Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, n-pentyl iodide 0.79 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 15 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.97 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[N:12]=[CH:11]3)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc3c(cnn3-c3ccc(C#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 4-fluorobenzonitrile (0.11 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 4-[5-(4-Methoxy-phenoxy)-indazol-1-yl]-benzonitrile (110 miligrams) MS: 342.4 [M+H]+ and 4-[5-(4-Methoxy-phenoxy)-indazol-2-yl-]-benzonitrile (75 miligrams) MS: 342.4 [M+H]+ as colorless syrups.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=O)[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.CC1C=CC2C(NC3C=CC=C(C(F)(F)F)C=3)=[N:45][CH:44]=[CH:43]C=2C=1N.NC1C=CC=CC=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[C:20]([CH3:38])=[CH:21][CH:22]=[C:23]4[C:24]=3[CH:43]=[CH:44][N:45]=[C:25]4[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=3)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Solvent: Nc1ccccc1
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1NC(=O)c1cccc2c(N)nccc12
Yield: 2 %

Procedure:
The procedures of Steps (3) and (4) of Example 2 were repeated step by step, except for using 6-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine obtained in Step (2) above instead of aniline in Step (3) of Example 1 to obtain the title compound (1.0 mg, 2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2
Reactant: [H][H]
Reactant: CC(C)CCC=Cc1cc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-(5-methyl-hex-1-enyl)-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-chloro-2-(5-methyl-hexyl)-1H-indole.
Reaction SMILES: [CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:8][CH:7]=[C:6]([CH:9]=O)[CH:5]=1)[CH3:2].[O:15]=[C:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:17]P(=O)(OCC)OCC.C([Li])CCC>>[CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:8][CH:7]=[C:6]([CH:9]=[CH:17][C:16](=[O:15])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:5]=1)[CH3:2]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC(=O)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Product: CCCCCCCCCCCC(=O)C=Cc1coc([Si](CC)(CC)CC)c1

Procedure:
5-Triethylsilyl-3-furaldehyde is reacted with diethyl 2-oxotridecylphosphonate and n-butyl lithium to give 5-triethylsilyl-3-(3-oxo-1-tetradecenyl)furan. Oxidizing using Rose Bengal and oxygen gives 4-(3-oxo-1-tetradecenyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]1=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:14]1=[O:32])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)[C@H]1CCc1ccco1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A solution of benzyl chloroformate (485 μL, 3.4 mmols) in methylene chloride (2.5 mL) was added dropwise to a stirred, cooled (ice/H2O bath) solution of (±)-t-butyl 2-[cis-3-amino-4-(2-(2-furyl)ethyl)-2-oxoazetidin-1-yl]acetate (1.0 g, 3.4 mmols) and diisopropylethylamine (592 μL, 3.4 mmols) in methylene chloride (10 mL). Stirring was continued with cooling for 0.5 hr and then for 0.33 hr at ambient temperatures. The solution was sequentially washed with 0.05M (pH 4) ammonium phosphate, H2O, dilute aqueous NaHCO3, and saturated NaCl. The solution was dried (Na2SO4) and concentrated, and the residue was chromatographed on SiO2 (50 g) with hexane-ethyl acetate (2:1). The appropriate fractions were combined and concentrated to leave a viscous oil which was crystallized from diethyl ether-hexane to afford the title compound (1.05 g, 72% yield).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:17]=[CH:16][C:15]3[N:18]=[CH:19][NH:20][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:22]1([C:28]([O:30][CH3:31])=[O:29])[C:26](=[O:27])[CH:25]=[CH:24][S:23]1>C(Cl)(Cl)Cl>[OH:27][C:26]1[CH:25]=[C:24]([N:20]2[C:14]3[CH:13]=[C:12]([C:10](=[O:11])[NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:17]=[CH:16][C:15]=3[N:18]=[CH:19]2)[S:23][C:22]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: O=C(NCCN1CCOCC1)c1cc2[nH]cnc2cn1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.27 g of 1H-imidazo[4,5-c]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide in 150 ml chloroform was slowly added a solution of 1.27 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 100 ml chloroform and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was washed with water (3×50 ml) and the organic layer was dried with MgSO4 and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by flash chromatography (dichloromethane/methanol, elution gradient 10/0 to 9/1 (v/v))) to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:26]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:22]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])[N:23]=[CH:24][N:25]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: CCOC(=O)c1c(Cl)ncnc1NCc1ccc(OC)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(NCc2ccc(OC)cc2)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Yield: 82 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one was treated with ethyl 4-chloro-6-((4-methoxybenzyl)amino)pyrimidine-5-carboxylate (6 mg, 0.02 mmol), N,N-diisopropylethylamine (16 μl, 0.09 mmol) and ethanol as a solvent according to the method described in Example 17. The solvent was concentrated and the solid was suspended in ethanol and filtered. The white solid obtained was washed with ether and dried in the oven to give 281 mg (82% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]>O1CCCC1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCCO)ccc1Cl
Temperature: 60 °C

