Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl>>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][CH:2]1[CH2:3][O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH2:7]1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COC1COC(c2ccccc2)OC1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
5-Hydroxy-2-phenyl-1,3-dioxane (8.4 g, 0.05 mole) was reacted with sodium hydride and 2-methoxybenzyl chloride (7.8 g, 0.05 mol) according to the method of Example 2, except that the mixture was heated at 100° C for 12 hours, to give 11.7 g of yellow oil. The oil was distilled under 1 × 10-5 mm to give 4.6 g of product, which distilled at a pot temperature of 180°-190° C. VPC analysis of the product showed it to contain 72% cis-5-(2methoxybenzyloxy)-2-phenyl-1,3-dioxane.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[C:1]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCCC1
Yield: 102 %

Procedure:
A 50 mL round-bottomed flask containing cyclohexanone (3.82 g, 39 mmol) in anhydrous toluene (20 mL) was fitted with a Dean-Stark trap containing 3 Å molecular sieves, reflux condenser and a heating mantle, pyrrolidine (6.00 mL) was added, and the solution heated to reflux for 18 h. The solvent was evaporated and the crude product 1-cyclohex-1-en-1-ylpyrrolidine was used directly for the next reaction. (6.0 g, 102% yield, 95% purity by HPLC). MS(ESI+): 152.3; MS(ESI−): 150.1.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][CH2:8][CH2:9][C@H:10]([NH:17][C:18](/[C:20](/[C:29]#[N:30])=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.ClCCl>C(#N)C>[Br:28][C:24]1[N:23]=[C:22]([CH:21]([S:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])[CH:20]([C:29]#[N:30])[C:18]([NH:17][C@H:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH3:7])=[O:19])[CH:27]=[CH:26][CH:25]=1
Reactant: OCC(O)CS
Reactant: CCC[C@H](NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCC[C@H](NC(=O)C(C#N)C(SCC(O)CO)c1cccc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.2 %

Procedure:
Thioglycerol (42 μL, 0.5 mmol) was added to a stirred solution of WP1130 (19 mg, 0.05 mmol) in acetonitrile (0.5 mL). The resulting mixture was stirred at room temperature for 17 hours. The mixture was distributed between water and dichloromethane. The separated organic layer was washed with sat. brine, dried over sodium sulfate, and concentrated to an oil. Purification by preparative TLC eluting with hexanes/ethyl acetate (6:4) afforded 20 (20 mg, 82%) as a clear oil: MS (ES+) m/z 492.0 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:20]([N:22](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.CS(C)=O>[C:20]([CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:22]
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCC(CCO)CCc1cccnc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)CCCC(CCC#N)CCc1cccnc1
Reaction time: 0.5 h

