Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC(C(O)=[O:8])=CC=1.C[C:15]1[CH:16]=[CH:17][C:18]([O:24][C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[C:19]2[C:23]=1[CH2:22][CH2:21][CH2:20]2>>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:18]2[CH:17]=[CH:16][CH:15]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:8])=[N:30][CH:29]=1
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1CCC2
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[(7-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinylamine obtained in Reference Example 29 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.C1(CCC(O)=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:4]1([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)CCC1CCCCC1
Product: C[C@H]1CC[C@H](N(CCCC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-cyclohexyl-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(Cl)Cl>[CH3:17][S:18]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:20])=[O:19]
Reactant: OCCc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.2 M solution of 2-(2-hydroxyethyl)pyridine (4.5 mmol) in methylene chloride is added triethylamine (24 mmol), followed by methanesulfonyl chloride (4.8 mmol.) The resulting mixture is stirred at room temperature overnight. The mixture is then poured into water and extracted with methylene chloride. The organic extracts are combined, washed with NaHCO3 (sat), and then 1M aq. HCl. The acidic aqueous extracts are neutralized with NaHCO3 (sat) and then extracted with methylene chloride. The organic extracts were combined, dried (MgSO4), filtered, and concentrated to afford the desired product (1).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[H-].[Na+].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35].O>CN(C)C=O>[N+:31]([C:28]1[CH:27]=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=[CH:30][C:29]=1[S:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])nc1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.30 g, 4.04 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% dispersion in liquid paraffin, 178 mg, 4.45 mmol) at 0° C., and the mixture was stirred at room temperature for 10 minutes. To this mixture was added 1-chloro-2,4-dinitrobenzene (900 mg, 4.45 mmol) and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was poured into water (30 mL) and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl [(2-(2,4-dinitrophenyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.17 g). To a solution of this compound (1.17 g, 2.40 mmol) in a mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-aqueous sodium hydroxide (3.0 mL) dropwise and the mixture was stirred at room temperature for 20 minutes. After the solvent was distilled off water reduced pressure, 1N-hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide 0.91 g of the title compound. Yield 49%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[CH2:16]([S:18][CH:19]=[C:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH3:17].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[CH2:16]([S:18][CH:19]=[C:20]1[S:24][C:23](=[O:25])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[C:21]1=[O:26])[CH3:17]
Reactant: ClCCCCSc1cccc2nccn12
Reactant: CCSC=C1SC(=O)NC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCSC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 601 mg (2.5 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 473 mg (2.5 mmol) of 5-(ethylthiomethylene)thiazolidine-2,4-dione in 5 ml of N,N-dimethylformamide, 0.37 ml (2.5 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 16 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/4→ethyl acetate) to yield 0.76 g (77.2%, light orange oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(Sc2ccnc(Cl)c2)c1
Yield: 91.6 %

Procedure:
Using the method of Example 3, Step A, 3-chlorobenzenethiol (912 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(3-chlorophenylthio)pyridine (1.48 g, 92% yield) as an oil. 1H NMR (CDCl3) δ 8.16 (d, 1H), 7.56 (s, 1H), 7.39-7.49 (m, 3H), 6.94 (s, 1H), 6.88 (d, 1H).
Reaction SMILES: O[C:2]1([OH:14])[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([OH:13])[CH:7]=[CH:6][CH:3]1[CH:4]=[O:5].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:15]([O:13][C:8]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:2]([OH:14])[C:3](=[CH:6][CH:7]=1)[CH:4]=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CCCC1=C(O)C=CC(C=O)C1(O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc(C=O)c1O
Yield: 71 %

