(Br)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution (20 mL) of (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanol (1.82 g) synthesized above in toluene was added thionyl chloride (469 μL) and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.73 g, 90%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][NH2:14])[N:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH:23]([C:27](=O)[CH3:28])[C:24](=O)[CH3:25])=[CH:18][CH:17]=1>C(O)CC>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][C:23]2[C:24]([CH3:25])=[N:14][N:13]([C:9]3[N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:12]=[CH:11][N:10]=3)[C:27]=2[CH3:28])=[CH:20][CH:21]=1
Reactant: NNc1ncnc(-c2ccccn2)n1
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Solvent: CCCO
Product: Cc1nn(-c2ncnc(-c3ccccn3)n2)c(C)c1Sc1ccc(Cl)cc1
Temperature: 95 °C
Yield: 8 %

Procedure:
A stirred suspension of the product of step 3 (0.333 g, 1.77 mmol) and 3-(4-chloro-phenylsulfanyl)-pentane-2,4-dione (0.473 g, 1.95 mmol) in n-propanol was heated at 95° C. overnight. The reaction solution was concentrated directly onto silica and flash chromatographed (methylene chloride/methanol) to afford a dirty yellow solid. This material was further purified by trituration with diethyl ether to afford 0.056 g (8%) of product as a white solid: 1H NMR (DMSO-d6) δ 9.44 (s, 1H), 8.94–8.77 (m, 1H), 8.68–8.43 (m, 1H), 8.18–7.96 (m, 1H), 7.77–7.57 (m, 1H), 7.45–7.24 (m, 2H), 7.20–6.98 (m, 2H), 2.83 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[N:6][C:5]=2[N:4]([CH3:17])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:17][N:4]1[C:5]2[N:6]=[CH:7][N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:9](=[O:11])[C:10]=2[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:3]1
Reactant: Cn1cc(I)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccccn2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 90 °C
Yield: 21.4 %

Procedure:
A mixture of 5-iodo-7-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (2 g, 5.60 mmol) and 2-(tributylstannyl)pyridine (2.2 ml, 6.79 mmol) in toluene (20 ml) was degassed. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.324 g, 0.280 mmol). The resulting mixture was heated at 90° C. for 18 h. The reaction mixture was cooled and placed directly onto a silica column and purified by flash chromatography (0-100% ethyl acetate/cyclohexane) to give the title compound (0.37 g, 21%). LCMS RT=0.63 min, M+H+=309.1
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[CH3:27]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:29]5[C@H:28]([CH2:26][CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)nn1
Yield: 6.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and (R)-4-ethyloxazolidin-2-one (35 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (8 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:15])[CH:5]=[C:4]1C(O)=O)[CH3:2].[BH4-].[Na+]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:15])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCn1c(C(=O)O)cc(=O)c2cc(F)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCC(=O)c2cc(F)c(F)cc21
Yield: 65.9 %

Procedure:
1-Ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline carboxylic acid(20 g) and sodium borohydride(12 g) were reacted in the same method as described in Preparation 1-A to give the bright-yellow above-indicated compound(11 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:18]=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO[CH:32]1[CH2:36][CH2:35][CH:34](OC)O1.C(O)(=O)C>O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[C:19]([S:21]([N:22]3[CH:32]=[CH:36][CH:35]=[CH:34]3)(=[O:23])=[O:24])[CH:18]=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)n2cccc2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 88.6 %

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide (compound of Example 87(2); 442 mg, 1 mmol), 2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (436.5 mg, 88.6%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11]2[NH:12][N:13]=[CH:14][N:15]=2)[CH:5]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].O>C(O)(=O)C>[Cl:18][CH2:19][C:20]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][C:6]=1[C:11]1[NH:12][N:13]=[CH:14][N:15]=1)=[O:21]
Reactant: Nc1ccc(OC(F)(F)F)cc1-c1ncn[nH]1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)Nc1ccc(OC(F)(F)F)cc1-c1ncn[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a cooled solution of 4-trifluoromethoxy-2-(2H-[1,2,4]triazol-3-yl)-phenylamine (3.00 g, 12.3 mmol) in acetic acid (62 mL) was added dropwise chloroacetyl chloride (1.96 mL, 24.6 mmol). The resulting light brown suspension was stirred for 20 h at ambient temperature and was then poured into water (246 mL) and stirred for another 3 h. The precipitate was filtered off and washed with water. Drying in vacuo afforded the title compound (3.22 g, 82%) as an off-white solid. MS: m/e=323.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(=O)(=O)(O)[OH:18]>C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1)(=[O:18])[CH2:2][CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of chromium trioxide (6.5 g) in acetic anhydride (29 ml) was added dropwise to a stirred, cooled solution of 6-(4-n-propylphenyl)pyridazin-3(2H)-one (5.11 g) in acetic anhydride (25 ml) containing concentrated sulphuric acid (5 ml). The reaction mixture was stirred at room temperature for 16 hours and then poured into crushed ice (250 ml) to afford 6-(4-propionylphenyl)pyridazin-3(2H)-one (0.78 g), m.p. 202°-205° C.
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.Cl[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[C:18]#[N:19])=[CH:13][CH:12]=1
Reactant: Clc1nccs1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(c1ccc(Cl)cc1)c1nccs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
At 0°-5°C add a suspension of 28.5 g. of sodamide in 300 ml. of toluene to a stirred solution containing 50 g. of p-chlorphenylacetonitrile and 40 g. of 2-chlorothiazole in 400 ml. of toluene. Maintain the temperature at 20°C for 2 hrs. and finally at 60°C. for 1 hr. Consecutively add 100 ml. of water and 35 ml. of acetic acid at 0°-10°C and filter the resulting mixture. Separate the toluene layer, concentrate in vacuo and distill the residue to give α-(p-chlorphenyl)-2-thiazolylacetonitrile as a mobile yellow oil, b.p. 155°-160°C/1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([CH3:7])=[CH2:6].[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([CH3:7])[CH3:6])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C=C(C)c1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)c1ccc(Cl)c(Cl)c1
Yield: 89.2 %