Procedure:
A solution of 0.8 g (3.0 mmol) of methyl 7-hydroxy-5-[2-(3-pyridyl)ethyl]-heptanoate in 3 ml methylene chloride is cooled to 0° and 0.52 mL (3.7 mmol) triethylamine is added followed by 0.26 mL (3.3 mL) methanesulfonyl chloride. The reaction mixture is stirred at 0° for 30 minutes and then 1.65 g (25 mmol) finely powdered potassium cyanide is added followed by 15 mL dimethyl sulfoxide. After stirring for 30 minutes the cold bath is removed and the mixture is stirred at room temperature for 18 hours. The reaction mixture is poured on to saturated aqueous ammonium chloride solution and then extracted with ethyl acetate (3×70 mL). Combined organic phase is washed with water (4×60 mL), brine (60 mL) and dried (MgSO4), filtered and evaporated to give an oil which is purified by flash chromatography to give both the desired methyl 7-cyano-5-[2-(3 -pyridyl)ethyl]-heptanoate and the mesylate of the starting alcohol. The mesylate is subjected to the cyanide displacement conditions described above to yield additional methyl 7-cyano-5-[2-(3-pyridyl)-ethyl]-heptanoate.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[C:39](=[O:40])[NH:38][N:37]=[CH:36]2)[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:38]2[C:39](=[O:40])[N:35]([C:27]3[S:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]([CH3:24])[N:26]=3)[CH:36]=[N:37]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: Fc1ccc(OCCBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(CCOc3ccc(F)cc3)c2=O)nc1C
Yield: 48 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(2-bromoethoxy)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 6.93-6.84 (m, 2H), 6.81-6.75 (m, 2H), 4.32-4.15 (m, 6H), 2.62 (s, 3H), 1.31 (t, J=7.1 Hz, 3H); MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][S:49](=[O:52])(=[O:51])[NH2:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C>ClCCCl.[Br-].[Zn+2].[Br-]>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][S:49]([NH2:50])(=[O:51])=[O:52])=[CH:38][CH:37]=2)=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNS(N)(=O)=O)CCC3)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCNS(N)(=O)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 1(e), the (3R,4R)-3-[1-(2-sulfamoylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with zinc bromide in 1,2-dichloroethane to yield the (3R,4R)-N-[2-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-ethyl]-sulfamide as a yellow oil; MS: 639 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CNCCc1ccccc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(CCc1ccccc1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N-methyl-2-phenylethanamine (1.2 equiv) to give 170 (14.5 mg, M+1 431.1)
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2ccns2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccns3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-isothiazol-5-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=O>C(Cl)Cl>[CH2:12]([C@@H:7]([C:8]1[C:9](=[O:11])[O:10][C:8]2[CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:15]=2[C:14]=1[OH:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: CC[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)c1c(O)c2c(oc1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3[S]-Phenylvaleric acid of formula WW-3 (400 mg) is added to methylene chloride (5 mL) followed by oxalyl chloride (0.21 mL). That mixture is heated at reflux for 3 hours. The methylene chloride is removed and 1,3,5-trimethylbenzene (10 mL) is added. The solution of the acid chloride is then heated to reflux temperatures and WW-2 (same as VV-2) (210 mg) and triethylamine (210 mg) (both in 1.5 mL of 1,3,5-trimethylbenzene) are added dropwise. After complete addition the reaction is heated for an additional 7 hours. The reaction is cooled to room temperature and the solid removed by filtration. The filtrate is evaporated and the resulting residue is diluted with methanol (35 mL) and 0.5N NaOH (4 mL) and that mixtured stirred at room temperature overnight. The methanol is removed and water (35 mL) added. The aqueous is extracted with ether/hexane (2×35 mL) and the aqueous is acidified with 1.6N HCl at 0° C. to pH 3. That aqueous is extracted with ethyl acetate, dried and solvent removed in vacuo to yield 287.0 mg of the title product. Chromatography over silica gel (EtOAc/methylene chloride 1:8) affords 199.4 mg of the title product WW-5.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([N:23]=[C:27]=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)N=C=O

Procedure:
(S)-5-(3′-Chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester is prepared from (S)-4-amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31) and triphosgene analogous to the procedure described for Example 6-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=O)C=1.S(=O)(O)[O-].[Na+].[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(N2CCCCC2)nc(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
44.0 mg (0.107 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 36.9 mg (0.213 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of toluene and 91.1 mg (1.07 mmol) of piperidine was added at room temperature and stirred at 80° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[K+].[K+].[CH:32]1[C:45]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>C(O)(=O)C.C(O)(C)(C)C.O>[CH:32]1[C:45]2[C:44](=[O:22])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=c1c2ccccc2oc2ccccc12

Procedure:
The above oxidation reaction may be carried out using dichromate anion such as sodium dichromate or potassium dichromate as the oxidizing agent. The reaction will proceed in from 15 minutes to 6 hours at a temperature of from 80° to 120°C. The amount of oxidizing agent is limited to the stoichiometric quantity required for oxidation of the 9-methylene group of the xanthene derivative. Suitable solvents for this conversion are, for example, water, acetic acid, tert-butyl alcohol, and the like, or combinations of these solvents. For example, by combining three moles of the xanthene derivative, Formula II, dissolved in acetic acid with four moles of sodium dichromate and refluxing the mixture for 1 to 3 hours, the corresponding xanthen-9-one derivative, Formula III, can be obtained.
Reaction SMILES: C(Cl)([Cl:3])=O.[CH:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]#[N:13])=[CH:7][CH:6]=1.N#N>C1(C)C=CC=CC=1>[Cl:3][CH:11]([C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1)[C:12]#[N:13]
Reactant: O=C(Cl)Cl
Reactant: N#CC(O)c1ccccc1
Agent: N#N
Solvent: Cc1ccccc1
Product: N#CC(Cl)c1ccccc1
Yield: 967.2 %