Procedure:
A mixture of 2,4-dihydroxy-3-propylsalicylaldehyde (15.5 g), benzyl chloride (12.0 g), potassium carbonate (13 g) and potassium iodide (0.5 g) in dry acetone (350 ml) was heated under reflux for 24 hours. The solid was removed by filtration and the solution evaporated to dryness. The oil obtained was distilled and the fraction bp0.5 mm 220°-224° was collected to yield 15.0 g of 4-benzyloxy-3-propylsalicylaldehyde.
Reaction SMILES: S([O-])([O-])(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:11]3[C:16]([N+:17]=2[CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=1.O.[BH4-].[K+]>CO>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[N:17]([CH3:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[CH:8]=1
Reactant: COC(=O)c1c2ccccc2[n+](C)c2ccc(Cl)cc12
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C1c2ccccc2N(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.4 gm of the metho sulfate of 2-chloro-9-methoxycarbonyl-10-methyl-acridinium were suspended in 50 cc of methanol and 2.5 cc of water and after the addition of 5 gm of potassium borohydride, the temperature maintained at 35- 40°C and the mixture was then stirred for 30 minutes at room temperature. The mixture was added to a mixture of ice and water and then filtered. The precipitate was washed with water and then iced methanol and dried to obtain 3.45 gm of 2-chloro-9-methoxycarbonyl-10-methyl-acridane melting at 166°C. The product occurred as a colorless solid soluble in alcohol and chloroform, slightly soluble in ether and insoluble in water. For analysis, the product was recrystallized from methyl ethylketone.
Reaction SMILES: C(O[CH:5]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:6][C:7]([CH2:17][O:18][C:19](=[O:21])[CH3:20])([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C>CCO.[Pd]>[C:19]([O:18][CH2:17][C:7]([NH:13][C:14](=[O:16])[CH3:15])([CH2:6][CH2:5][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH2:8][O:9][C:10](=[O:12])[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)NC(COC(C)=O)(COC(C)=O)CC(OC(C)=O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(CCc1ccc(-c2ccccc2)cc1)(COC(C)=O)COC(C)=O

Procedure:
Acetic acid 4-acetoxy-2-acetoxymethyl-2-acetylamino-4-biphenyl-4-yl-butyl ester (5 mmol) is dissolved in EtOH (50 mL) and hydrogenated at atmospheric pressure using 10% Pd-C (10%) at room temperature for 12 h. After filtration and concentration, the crude product is obtained as a white solid and used in the next step without further purification. MS: (ES+): 398.2 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:22]#[N:23])=[C:4]([O:34][CH3:35])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:45][CH2:44]C1>CCOCC>[F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]2[N:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:44](=[O:45])[NH:23][CH2:22]2)=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1ccc(CNC(C#N)c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)NCC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 100 mg of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-methoxybenzyl)amino]acetonitrile in 4 mL of THF was added 620 μL of a 1 M solution of LiAlH4 in Et2O. The cooling bath was removed and the mixture was stirred for 45 min at r.t. The mixture was recooled to 0° C. and carefully quenched by dropwise addition of 24 μL of water, 24 μL of 15% aqueous NaOH solution, and 60 μL of water. The solids were filtered, washing liberally with Et2O, and the filtrate was concentrated. The residue was dissolved in 2 mL of CH2Cl2 and cooled to 0° C. Triethylamine (55 μL) and then triphosgene (32 mg) were added. The mixture was stirred for 45 min at 0° C. The reaction mixture was partitioned between 10 mL of EtOAc and 10 mL of water. The aqueous was extracted with 10 mL of EtOAc and the combined organics were washed with 10 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 15% EtOAc in hexanes followed by a linear gradient of 15→100% EtOAc in hexanes over 10 CV to provide the title compound. Mass spectrum (ESI) 517.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19](S(C)=O)[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:25])[CH2:9][CH2:8]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19]([NH:37][C:36]4[CH:35]=[CH:34][C:33]([N:30]5[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]5)=[CH:39][CH:38]=4)[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:25])[CH2:9][CH2:8]2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1cccc2c1C(n1c(=O)ccc3cnc(S(C)=O)nc31)CC2
Solvent: ClCCl
Product: COc1cccc2c1C(n1c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc31)CC2
Yield: 8.6 %

