Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1.[OH-].[Na+].S(OC)(OC)(=O)=O.Cl>O.C(O)CO.C1(C)C=CC=CC=1>[NH2:6][C:5]1[C:7]([CH3:15])=[C:8]([CH:9]=[CH:10][C:4]=1[S:3][CH3:2])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2sc(N)nc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(C(=O)O)c(C)c1N
Temperature: 130 °C
Reaction time: 20 h

Procedure:
10 g of methyl 2-amino-4-methylbenzothiazole-5-carboxylate (0.045 mol.) were dissolved in a mixture of 120 ml of water, 120 ml of ethylene glycol and 50 g of NaOH, and the mixture was stirred at 130° C. for 20 h. The mixture was then diluted with 50 g of ice, 3 drops of (n-Bu)4N+OH— solution were added and finally, at 20° C., 6.25 ml of dimethyl sulfate (0.05 mol) in 15 ml of toluene were added dropwise. After 30 min, the mixture was acidified with conc. HCl and the precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-carboxylate and 4-methylbenzyl bromide in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a semi-solid contained 0.8 mole equivalent DMF. Mass spectrum (ESI, [M+H]+) m/z 372. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H, J=7.94 Hz), 7.55 (d, 1H, J=9.01 Hz), 7.40 (dd, 1H, J=8.85 and 1.98 Hz), 7.32 (s, 1H), 7.04 (d, 2H, J=7.96 Hz), 6.90 (d, 2H, J=7.94 Hz), 5.79 (s, 2H), 4.28 (q, 2H), 2.20 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2,2-dimethyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (598 mg) from above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The mixture was partitioned between ether and sodium hydroxide solution (1N). The organic layer was washed with brine and dried. Evaporation of solvents gave 2,2-dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (370 mg) as an oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:19])[C:17]=2[CH3:18])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO.O>[CH2:20]([C:15]1[N:14]=[N:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[C:17]([CH3:18])[C:16]=1[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester (0.88 g, 2.5 mmol) in EtOH (8 mL) is added a solution of sodium hydroxide (0.8 g, 20.1 mmol) in H2O (8 mL). After being stirred at 25° C. for 2 h, the mixture is concentrated, and extracted with CH2Cl2 (2×10 mL) to remove impurities. The aqueous layer is acidified by 1N HCl to pH ˜5, and extracted with CH2Cl2 (6×20 mL). The combined organic solution is dried over Na2SO4, filtered and concentrated to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (0.68 g, 83%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24]>>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Product: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:27])=[C:5]2[C:9](=[C:10]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=1[CH2:12][CH:13]=[C:14]([CH2:17]O)[CH2:15][CH3:16])[C:8](=[O:26])[O:7][CH2:6]2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:17][C:14]([CH2:15][CH3:16])=[CH:13][CH2:12][C:11]1[C:10]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:26])=[C:4]([CH3:27])[C:3]=1[CH2:1][CH3:2]
Reactant: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-bound triphenylphosphine (3 mmol/g, 90.7 mg) was added, and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (90.2 mg, 0.272 mmol) was added and the solution was stirred at room temperature. After 2 hours, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography to provide 32.0 mg (78%) of the desired product. The material was used in the next step without further characterization.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@:11]1([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][C:15](=[O:17])[C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20]C(C)(C)C)=[O:19])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][C@@:11]1([C:25]([OH:27])=[O:26])[CH2:16][C:15](=[O:17])[C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([OH:20])=[O:19])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Add 2.5M sodium hydroxide (15.55 mL, 38.88 mmol) to a stirred solution of the ditert-butyl(1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.0 g, 4.86 mmol) in tetrahydrofuran (24.3 mL) and ethanol (9.72 mL). Heat the reaction mixture to 60° C. and maintain stirring overnight. Continue heating for 4 hours then wash with ethyl acetate. Cool the aqueous phase in an ice bath and acidify to pH=2-3 with 1N hydrochloric acid solution. Extract with ethyl acetate (3 times), dry the organic on sodium sulfate, filter and concentrate to give the title compound as an orange solid (1.4 g, 96%). MS (m/z): 322 (M+23).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[C:14]1([CH:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(C2CCNC2)cc1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Hydrogen chloride (4N) in ethyl acetate (6 ml) was added to a solution of 1-tertbutoxycarbonyl-3-phenyl-pyrrolidine (1.84 g, 7.4 mmol) in ethyl acetate (2 ml) and the mixture was stirred for 2 hours. After azeotropical removal of the solvent and hydrogen chloride, the residue was partitioned between aqueous potassium carbonate and diethyl ether, and the organic layer was washed with brine, and dried over sodium sulfate. Removal of the solvent afforded 3-phenyl-pyrrolidine (0.95 g, 87%).
Reaction SMILES: C[Al](C)C.[NH4+:5].[Cl-].C.C[O:9][C:10]([C@@H:12]1[C@H:16]([CH3:17])[CH2:15][CH2:14][N:13]1[C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])=O>C1(C)C=CC=CC=1>[CH3:17][C@@H:16]1[CH2:15][CH2:14][N:13]([C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C@@H:12]1[C:10]([NH2:5])=[O:9]
Reactant: COC(=O)[C@@H]1[C@H](C)CCN1[C@@H](C)c1ccccc1
Reactant: [NH4+]
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylaluminum in toluene (2 M, 6.46 mmol) was added dropwise to a mixture of NH4Cl (6.47 mmol) in toluene (3.2 mL) at 0° C. with the formation of methane gas. The reaction mixture was allowed to warm to rt, stirred for a further 15 min and then slowly treated with (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described in Tet. Lett. 1997, 38, 85-88) (6.47 mmol). After stirring for 56 h, the mixture was cooled to 0° C., quenched with 1M HCl and then washed with CH2Cl2 (3×). The aqueous phase was basified with a saturated solution of NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a colorless oil. ESI-MS: [M+H]+ 233; HPLC: tR 2.35 min (method A).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[I:12]I>CN(C)C=O.S([O-])([O-])(=O)=O.[Ag+2]>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([I:12])[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(C(F)(F)F)cc1I
Reaction time: 14 h