Procedure:
150 g of toluene and 7 g (0.02 mol) of Cyanex® 923 are initially introduced into a phosgenation apparatus with attached carbonic acid condenser and heated. At 99° C., 13 g of phosgene are gassed in over the course of 10 minutes. Thereafter, over the course of 2 hours, 192 g (1.44 mol) of benzaldehyde cyanohydrin and a further 149 g (total=172 g or 1.74 mol) of phosgene are added in parallel. The internal temperature is maintained between 99 and 102° C. throughout. After a post-reaction of 60 minutes at 99° C., excess phosgene is stripped out using N2 at 50° C. for 2.5 h. The discharge of 359 g is fractionally distilled on a 30 cm Vigreux column. The main fraction passes over at 0.6 mbar and a head temperature of from 68 to 73° C. 192.7 g (88.3% of theory) of α-chlorophenylacetonitrile are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.OC[C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:34][C@H:35]5[CH2:36][CH2:37][CH2:32][N:33]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
1,1-Dimethylethyl (2R)-2-[{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]-methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidine-1-carboxylate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1,1-dimethylethyl (2R)-2-(hydroxymethyl)piperidine-1-carboxylate following General Procedure J.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][N:45]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:44][CH2:43]1)=[O:41]
Reactant: COC(=O)C1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)OC)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperidine-4-carboxylic acid methyl ester (Aldrich) to give title compound. HR-MS (ES, m/z) calculated for C36H43Cl2N4O4 [(M+H)+] 665.2656, observed 665.2652.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[C:22]([F:23])=[C:21]([CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=1)=[O:16]>C(O)(=O)C.Cl>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:15]([C:17]1[C:22]([F:23])=[C:21]([CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=1)=[O:16])=[C:5]2[CH2:4][C:3]([OH:26])=[O:2]
Reactant: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1F
Agent: Cl
Solvent: CC(=O)O
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1F
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A stirred solution of methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate (Example 111, 391.2 mg, 1.044 mmol) in acetic acid (12 ml) and 2N aqueous HCl (4 ml) was heated at reflux temperature for 24 h. After cooling to room temperature, the resulting mixture was concentrated. The residue was diluted in THF (100 ml), dried (MgSO4) and concentrated. The crude product was purified by recrystallization to afford 349.2 mg (93%) of the title compound.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:16]2=[O:27])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:16]2=[O:27])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N2CCN(CCC(=O)OCC)C2=O)cc1
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCCCCCCCc1ccc(N2CCN(CCC(=O)O)C2=O)cc1
Yield: 33 %

Procedure:
When the product of Step A is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 33% yield, as a colourless solid. 1H-NMR (CDCl3) 7.39 (d, 2H, J=8.4 Hz); 7.11 (d, 2H, J=8.4 Hz); 3.78 (t, 2H, J=7.3 Hz); 3.6-3.4 (m, 4H); 3.22 (s, 3H); 2.66 (t, 2H, J=6.5 Hz); 2.53 (t, 2H, J=7.7 Hz); 1.55 (m, 2H); 1.25 (m, 10H); 0.85 (t, 3H, J=6.9 Hz).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=[N:20][NH:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)=[O:23])[CH3:19].[OH-].[Na+].Cl>CO>[CH3:17][C:4]1[C:3](=[C:18]([NH:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])[C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2c(C)nn(-c3ccc(C(F)(F)F)cn3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(c2ccc(C(F)(F)F)cn2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
50 mg of the methyl 4-([2-(1-{5-hydroxy-3-methyl-1[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}ethylidene)hydrazino]carbonyl)benzoate synthesized in 1) was heated in 3 ml of methanol and 0.3 ml of 1M aqueous sodium hydroxide at 60° C. for 8 hours with stirring. After it was cooled to room temperature, 0.3 ml of 1M hydrochloric acid was added to precipitate crystals, and crystals were collected by filtration and dried to obtain 30 mg of the desired product, 4-[(2-{1-[3-methyl-5-oxo-1-(5-trifluoromethyl-2-pyridinyl)-1,5-dihydropyrazol-4-ylidene]-ethyl}hydrazino)carbonyl]benzoic acid as a pale brown solid (yield 62%).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH:23]([C:27]([Cl:29])=[O:28])[CH2:22][C:21]2=[O:30]>C(N(CC)CC)C>[ClH:29].[ClH:1].[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:27]([CH:23]2[C:24]3[C:20](=[CH:19][C:18]([CH3:17])=[CH:26][CH:25]=3)[C:21](=[O:30])[CH2:22]2)=[O:28])[CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1
Reactant: Cc1ccc2c(c1)C(=O)CC2C(=O)Cl
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(=O)CC2C(=O)N1CCN(C)CC1CN1CCCC1
Yield: 57.4 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 0.75 g of 5-methyl-3-oxoindan-1-carbonyl chloride, to afford 0.84 g of the title compound, melting at 220°-223° C. (dec.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH:14][C@H:15]([C:26]([O:28]C)=[O:27])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc(C=CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Yield: 87.6 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 160 (4.5 g), 1 mol/L of an aqueous sodium hydroxide solution (17 mL), and methanol (170 mL), to give the captioned compound (3.8 g, 87%) as crystals.