Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:43][C:44]([F:74])([F:73])[C:45]1[CH:46]=[C:47]([C:55]([CH3:72])([CH3:71])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][NH:61][CH2:60]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>C1COCC1>[F:53][C:51]([F:52])([F:54])[C:49]1[CH:48]=[C:47]([C:55]([CH3:71])([CH3:72])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][N:61]([C:6]([C@@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:60]2)=[O:57])[CH:46]=[C:45]([C:44]([F:43])([F:73])[F:74])[CH:50]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)[C@@H]2CCCO2)C[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 21.3 %

Procedure:
To a stirred solution of (S)-tetrahydro-furan-2-carboxylic acid (described in J. Med. Chem., 1995, 38(15, 2830) (5.0 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 5.1 mg (25%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
Part A: To a solution of oxalyl chloride (1.3 mL, 15 mmol) in 20 mL of dichloromethane at −60° C. was added methyl sulfoxide dropwise over period of 10 min. After stirring at −60° C., a solution of 1,1-dimethylethyl 3-hydroxypyrrolidine-1-carboxylate (1.87 g, 10 mmol) in 20 mL of dichloromethane was added over 20 min. Then, diisopropylethylamine (8.8 mL, 50 mmol) was added over 5 min. The resulting mixture was stirred at −60° C. for 25 min, and at room temperature for 30 min. The reaction was diluted with dichloromethane (100 mL). The organic layer was washed sequentially with saturated sodium bisulfate solution (2×), saturated sodium bicarbonate solution, water, and brine; dried over sodium sulfate; and concentrated to afford 1.8 g (97%) of 1,1-dimethylethyl 3-oxo-pyrrolidine-1-carboxylate: 1H-NMR (CDCl3) δ 3.75 (4H, m), 2.58 (2H, t, J=7.8 Hz), 1.49 (9H, s).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][CH2:13][C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cnc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
(2-Phenylpyrimidin-5-yl)methanol (1.75 g) synthesized in Reference Example 30 was dissolved in dichloromethane (20 mL) and, after ice-cooling, thionyl chloride (1.45 g) was added thereto, and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (1.83 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)CCc1ccc(O)c(F)c1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 85.6 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 8 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
5-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-chlorosalicylate (147 mg, yield 37%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[Cl:14])[N:4]([CH3:15])[N:3]=1.[I:16]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([I:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[Cl:14])[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(Br)cc1-c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(Br)c(I)c1-c1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-bromo-5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazole (i.e. the product of Step C) (620 mg, 2.14 mmol) in N,N-dimethylformamide (8 mL) at 60° C. was added N-iodosuccinimide (963 mg, 4.28 mmol). The reaction mixture was stirred at 60° C. for 3 h, and then diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The material was purified by silica gel chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a pale yellow solid (515 mg) melting at 139-141° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12.C(N(CC)C(C)C)(C)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[N:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12
Reactant: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)C2(C)C
Yield: 38 %

Procedure:
15 g of tert-Butyl 3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0° C. under Ar atmosphere, first with N,N-diisopropylethylamine (50 ml) and then with ClCO2Et (4.65 ml, 1 eq.) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 l), washed with water and then with brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate as the major compound in 38% yield, together with 5.7 g of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate in 30% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15]([NH2:17])=[O:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:6][C:5]2=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[C:12](=[C:13]([C:15]([NH2:17])=[O:16])[CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])[CH2:6][C:5]3=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c3c([nH]c12)CCC(C(=O)N1CCOCC1)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4c(c3c2)CC(C(=O)N2CCOCC2)CC4)cc1
Temperature: 120 °C
Yield: 33.8 %

Procedure:
A suspension of 6-bromo-3-(morpholine-4-carbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (50 mg, 0.123 mmol), 4-methoxyphenylboronic acid (37.4 mg, 0.246 mmol), K2CO3 (42.5 mg, 0.308 mmol), and PdCl2(dppf)-CH2C12 adduct (10.05 mg, 0.012 mmol) in dioxane (3 mL) was sealed in a microwave vial and it was heated in an oil-bath at 120° C. for 16 h. The reaction mixture was concentrated and the crude was purified by preparative HPLC to give 18 mg of 6-(4-methoxyphenyl)-3-(morpholine-4-carbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as light brown solid. MS (ESI) m/z 434.2 (M+H). 1H NMR (methanol-d4) d ppm 7.64-7.73 (m, 2H) 7.52 (d, J=8.8 Hz, 2H) 6.89 (d, J=8.8 Hz, 2H) 3.73 (s, 3H) 3.52-3.67 (m, 8H) 3.00-3.12 (m, 1H) 2.70-2.89 (m, 4H) 1.83-2.09 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1.S(Cl)(Cl)(=O)=O>O1CCCC1>[C:12]1([C:11]2[N:10]=[C:9]([S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[N:8]([CH:33]3[CH2:37][CH2:36][CH2:35][O:34]3)[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClC1CCCO1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)n1C1CCCO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 1.8 g (0.005 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole and 5 g (0.05 mole) triethylamine in 20 ml tetrahydrofuran, was added dropwise at room temperature a solution of 2-chlorotetrahydrofuran, which had been prepared by adding 2.4 g (0.018 mole) of sulfuryl chloride to 30 ml tetrahydrofuran and waiting until the exothermic reaction mixture had returned to room temperature. The reaction mixture was stirred at room temperature for four days, then poured into ice water containing excess sodium bicarbonate. The aqueous mixture was extracted with methylene chloride, which was dried and concentrated. The crystalline residue was purified by chromatography on silica gel, eluting with toluene, to give 1.6 g of product, mp 145°-6° (from methylcyclohexane).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>ClCCl>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])([CH3:17])[CH3:18])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(N)c1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC(C)(C)c1ccc(OCc2ccccc2)cc1