Procedure:
4-Amino-1-butanol (0.11 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.25 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesian sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) gave the title compound as the acetate salt. Treatment with aqueous 2M sodium hydroxide and extraction into ethyl acetate gave the title compound (0.065 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:33][CH:32]([O:35][CH3:36])[O:31][CH3:30])[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(CBr)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21)OC
Temperature: 50 °C
Yield: 136.2 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 1 mmol) in DMF (1 mL) was added KHMDS (0.5 M in THF, 1.1 mL) was dropwise at room temperature. The mixture was stirred for half an hour before adding bromoacetaldehyde dimethyl acetal (95 mg, 0.55 mmol). The mixture was warmed to 50° C. and stirred at that temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate (3×15 mL), dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) gave the desire product as colorless oil (268 mg, 75%). LC/MS m/e calcd. for C20H20ClNO3: 3570, observed (M+H)+: 358.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[OH:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:3]([C:2]([CH3:10])([CH3:1])[CH2:8][CH2:7][C:6]([O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)=[O:9])([OH:5])=[O:4]
Reactant: COc1ccc(CO)cc1
Reactant: CC1(C)CCC(=O)OC1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CCC(C)(C)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2,2-dimethylglutaric anhydride (19.34 g), anise alcohol (22.08 g) and triethylamine (19.39 g) in dry dioxane (360 ml) was stirred at 80° C. for 3.5 hours. The reaction mixture was evaporated and the residue was diluted with water and adjusted to pH 9 with potassium carbonate. The aqueous layer was washed with benzene, acidified with dilute hydrochloric acid and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give p-methoxybenzyl 4-carboxy-4-methylvalerate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:23](=[O:24])[CH2:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 50 ml of pyridine and 7.42 g (0.048 mol) of phenylacetyl chloride were added dropwise thereto at 0°. After stirring overnight at room temperature the mixture was poured into water, extracted with ethyl acetate, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) gave 8-chloro-4-(phenylacetyl)-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:9](C(OC(C)(C)C)=O)[CH:10]1[CH2:12][CH2:11]1)[C:6](=[O:8])[CH3:7])[CH3:2].[ClH:21].C(OCC)C>O1CCOCC1>[ClH:21].[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:9][CH:10]1[CH2:11][CH2:12]1)[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)N(C(=O)OC(C)(C)C)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)C(NC1CC1)C(C)=O
Reaction time: 2 h
Yield: 70 %

Procedure:
To 6.4 g (23 mmol) of 2-(tert-butoxycarbonyl-cyclopropyl-amino)-3-oxo-butyric acid ethyl ester was added 10 ml of 4M hydrochloric acid in dioxane and the mixture stirred for 2 h. Diethyl ether was then added and 3.5 g (70%) of product was isolated by filtration. MS: 186.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na].[CH3:10][O:11][CH2:12][C:13]([C:16]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:18][O:17]1)([CH3:15])[CH3:14]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([OH:17])([C:13]([CH3:15])([CH3:14])[CH2:12][O:11][CH3:10])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COCC(C)(C)C1(Cn2cncn2)CO1
Agent: [Na]
Solvent: CCO
Product: COCC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.5 %

