Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:5]=1C(NC)=O.ClC(OC1C=CC=CC=1)=[O:17].[CH3:25][N:26]([CH3:29])[CH:27]=[O:28]>>[F:14][C:12]1[CH:13]=[C:4]2[C:5]([C:27](=[O:28])[N:26]([CH3:29])[C:25](=[O:17])[NH:3]2)=[CH:10][CH:11]=1
Reactant: CNC(=O)c1ccc(F)cc1N
Reactant: CN(C)C=O
Reactant: O=C(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cn1c(=O)[nH]c2cc(F)ccc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A suspension of sodium hydride (60% in mineral oil, 368 mg, 9.2 mmol) in dimethylformamide (12 mL) was cooled to 0° C. and treated with 2-amino-4-fluoro-N-methylbenzamide [Intermediate 137] (0.67 g, 4.0 mmol). Phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added over 40 minutes. After 1 hour a further portion of phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added. The reaction was allowed to warm to room temperature and stir for two hours. The reaction was slowly added to 200 mL of ice. The solid was filtered, washed with methanol to obtain the product (395 mg, 51%).
Reaction SMILES: C(O)(=O)C(O)=[O:3].C(O)(=O)C(O)=O.[CH3:13][N:14]1[C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=2)=[N:17][N:16]=[C:15]1[CH2:37][C:38]#[N:39].[OH-].[Na+]>Cl>[CH3:13][N:14]1[C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=2)=[N:17][N:16]=[C:15]1[CH2:37][C:38]([NH2:39])=[O:3]
Reactant: O=C(O)C(=O)O
Reactant: Cn1c(CC#N)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(N)=O)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 28.4 %

Procedure:
A solution of 4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triazole-3-acetonitrile dioxalate (0.05 g) in 35% hydrochloric acid (1 ml) was heated at 40° C. for 3 h. The mixture was basified with sodium hydroxide and extracted with chloroform. Evaporation of the organic solution gave the title compound (0.01 g) as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[K+]>>[CH:4]1([C:5]([OH:7])=[O:6])[CH2:2][CH2:3]1.[C:5]1(=[O:7])[O:6][CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)CCCCl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CC1
Product: O=C1CCCO1

Procedure:
It is known to condense the ethyl ester of 4-chlorobutyric acid with aqueous potassium hydroxide on pumice. There is obtained thereby in moderate yield the ethyl ester of cyclopropane carboxylic acid besides the free acid and γ-butyrolactone (Rambaud, BL. [5] (1938), pages 1552, 1564).
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]/1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:24]=[C:25]([NH2:27])[N:26]=[CH:4][C:5]=2[CH2:14]1
Reactant: CN(C)/C=C1\C[C@@H](c2ccccc2F)c2ccccc2C1=O
Reactant: N=C(N)N
Agent: Cl
Product: Nc1ncc2c(n1)-c1ccccc1[C@H](c1ccccc1F)C2

Procedure:
This was synthesized by using (R,E)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and guanidine hydrochloride as described in general procedure 1 to afford the desired product as hydrochloride salt. M.p.=154-155° C. 1H NMR 400 MHz (DMSO-d6) δ 8.26-8.24 (m, 1 H), 8.08 (s, 1 H), 7.46-7.39 (m, 2 H), 7.31-7.20 (m, 2 H), 7.05-7.00 (m, 2 H), 6.80-6.76 (m, 1 H), 6.51 (s, 2 H), 4.59 (t, J=6.8 Hz, 1 H), 3.11-3.2.96 (m, 2 H). LCMS m/e 292 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([SH:27])[CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.I[CH:33]1[CH2:36][O:35][CH2:34]1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([S:27][CH:33]3[CH2:36][O:35][CH2:34]3)[CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: IC1COC1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SC2COC2)cc(C(F)(F)F)c1

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.093 g, 206 μmol) in acetonitrile (2 mL) were added 3-iodooxetane (57.0 mg, 310 μmol) and DIPEA (66.7 mg, 90.1 μL, 516 μmol) and the clear, light yellow solution was heated under reflux for 2.5 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.05 g; 47%). MS (ESI): m/z=507.14 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.Cl.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][NH2:30])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>C1COCC1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:30][CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)NCCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of 4-methoxybenzeneacetic acid (8.3 g) in dry THF (250 ml) was treated with triethylamine (6.9 ml) and wooled in a salt/ice-bath with stirring under a nitrogen atmosphere. Pivaloyl chloride (6.1 ml) was added and stirring continued for 1 h. A further aliquot of triethylamine (6.9 ml) was added followed by p-nitrophenethylamine hydrochloride (10 g). The resultant suspension was warmed to room temperature and stirred for 19.5 h (overnight). The reaction mixture was acidified to pH 1 using hydrochloric acid solution (2N; 30 ml) and the resultant solution was extracted with EA (1×250 ml, 1×100 ml). The combined organic extracts were washed with 8% NaHCO3 solution (200 ml), dried (MgSO4) and evaporated under reduced pressure to give a brown oil. Purification by `flash` chromatography, ER:CH2Cl2 (4:1) gave the title compound as a pale yellow solid (7.4 g) m.p. 109°-110°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:20])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]=[CH:9][N:10](C)C)=[O:7])=[C:4]([CH3:15])[CH:3]=1.Cl.[CH3:17][O:18]N>O1CCOCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:18][CH3:17])=[O:7])=[C:4]([CH3:15])[CH:3]=1