Procedure:
8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.29 g, 0.81 mmol) and 4-(4-methylpiperazino)aniline (0.15 g, 0.81 mmol) were stirred at 140° C. for 4 h. The reaction mixture was dissolved in dichloromethane (35 mL) and washed with 10% sodium hydroxide solution (1×15 mL) then with water (1×15 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using dichloromethane:methanol (9:1) to give 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (32 mg, 0.07 mmol, 8.6%) as the major product. ESMS m/z 483 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 9.81 (br. s., 1H), 8.73 (s, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.87 (br.s., 1H), 6.84 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 6.13 (d, J=9.3 Hz, 1H), 3.43 (s, 3H), 3.10-3.00 (m, 4H), 3.00-2.85 (m, 2H), 2.45-2.38 (m, 4H), 2.35-2.25 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: N([O-])=[O:2].[Na+].[CH2:5]([NH:12][CH:13]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21](N)[CH:22]=[CH:23][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N>S(=O)(=O)(O)O.O>[CH2:5]([NH:12][CH:13]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([OH:2])[CH:22]=[CH:23][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Reactant: O=N[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Sodium nitrite (609 mg) aqueous solution (6 ml) was added dropwise to a stirred suspension of N7 -benzyl-6,7-dihydro-5H-benzocycloheptene-2,7-diamine (2.22 g) in 6N sulfuric acid (22 ml) under ice cooling over 15 minutes and the resulting solution was stirred at the same temperature for 30 minutes. The solution was added dropwise to a stirred solution of sulfuric acid (3 ml) in water (15 ml) at 75° C. over 15 minutes. The resulting mixture was stirred at the same temperature for 30 minutes, cooled with ice-water bath, basified with 28% ammonia solution (15 ml), and extracted six times with dichloromethane. The combined extracts were evaporated in vacuo and chromatographed over silica gel using dichloromethane and methanol to afford 7-benzylamino-6,7-dihydro-5H-benzocyclohepten-2-ol (1.72 g) as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl:16][C:17]1[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[S:20][C:21]=1[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:22][C:21]2[S:20][C:19]3[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=3[C:17]=2[Cl:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: OCc1sc2ccccc2c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.9 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.0 g, 4.8 mmol), (3-chloro-benzo[b]thiophen-2-yl)-methanol (1.9 g, 9.5 mmol), and polymer-supported triphenyl phosphine (3.0 g, 9.5 mmol) in THF (30 mL) in an ice-bath was slowly added diisopropyl azodicarboxylate (1.9 mL, 9.5 mmol) and stirred at r.t. overnight. The mixture was filtered and the solid was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (2.1 g, 109% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:10].C1[C@@H](C(O)=O)NC[C@@H]1O.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.[NH4+].[Cl-].[Cu]I>[N:6]1[CH:7]=[CH:8][C:3]([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:10])=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)NN
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(N)c1ccncc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 39.5 %