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3). The iodide (3-b, with R4=CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3). 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4═CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[CH:5]=[N:6][C:7]([CH2:13][S+:14]([O-:26])[C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[N:23]=2)=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11]>CO>[CH3:3][C:4]1[CH:5]=[N:6][C:7]([CH2:13][S+:14]([O-:26])[C:15]2[N-:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[N:23]=2)=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 79.2 %

Procedure:
2.31 g of sodium hydroxide and 70 ml of methanol were taken into a round bottom flask and stirred for dissolution. A solution of 20 g of esomeprazole in 70 ml of methanol was added to the above methanolic sodium hydroxide. The mixture was stirred at 30° C. for 3.5 hours. The mixture was then distilled using a flash distillation technique at 30° C. to obtain 16.8 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:12]([Cl:21])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([Br:29])=[CH:19][CH:20]=2)=[C:12]([Cl:21])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccc(Br)cc1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c (0.327 g, 1.08 mmol) is dissolved into DMF (16 mL) and NBS (0.193 g, 1.08 mmol) is added. After one hour, the reaction mixture is quenched by the addition of saturated aqueous NaHSO3. The reaction mixture is then partitioned between EtOAc/THF and water. The organic layer is washed with water and brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The recovered solid is triturated with ether to give 0.225 g (54%) pure desired product. MS ESI (+) m/z 382, 384 (M+, Br pattern) detected.
Reaction SMILES: [Cl:1][CH:2]1[N:5]([CH:6]([C:23]([CH3:25])=[CH2:24])[C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:26])[CH:3]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC)=O.[Cl:42]OC(C)(C)C>C(OCC)(=O)C>[Cl:1][CH:2]1[N:5]([CH:6]([C:23]([CH2:25][Cl:42])=[CH2:24])[C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C:4](=[O:26])[CH:3]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OCl
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Solvent: COC=O
Solvent: CCOC(C)=O
Product: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5.18 g. portion of diphenylmethyl 2-(4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl)-3-methyl-3-butenoate was dissolved in 200 ml. of methyl formate, and 1.71 ml. of t-butyl hypochlorite was added. The mixture was stirred at room temperature for 16 hours. It was then evaporated under vacuum to obtain a white foam, which was taken up in ethyl acetate and washed three times with water. The organic layer was then decolorized with activated carbon, dried over magnesium sulfate, and evaporated to a white foam. The foam was taken up in 100 ml. of dry diethyl ether, from which 1.12 g. of the desired product was obtained in crystalline form. The product was analyzed by infrared in chloroform, showing maxima at 1795, 1745 and 1695 cm-1 ; a second spectrum in methanol showed maxima at 1775, 1740 and 1695 cm-1. NMR analysis on a 100 megacycle instrument in CDCl3 showed the following δ values. 4.24(s); 4.63(s); 5.73(center of q); 6.2(d); 5.09(s); 5.33(s); 5.5(s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH2:36].C[Al](C)C>C1(C)C=CC=CC=1>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1nc2ccccc2[nH]1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccccc2[nH]1
Yield: 32.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 1H-benzo[d]imidazol-2-amine (0.046 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.040 g of desired product. 1H NMR (DMSO-d6): δ 4.01 (s, 3H), 7.11 (m, 2H), 7.48-7.76 (m, 6H), 7.81 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 11.16 (br s, 1H), 12.28 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 478.90 [M]+
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([C:14]([CH:16]([C:18]2[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=2)O)=O)[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[S:32])=[CH:29][CH:28]=1>O1CCOCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]2[S:32][C:16]([C:18]3[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=3)=[C:14]([C:6]3[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=3)[N:33]=2)=[CH:29][CH:28]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccc(F)cc3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
Three ml. of concentrated sulfuric acid, 250 ml. of dioxane, 27.2 g. (0.10 mole) of anisoin, and 15.5 g. (0.10 mole) of 4-fluorothiobenzamide were placed in a round bottom flask. The mixture was stirred at reflux for 3 days, then cooled to room temperature, and poured onto ice. Then the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. After the ethyl acetate was evaporated, a crude solid of 35 g. remained. The solid was then recrystallized from ethyl acetate and weighed 27.5 g. (70% yield). It had a melting point of about 140°-141.5° C. and the mass spectrum showed the expected molecular ion at m/e=391.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]([C:6]#[N:7])[CH3:5].[N+:12]([O-])([OH:14])=[O:13]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[CH:4]([C:6]#[N:7])[CH3:5]
Reactant: O=[N+]([O-])O
Reactant: CC(C#N)c1ccccc1F
Product: CC(C#N)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C