Reactant: CON
Reactant: Cc1cc(Br)ccc1C(=O)N=CN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CON=CNC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
In a solution of 0.67 g of 4-bromo-N-(dimethylaminomethylidene)-2-methyl benzoic acid amide in 10 mL of 1,4-dioxane, a solution of 0.36 g of methoxyamine hydrochloride in 2 mL of water was added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with 50 mL of ethyl acetate, washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.70 g of the aimed product as white crystal.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]=[O:11].C(N(CC)CC)C.[O:19]1CCOC[CH2:20]1>O>[OH:19][CH2:20][C:2]([CH2:10][OH:11])([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C1COCCO1
Reactant: C=O
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CO)(CO)C(C)=O
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl acetoacetate (150 g, 1.2 mol) in formaldehyde (210 mL, 2.8 mol, 40% aq.) and dioxane (550 mL) was added dropwise triethylamine (1.0 M in tetrahydrofuran, 57 mL, 0.06 mol) at 0° C. The temperature was raised up to 35-40° C. and the mixture was stirred for 1 h. The reaction mixture was diluted with water (400 mL), and the side products were extracted with toluene (3×600 mL). The aqueous phase was evaporated at 35° C. to one fourth of the initial volume and extracted with ethyl acetate (3×900 mL). The extracts were dried over sodium sulfate and evaporated to get the crude product (75 g) as yellow oil, which was used directly to the next step without purification.
Reaction SMILES: [NH2:1][CH:2]([P:16]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[SH2:32].[C:33](=O)=O>>[CH:33]([NH:1][CH:2]([P:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:17])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4])=[S:32]
Reactant: S
Reactant: NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(NC=S)P(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of p-nitrobenzyl α-amino-diphenylphosphonoacetate (5.0 g), ethyl thionoformate (5 ml), and hydrogen sulfide (5 ml) in a sealed thick-walled tube is left standing overnight at room temperature. The tube is cooled in dry-ice and the seal removed. A boiling chip is placed in the solution and it is allowed to slowly come to room temperature. Nitrogen is bubbled in to remove final traces of hydrogen sulfide. The residue is dissolved in methylene chloride, filtered, and evaporated under reduced pressure. Chromatography of the residue on silica gel gives p-nitrobenzyl α-thioformamido-diphenylphosphonoacetate.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].C([O-])(=O)C.[NH4+]>O1CCCC1.O.[Zn]>[OH:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:23]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Zinc dust (1.30 g, 20.32 mmol) was added to a solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (400 mg, 0.92 mmol) in tetrahydrofuran (20 mL). This suspension was treated with a solution of ammonium acetate (1.10 g, 13.9 mmol) in water (7 mL). After stirring at room temperature for 16 h, zinc residues were filtered off and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium hydrogen sulfate solution, the aqueous layer was extracted with ethyl acetate (2×), the organic layers were combined and the volatiles were removed in vacuo. The residual acetic acid was azeotroped off with toluene (3×10 mL) to give crude (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid which was combined with crude [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-methyl-amine hydrochloride in anhydrous acetonitrile (15 mL) and N,N-diisopropylethylamine (0.801 mL, 4.60 mmol). This solution was then treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (464 mg, 1.22 mmol). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and subsequently washed with saturated ammonium chloride solution and sodium bicarbonate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 0:1 to afford the title compound (318 mg, 58%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.85 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.9 Hz, 3H), 1.33 (d, J=6.9 Hz, 3H), 1.69 (d, J=6.9 Hz, 3H), 1.72-2.15 (m, 6H), 2.98 (s, 3H), 2.85-2.95 (m, 1H), 3.80-3.90 (m, 1H), 4.30-4.40 (m, 1H), 5.25-5.35 (m, 1H), 5.95-6.10 (m, 1H), 7.45-7.78 (m, 1H), 7.65-7.72 (m, 1H), 7.80-7.90 (m, 1H), 8.18-8-38 (m, 2H). LCMS (m/z) 548.1, 550.1 [M+H], Tr=2.60 min.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.[N:13]([O-])=[O:14].[Na+]>O>[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[N:13]=[O:14]
Reactant: O=N[O-]
Reactant: CC1NCCc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1c2ccccc2CCN1N=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
21.5 g of 1-methyl-1,2,3,4-tetrahydro-isoquinolinehydrochloride (its preparation: Monatshefte, volume 53-54, 959 (1929) are dissolved in 50 cm3 water and to the solution a solution of 8.22 g of sodium nitrite in 25 cm3 water is added within 1 hour at 75° C. dropwise. The reaction mixture is cooled at 75° C. after stirring for 2 hours and it is extracted with 6×30 cm3 chloroform. The chloroform solution is washed with 50 cm3 water, dried and evaporated in vacuo. 19.2 g (93%) 1-methyl-2-nitroso-1,2,3,4-tetrahydro-isoquinoline are obtained as a brown oil which is used for the next step without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1.C([O-])(=[S:29])C.[K+].O>CC(N(C)C)=O>[SH:29][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CC([O-])=S