Procedure:
8.1 g (0.0633 mol) of 4-chlorophenol were added to a solution of 0.32 g (0.014 mol) of sodium in 100 ml of absolute ethanol. 10.3 g (0.0488 mol) of 2-(methoxy-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane, dissolved in 300 ml of absolute ethanol, were added, and the reaction mixture was heated under reflux for 48 hours. The reaction mixture was allowed to cool and was concentrated. The residue was taken up in ethyl acetate, and the solution was washed once with water, once with 1N sodium hydroxide solution, again with water, thereafter with 1N hydrochloric acid and 1N sodium hydroxide solution, again with water, and finally with saturated sodium chloride solution. The organic phase was dried over sodium sulphate, and concentrated. 10.7 g (64.6% of theory) of 2-(4-chlorophenoxymethyl)-3,3-dimethyl-4-methoxy-1-(1,2,4-triazol-1-yl)-butan-2-ol of refractive index nD20 =1.531 were obtained.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([NH2:30])=[O:21])[N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(-c3nc(CCC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3nc(CCC(N)=O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)propanoic acid (0.11 g), 1H-1,2,3-benzotriazol-1-ol (40 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg) at room temperature. The mixture was stirred for 20 min, and 28% aqueous ammonia (0.08 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.04 g, yield 36%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (4:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 200-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])=[C:5]([CH3:38])[CH:4]=1.Br[CH2:40][C:41](OC)=[O:42]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:41](=[O:42])[CH2:40][S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:20][CH:21]=2)=[C:5]([CH3:38])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(C)c(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Solvent: CCO
Solvent: O
Product: COc1cc(C)c(N2C(=O)CS/C2=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Temperature: 70 °C
Yield: 76.1 %

Procedure:
To a solution of (E)-N-(4-methoxy-2,6-dimethylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazine-carbothioamide (250 mg, 0.462 mmol) in EtOH (5 mL) was added methyl bromoacetate (100 mg, 0.65 mmol), and the mixture was heated to 70° C. for 4 h. The mixture was allowed to cool to room temperature and diluted with water (1 mL). The precipitate was vacuum filtered, giving the title compound as a white solid (204 mg, 76%): mp 188-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.33 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.90-7.70 (m, 4H), 7.39 (d, J=8.7 Hz, 2H), 6.72 (s, 2H), 4.01 (s, 2H), 3.87-3.73 (s, 3H), 2.18 (s, 6H); ESIMS m/z 581 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH2:26][CH2:27][N:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH2:26][CH2:27][N:28]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSC2=NCCS2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSC4=NCCS4)CC3)c2c1
Temperature: 75 °C
Yield: 70.5 %

Procedure:
A mixture of 0.15 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylate in 5 cm3 of dioxane, 5 cm3 of methanol and 1 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 75° C. for 20 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (Bond Elut; particle size 70-200μ; mass 7 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (40/5/0.5 by volume). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and then oven-dried under reduced pressure (10 kPa) at about 50° C. 0.1 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.Cl.[NH2:12]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)#[N:12]
Reactant: NO
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A 250-mL, three-neck, round-bottom flask equipped with a mechanical stirrer, a heating mantle, and a condenser was charged with 5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60 mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and the mixture was heated to 85° C. Acetic anhydride (40 mL) was added and the reaction was stirred at 85° C. for 3 h, after which time the solvent was evaporated at 40° C. under reduced pressure. The residue was dissolved in water, basified with 2.0 N NaOH solution to pH 9, and extracted with 4:1 dichloromethane/2-propanol until the pyridine was completely removed (5×200 mL). The aqueous solution was then acidified with 2.0 N HCl solution to pH 2, saturated with solid NaCl, and extracted with 4:1 dichloromethane/2-propanol (5×200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to dryness. The residue was crystallized from dichloromethane to give 6.80 g of the title compound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. for C6H3NO3, 136.0 (M−H), found 136.1. The 1H NMR spectrum was consistent with the assigned structure.