Procedure:
To 24 g of 2-fluoro-α-methylbenzyl cyanide was added dropwise 40 ml of fuming nitric acid while maintaining the temperature 0°-5° C. After addition, the mixture was gradually warmed up to room temperature, poured into ice-water and extracted with ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated off. The crude crystals obtained were recrystallized from benzene--n-hexane to afford 25.8 g of 2-fluoro-α-methyl-5-nitrobenzyl cyanide, m.p. 55°-56° C.
Reaction SMILES: [Cl-].[NH4+].Cl[C:4]1(Cl)[C:7](=[O:8])[CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C@@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.ClCCl>C1COCC1.[Zn]>[F:23][C:22]([F:24])([F:25])[C@H:21]([CH3:26])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:5]2[CH2:6][C:7](=[O:8])[CH2:4]2)=[CH:14][CH:13]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(c1ccc(C2CC(=O)C2(Cl)Cl)cc1)[C@@H](C)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(c1ccc(C2CC(=O)C2)cc1)[C@@H](C)C(F)(F)F
Temperature: 75 °C
Reaction time: 5 h

Procedure:
100 ml of saturated aqueous ammonium chloride solution were added to 4.57 g (11.51 mmol) of ethyl (3R)-2-[4-(2,2-dichloro-3-oxocyclobutyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate and 3.76 g (57.5 mmol) of zinc dust in 100 ml of THF, and the mixture was then stirred at 75° C. for 5 h. After cooling to room temperature and addition of dichloromethane, the reaction mixture was washed with water. After separation of the phases, the aqueous phase was back-extracted three times with dichloromethane. The combined organic phases were then dried over magnesium sulphate, filtered and concentrated under reduced pressure. This gave 1.21 g of the title compound (32% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]=1[CH2:13]2)(=[O:3])[CH3:2].CO.[BH4-].[Na+].O>C(O)(=O)C>[OH:3][CH:1]([C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]=1[CH2:13]2)[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)=O)c1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)O)c1O2
Reaction time: 0.25 h

Procedure:
To a solution of 6 g. of methyl 5-acetyl-7-methyl-xanthene-2-carboxylate in 500 ml. of absolute methanol are added 1.1 g. of sodium borohydride in 50 ml. of water at a temperature of from 25° to 30° C with stirring, over a period of about 30 minutes. After 15 minutes under these conditions, 400 ml. of water and 20 ml. of acetic acid are added and the resultant mixture is stripped of solvent. The resultant mixture is extracted with methylene chloride and washed with bicarbonate and water. The washed extracts are concentrated to give methyl 5-(1-hydroxyethyl)-7-methylxanthene-2-carboxylate.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[CH:7]=1>O1CCCC1>[F:13][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH3:12])[CH:9]=1)[C:5]([OH:14])=[O:4]
Reactant: COC(=O)c1cc(C)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(F)cc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
0.5 N Lithium hydroxide (7.4 ml, 3.7 mmol) was added to a solution 3-fluoro-5-methyl-benzoic acid methyl ester (520 mg, 3.1 mmol) in tetrahydrofuran (7.4 ml). The reaction was stirred at 75° C. for 2 h and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH about 2) by the addition of 10% HCl (aq.). Following extraction of the aqueous layer with ethyl acetate, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 469 mg (98%) of 3-fluoro-5-methyl-benzoic acid as a white solid. 1H NMR (DMSO), d (ppm): 7.62 (s, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 2.38 (s, 3H).