Procedure:
1-(4-Benzyloxyphenyl)-1-methylethylamine hydrochloride (25.0 g) was treated with acryloyl chloride (8.43 ml) in dichloromethane (250 ml) containing triethylamine (14.4 ml) to give N-[1-(4-benzyloxyphenyl)-1-methylethyl]acrylamide, m.p. 116°117° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Cl:25]Cl.O>C(O)(=O)C>[Cl:25][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: ClCl
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiaz-3-one in 12.5 L of glacia acetic acid was added 1.25 kg of ptassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 L of H2O with vigorous stirring. The 4-chlorophenothiazin-3-one precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chlorophenothiazin-3-one which was recrystallized from toluene.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:5][CH:4]([CH2:13][CH3:12])[CH2:3][CH2:2][CH2:15][CH3:14])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:20]
Reactant: CCCCC(CC)CBr
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc2c(c1)C(=O)c1ccc(OCC(CC)CCCC)cc1C2=O
Temperature: 90 °C
Yield: 128.3 %

Procedure:
2,6-Dihydroxyanthraquinone (100.0 g, 0.42 mol) and 2-ethylhexyl bromide (165.0 g, 0.86 mol) were dissolved in 1 L of DMF. To this solution was added anhydrous K2CO3 (120.0 g, 0.87 mol). The reaction was heated at 90° C. overnight. Most of DMF was removed and 500 mL of water was added. The reaction was extracted with ether (3×400 mL), washed with brine (1×200 mL), and dried over MgSO4. Solvent was removed and the crude product was recrystallized from methanol to give 125.2 g of yellow powdery product at 65% yield. 1H NMR (CDCl3)δ (ppm): 0.92-0.98 (m, 12 H, CH3), 1.34-1.54 (m, 16 H), 1.75-1.81 (m, 2 H, CH(CH3)), 4.02 (d, J=5.5 Hz, 4 H, OCH2), 7.19 (d, J=8.4 Hz, 2 H), 7.70 (s, 2 H), 8.19 (d, J=8.5 Hz, 2 H). 13C NMR (CDCl3): 11.12, 14.06, 23.04, 23.88, 29.08, 30.51, 39.34, 71.34, 110.64, 120.84, 127.00, 129.62, 135.88, 164.29, 182.27. M.p. 49-51° C. FD-MS: m/z 464 (M+).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[N:11]1([CH:16]([C:18]([C:20]([CH3:30])([CH3:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=O)[CH3:17])[CH:15]=[N:14][CH:13]=[N:12]1.C[O-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]([C:18]2([CH:16]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH3:17])[CH2:7][O:6]2)([CH3:29])[CH3:30])=[CH:23][CH:24]=1
Reactant: CC(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC(n1cncn1)C1(C(C)(C)Cc2ccc(Cl)cc2)CO1
Reaction time: 20 h
Yield: 98.1 %