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCI)cc1)N(C)C
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCS)cc1)N(C)C
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
6.4 g (0.014 mol) of 1-[4-(3-Iodopropylamino)phenyl]-2-dimethylamino-2-benzyl-butan-1-one are dissolved in 50 ml of dimethylacetamide. To the solution are added 2.28 g of potassium thioacetate and heated up to 50° C. After the reaction mixture is stirred at 50° C. for 15 min, it is poured into 150 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is dissolved in 50 ml of ethanol and the solution is bubbled by nitrogen for 30 min. to remove oxygen. To the solution are added 7 ml of 2 N sodium hydroxide solution and stirred at 0° C. for 15 min. After the reaction mixture is neutralized by adding 2% hydrochloric acid solution, the resulting solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.41 (t, 1H), 1.83-2.08 (m, 4H), 2.35 (s, 6H), 2.66 (q, 2H), 3.17 (d, 1H), 3.20 (d, 1H), 3.34 (br, 2H), 4.15 (br, 1H), 6.52 (d, 2H), 7.14-7.28 (m, 5H), 8.32 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1[C:42](C)=[CH:41]C=[CH:39][C:38]=1C.C(NCC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:24])[N:37]([CH2:42][CH3:41])[CH2:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, diethylamine (25 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-diethylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (66 mg, 59%) as a white solid: ESI-LRMS m/e calcd for C24H33ClN4O4S [M+] 508.19, found 509.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.18 (m, 5H, CH3 and CH2), 1.21 (t, J=7.2 Hz, 3H, CH3), 1.43-1.94 (m, 8H, 4×CH2), 2.18-2.27 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.33 (q, J=7.2 Hz, 2H, CH2), 3.39 (q, J=7.2 Hz, 2H, CH2), 3.54 (t, J=7.6 Hz, 1H, CH), 4.80 (s, 2H, NCH2), 6.71 (d, J=2.4 Hz, 1H, Ar), 7.36 (d, J=2.4 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.93 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (10.0 g) and ethyl bromoacetate (15.0 g) in DMF (150 mL) was added potassium carbonate (17.0 g), and the mixture was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (16.7 g) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=[CH:24]2)[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(N(CC)CC)C>ClCCl>[CH3:35][Si:34]([CH3:37])([CH3:36])[CH2:33][CH2:32][O:31][CH2:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([C:12]([C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[O:11])=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C(O)c3ccccc3C#N)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ccc2cc(C(=O)c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of oxalyl chloride (0.097 mL, 1.1 mmol) in dichloromethane cooled to −60° C. was added dimethyl sulfoxide (0.16 mL, 2.2 mmol), followed by 2-{hydroxy[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]methyl}benzonitrile (0.21 g, 0.55 mmol in 2 mL dichloromethane). Triethylamine (0.46 mL, 3.3 mmol) was added and the solution was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was quenched with an excess of water, and diluted with dichloromethane and brine. The layers were separated, and the aqueous layer was extracted (2×100 mL dichloromethane), dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 4:1 hexanes/ethyl acetate) gave 0.12 g (58%) of 2-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]carbonyl}benzonitrile. 1H NMR (400 MHz, CDCl3): 8.07 (d, 1H), 7.88 (dd, 2H), 7.70 (m, 3H), 7.60 (d, 1H), 7.30 (d, 1H), 6.65 (m, 1H), 5.56 (s, 2H), 3.53 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H); 13C NMR (400 MHz, CDCl3): 194.90 (C═O), 144.16, 140.45, 135.12, 133.07, 131.72, 131.03, 130.81, 129.82, 129.66, 127.08, 125.30, 118.39, 112.98, 111.50, 105.56, 77.05, 67.48, 19.09, 0.00.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][CH:13]=C)=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2].C[N+]1([O-])CC[O:33]CC1.I([O-])(=O)(=O)=O.[Na+]>O.O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][CH:13]=[O:33])=[C:9]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCOc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCC=O
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4-allyloxy-5-(4-chlorophenyl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-1e (337 mg, 0.8 mmol) osmium tetroxide (53 microliters of a 0.15 M solution in water) and N-methylmorpholine-N-oxide (120 mg, 0.9 mmol) in dioxane (2.4 ml)/water (0.6 ml) was stirred at ambient temperature for 18 hours, then sodium periodate (1.7 g, 8.1 mmol) was added and stirring was continued for 3.5 hours. The thick slurry was diluted with ethyl acetate (100 ml), filtered and solids washed 2× with ethyl acetate. The combined filtrates were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford an oil. Silica gel chromatography (25% ethyl acetate/hexanes) afforded the title compound (I-1f) as a colorless foam, 130 mg.