Procedure:
3,4-dichloro-α-methylstyrene (21.9 g, 118 mmole), approximately 100 mg platinum oxide, and 125 ml absolute ethanol were shaken on a Paar Hydrogenator for four hours, at an initial hydrogen pressure of 50 psi. The material was then filtered through celite, and the solvent removed by distillation at atmospheric pressure. The resulting residual material was distilled at reduced pressure to produce 19.9 g (95% yield) of 3,4-dichlorocumene, bp 123°-126° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14]([S:19][CH2:20][C:21]([O:23]C)=[O:22])=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CSc1nccnc1-c1ccc(C#N)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(-c2nccnc2SCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
A mixture of methyl 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetate (0.125 g, 0.37 mmol), aqueous sodium hydroxide solution (1M, 0.5 mL) and methanol (1 mL) was stirred at room temperature for 12 hours. Methanol was removed and the mixture washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to dryness. Solid residue was recrystallized from ethyl acetate and hexanes to yield 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetic acid (0.102 g, 86%).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13]([S:16][CH3:17])=[N:14][N:15]=[C:3]12.ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13]([S:16]([CH3:17])=[O:26])=[N:14][N:15]=[C:3]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1c2ccccc2C=Cn2c(SC)nnc21
Product: C=C1c2ccccc2C=Cn2c1nnc2S(C)=O

Procedure:
By a procedure similar to that of Example 17, the reaction of 11-methylene-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine with m-chloroperbenzoic acid gave 11-methylene-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate yielded colorless prisms, m.p. 140°-142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([O:21][C@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:40])[F:41])=[C:34]([O:42][CH2:43][CH:44]3[CH2:45][CH2:46]3)[CH:33]=1)[CH2:29][C:28]1[C:27]([Cl:47])=[CH:26][N+:25]([O-:48])=[CH:24][C:23]=1[Cl:22])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1ccc2cc(OCc3ccccc3)ccc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cn1ccc2cc(OCc3ccccc3)ccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
To a mixture of 2-(5-(benzyloxy)-1H-indol-1-yl)acetic acid (164 mg, 0.583 mmol) in DCM (20 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (245 mg, 0.583 mmol), EDC (335 mg, 1.749 mmol) and DMAP (35.6 mg, 0.291 mmol) were added, and the reaction was stirred at room temperature for 5 hours. The organic solution was washed with NaHCO3 sat. sol. and 1N HCl, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH from 99.5:0.5 to 98.5:1.5) affording (S)-4-(2-(2-(5-(benzyloxy)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (319 mg, 0.467 mmol, 80% yield). MS/ESI+ 683.0 [MH]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[CH3:20][N:21](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C#N)cc2C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 73) (2.67 g, 8.14 mmol), zinc cyanide (1.715 g, 16.27 mmol) and tetakis(triphenylphosphine)palladium(0) (1.410 g, 1.220 mmol) in DMF (30 ml) was heated at 80° C. overnight. Additional tetakis(triphenylphosphine)palladium(0) (700 mg) was added and the yellow suspension heated at 80° C. for a further 5 hrs. The cooled reaction mixture was diluted with EtOAc/water, separated, and organics dried over anhydrous magnesium sulphate and evaporated. The crude was purified by flash chromatography eluting with EtOAc/iso-hexane 1:9. The combined fractions were evaporated to give the title compound (2.01 g) as a yellow solid. 6H (CDCl3, 400 MHz): 1.42 (9H, br.s), 3.81 (2H, t), 4.09 (2H, m), 4.43 (1H, s), 4.51 (1H, s), 7.09 (1H, m), 7.47-7.59 (2H, m).