Procedure:
A solution of 9.8 g (0.77 mole) of dimethyl sulphate and 5.3 g (0.085 mole) of dimethyl sulphide in 50 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 13 g (0.044 mole) of 4-chlorophenyl-tert.butyl 1-(1,2,4-triazol-1-yl)-ethyl ketone in 20 ml of acetonitrile is then added dropwise at room temperature. At the same temperature, 4.8 g (0.088 mole) of sodium methylate are introduced and the mixture is subsequently stirred for 20 hours and then concentrated in vacuo. The residue is stirred overnight with a mixture of 35 ml of ethyl acetate and 25 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 13.2 g (98.2% of theory) of 2-(4-chlorophenyl-tert.-butyl)-2-[1-(1,2,4-triazol-1-yl)-ethyl]oxirane of refractive index nD20 1.5431 are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[N:13][C:14]([Cl:18])=[C:15]([CH3:17])[CH:16]=1)(=O)C>CO>[Cl:18][C:14]1[N:13]=[CH:12][C:11]([OH:10])=[CH:16][C:15]=1[CH3:17]
Reactant: CC(=O)Oc1cnc(Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(O)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (1.10 g, 0.0081 mol) was added to a stirred solution of 6-chloro-5-methylpyridine-3-yl acetate (750 mg, 0.004 mol) in MeOH (15 mL) at RT. The reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with minimum amounts of water and neutralized with 1N HCl (15 mL). After neutralization, the solution was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 6-chloro-5-methylpyridine-3-ol as a off white solid (500 mg, 89%). MS m/z=143.01 [M+H]+.
Reaction SMILES: [F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].C1([I+][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C=CC=CC=1.[C:21]1([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:28]1([S+:27]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: [Cu+2]
Agent: F[As-](F)(F)(F)(F)F
Agent: O=C([O-])c1ccccc1
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 11.75 parts of diphenyliodonium hexafluoroarsenate, 4.065 parts of diphenyl sulfide and 0.2 part of copper benzoate was heated with stirring at a temperature of 120°-125° C. for 3 hours. The mixture was then poured while it was hot into a container whereupon the product crystallized. The product was extracted three times with diethylether and then air dried. There was obtained a 97% yield of triphenylsulfonium hexafluoroarsenate. The triphenylsulfonium hexafluoroarsenate product had a melting point of 195°-197° C. after it was further recrystallized from 95% ethanol.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:8][CH:7]=1)[C:4]#[N:5])=O.O.Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25]>CO>[NH2:5][C:4]1[N:23]([C:24](=[O:25])[NH2:26])[N:22]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:8][CH:7]=1
Reactant: Cc1cccc(Cc2ccc(C(C#N)C=O)cc2)c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Reaction time: 13 h

Procedure:
To a solution obtained by dissolving α-formyl-4-(3-methylphenylmethyl)phenylacetonitrile thus obtained in methanol (50 ml) and water (10 ml) was added semicarbazide hydrochloride (3.2 g) under stirring on ice-cooling. Ice bath was removed, and after 13 hours, the mixture was adjusted to alkaline (pH 10 to 11) with 5N-sodium hydroxide aqueous solution, and stirred for 1 hour. Next, the reaction mixture was neutralized (pH 8 to 9) with 10% hydrochloric acid aqueous solution, and the precipitate was separated by filtration. By washing and drying, 3-amino-2-carbamoyl-4-{4-(3-methylphenylmethyl)phenyl}pyrazole (6.3 g) was obtained. The product was used in subsequent procedure without purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][C:2]1[C:3]([O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(O)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(OC2CCCCO2)cc1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a round bottom containing 66.43B (13.15 g, 52.8 mmol) in dry DCM (90 mL) was added 3,4-dihydro-2H-pyran (10 mL, 110 mmol) followed by PPTS (0.13 g, 0.53 mmol). The reaction mixture was heated to a gentle reflux (50° C.) and monitored with TLC and LC-MS. After 24 hours, the reaction was concentrated under reduced pressure and then diluted with MeOH. After concentration, the residue was heated in a round bottom flask containing MeOH on the rotary evaporator (without vacuum.) at 40° C. After about 30 minutes, the solution was concentrated to a volume of about 5 mL. After cooling to room temperature, the white solid was filtered and rinsed once with MeOH to yield 66.43C (13.35 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, m), 6.96 (1H, d, J=12.5 Hz), 5.56 (1H, m), 3.91 (3H, s), 3.79 (1H, td, J=11.1, 2.5 Hz), 3.65 (1H, d, J=10.6 Hz), 2.23 (2H, m), 1.96 (3H, m), 1.68 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.OC1C=CC([N:16]2[C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[NH:17]2)=CC=1>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N:16]1[C:20](=[O:21])[N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:28])[NH:17]1
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Reactant: Oc1ccc(Cl)cc1
Product: O=c1[nH]n(-c2cc(Cl)ccc2O)c(=O)n1-c1ccccc1

Procedure:
Compound 34 was prepared from 4-chlorophenol in the same manner of compound 27, and was obtained as white solids (56%). 1H NMR (300 MHz, Methanol-d4): δ 7.75 (d, J=3.0 Hz, 1H), 7.52-7.46 (m, 4H), 7.38 (m, 1H), 7.08 (dd, J=1.8, 8.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 153.70, 152.32, 132.28, 129.63, 128.93, 128.19, 127.12, 126.41, 126.23, 124.62, 123.70, 118.20. HRMS: calcd for C14H10ClN3O3 (MH+) 304.0483. found 304.0487.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][C:12]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[CH:13][CH:14]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Clc1ccncc1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(Nc2ccncc2)c1

Procedure:
3-(4-Pyridinylamino)benzoic acid was prepared from 41.1 g of m-aminobenzoic acid and 34.0 g of 4-chloropyridine in 110 ml of acetic acid, heated at reflux for 6 hours. With a work-up procedure similar to that of Example 33, there was obtained 48.5 g of product, m.p. 172°-180° C.