Procedure:
A mixture of 4-bromo-pyridine hydrochloride salt (8.0 g), tert-butyl hydrazinecarboxylate (10.87 g), CuI (784 mg), L-4-hydroxyproline (1.08 g) and Cs2CO3 (33.50 g) in dry DMSO (41 mL) under N2 was heated at 80° C. with efficient stirring for 5-6 hrs. After cooled to rt, the reaction mixture was diluted with EtOAc (150 mL) and saturated NH4Cl (150 mL). The organic layer was separated and the aqueous was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (DCM to 10% MeOH/DCM gradient) to provide the title compound (3.4 g, 40%). ESI-MS (EI+, m/z): 210.0 [M+H]+. 1H NMR (300 MHz, DMSO) δ 8.38 (d, J=4.9 Hz, 2H), 7.64 (d, J=6.4 Hz, 2H), 5.12 (s, 2H), 3.34 (s, 1H), 1.51 (s, 9H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:12]([F:17])=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:12]([F:17])=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C=O)cc1OC1CCCC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(F)c(C(=O)O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A solution of 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.4 g) in glacial acetic acid (20 mL) is treated with sulfamic acid (0.82 g) at room temperature and stirred for 10 minutes. The resulting yellow solution is cooled to 0° C. and treated with a solution of sodium chlorite (0.69 g of an 80% pure sample) in water (20 mL) during 10 minutes. The resulting yellow suspension is stirred at room temperature for 3 hours, poured into water (100 mL) and filtered to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid (0.88 g), in the form of a white solid. [NMR (CDCl3):—7.46(d,1H,J=8 Hz),6.65(d,1H,J=12 Hz), 4.80–0.76 (m, 1H), 3.90(s,3H), 2.01–1.58(m,8H)].
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH2:5][CH2:4]1>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:7]([NH:6][C:3]1([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: O=C(NC1(CO)CC1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)NC2(CO)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of N-(1-(hydroxymethyl)cyclopropyl)-3-nitrobenzamide (0.135 g, 0.571 mmol) in methanol Pd—C (50% wet) (0.015 g) was added and stirred at room temperature under hydrogen for 2 hr. Reaction mixture was filtered through celite and concentrated to afford product (01 g, 85%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4](C)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[CH:27]O)[C:22](OCC)=[O:23])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22](=[O:23])[N:2]([CH3:1])[C:3]3[NH:4][C:5]4[C:10]([C:11]=3[CH:27]=2)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=4)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=CO)c1ccc(Br)cc1
Reactant: CNc1cc2cc(C)ccc2n1C
Product: Cc1ccc2[nH]c3c(cc(-c4ccc(Br)cc4)c(=O)n3C)c2c1

Procedure:
This compound is prepared according to the usual methods by reaction of N,1,5-trimethyl-1H-indole-2-amine with ethyl 2-(4-bromophenyl)-3-hydroxy-2-propenoate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][C:10]1[C:11]([CH2:19][CH2:20][CH3:21])=[N:12][N:13]([CH3:18])[C:14]=1[C:15]([NH2:17])=[O:16])=O)[CH:2]=[CH2:3].[OH-].[Na+].O>C(O)C>[CH2:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]1[NH:17][C:15](=[O:16])[C:14]2[N:13]([CH3:18])[N:12]=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 41.9 %

Procedure:
A mixture of 4-(2-allyloxybenzamido)-1-methyl-3-n-propyl-pyrazole-5-carboxamide (1.2 g, 0.0035 mol), sodium hydroxide (0.70 g, 0.018 mol), water (34 ml) and ethanol (8 ml) was refluxed for 5 hours. After cooling, the solution was exhaustively extracted with ethyl acetate. The combined extracts were washed with brine (30 ml), dried (Na2SO4), filtered and the solvent evaporated under vacuum to give a crude product which was crystallised from ethyl acetate/hexane to afford the title compound (0.476 g, 37%), m.p. 116°-119° C. Found: C,67.00; H,6.21; N,17.23. C18H20N4O2 requires C,66.65; H,6.21; N,17.27%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.I[CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][O:20][CH2:25][CH3:26])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=c1ccc(-c2ccc(CO)cc2)cn1Cc1ccc(Cl)cc1
Reactant: CCI
Product: CCOCc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 40.8 %

Procedure:
According to Scheme 25 Method A: The title compound was prepared from 1-(4-chlorobenzyl)-5-(4-(hydroxymethyl)phenyl)pyridin-2(1H)-one (1 eq, 2.50 mmol, 0.80 g) and iodoethane (3 eq, 7.40 mmol, 1.10 g)) according to the procedure described for Example 34 Step 3. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 5 g SiO2) using CH2Cl2/MeOH 99/1 as eluent to afford 1-(4-chlorobenzyl)-5-(4-(ethoxymethyl)phenyl)pyridin-2(1H)-one (1.02 mmol, 0.36 g, 41%) as a yellow solid.