Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=[O:2].[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]3[CH:12]([NH:24]C(OCC3C=CC=CC=3)=O)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd]>[CH:1]([OH:3])=[O:2].[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]3[CH:12]([NH2:24])[N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a 4.5% solution of 90% aqueous formic acid in methanol was added 120 mg of 10% palladium on carbon catalyst under nitrogen. To this suspension was added 150 mg of 6-phenyl-4-benzyloxycarbonylamino-4H-[1,2,4]triazolo-[4,3-a][1,4]benzodiazepin. The reaction mixture was stirred under nitrogen at 23° C. for 1.5 hours and filtered through Celite. The filtrate was concentrated under reduced pressure and azeotropically dried with toluene to yield the title compound.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([CH2:10]O)[CH:2]=1.P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:13][CH2:10][C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: BrP(Br)Br
Reactant: OCc1cnn2ccccc12
Solvent: ClCCl
Product: BrCc1cnn2ccccc12

Procedure:
To the solution of pyrazolo[1,5-a]pyridin-3-ylmethanol (2) (50 mg, 0.338 mmol) in DCM (2 mL) was added PBr3 (36.58 mg, 0.135 mmol) at room temperature for 30 min. The reaction solution was used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[O:13])[CH3:2].[Cl-].[NH4+].[C:28](=[O:31])([O-])O.[Na+].[CH3:33]O>>[CH2:24]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:17]=[C:3]([CH2:1][CH3:2])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([O:31][CH3:28])[O:13][CH3:33])[CH3:25]
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Reactant: CO
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC(OC)OC
Yield: 71 %

Procedure:
First, 0.39 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde was dissolved in 10 ml of anhydrous methanol, to which 5 mg of ammonium chloride was added, and the mixture was heated under reflux for 3 hours After left alone for cooling, the reaction mixture was mixed with 10 ml of saturated aqueous sodium hydrogencarbonate solution. The methanol was distilled out, and the residue was extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.31 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-dimethoxyethoxy)butyloxy)benzene (yield, 71%), nD24.0 1.5068.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:20])C=1.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:20][CH2:11]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCCCOC(=O)C(=C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCC1CO1
Reaction time: 5 h

Procedure:
A solution of 4-pentenyl methacrylate (9 g) in methylene dichloride (15 ml) was added to a solution of m-CPBA (18 g) in methylene dichloride (150 ml) and the reaction was allowed to proceed for 5 hr. The reaction mixture was then poured into water, the organic phase was separated and then washed several times with a dilute solution of potassium carbonate. The reaction product was washed with water and then dried with anhydrous magnesium sulfate. A pure product was isolated by column chromatography on silica gel. Yield 7 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:31]1[C:32](=[O:48])[N:33]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=[C:35]([C:37](O)=[O:38])[CH:36]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:49]([NH:56][C:57]1[CH:58]=[N:59]NC=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O.O[N:64]1[C:68]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:31]1[C:32](=[O:48])[N:33]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[CH:34]=[C:35]([C:37](=[O:38])[NH:59][C:58]2[CH:68]=[N:64][N:56]([CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:57]=2)[CH:36]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: c1ccc(CNc2cn[nH]c2)cc1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)cc(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)cc(-c2cc(C(=O)Nc4cnn(Cc5ccccc5)c4)cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
Intermediate (4c), 5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester, (1 g, 1.46 mmol), benzyl-1H-pyrazole-4-yl amine (0.75 g, 4.39 mmol), 1-hydroxybenzotriazole hydrate (0.59 g, 4.39 mmol) and tetrahydrofuran (15 mL) were placed in a microwave vial. To this solution was added N,N-diisopropylethylamine (0.58 g, 0.78 mL, 4.49 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.84 g, 4.39 mmol), the vial capped and heated in the microwave at 90° C. for 30 minutes. After cooling, the mixture was concentrated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was separated and the aqueous was extracted with a further portion of dichloromethane. The combined dichloromethane layers were dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—15% methanol/dichloromethane (gradient) to afford the desired title compound as a yellow foam, 1.0 g, 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9](N)[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O[C:15](=[O:23])[C@@:16](S(C)(=O)=O)([CH3:18])O)C.C([N:26](CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][NH:26][C@H:16]([CH3:18])[C:15]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(N)Nc1cccc(Cl)c1
Reactant: CCOC(=O)[C@@](C)(O)S(C)(=O)=O
Solvent: Cc1ccccc1
Product: C[C@H]1NCCN(c2cccc(Cl)c2)C1=O

Procedure:
A solution of 18.4 g (0.108 moles) of N-(3-chlorophenyl)-ethanediamine (J. Med. Chem., 9, 858-860 (1966)), 19.3 ml (0.119 moles) of (S)-methanesulfonyl-lactic acid ethyl ester and 22.8 ml (0.163 moles) of triethylamine in 200 ml of toluene was boiled and refluxed overnight.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
5.0 mL of methylene chloride, 0.056 mL of triethylamine and 51 mg of 4-methoxybenzoyl chloride were added sequentially to 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature, and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufacture by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(4-methoxybenzamido)-4-phenoxybenzoate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][CH2:13][C@H:14]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1.CC[N:32]([CH:36](C)C)C(C)C.C[N:40](C=O)C>>[NH:1]([CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][C@H:14]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[C:15]([OH:17])=[O:16])=[O:11])=[CH:28][CH:29]=1)[C:36]([NH2:32])=[NH:40]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCOCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reactant: CN(C)C=O
Product: N=C(N)NCCOCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1

Procedure:
Amine 15-5 (40 mg, 0.095 mmol), PCA·HCl (15 mg, 0.10 mmol), and DIPEA (35 mL, 0.20 mmol) were combined in 1 mL DMF and heated at 50° for 16 h. Concentration, and flash chromatography (silica, 20:1:1 EtOH/NH4OH/H2O) provided 15-6 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.Cl[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:29]>C(Cl)Cl>[Cl-:1].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:27][C:28](=[O:29])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:7]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Cn1cc[n+](CC(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c1)c1ccc(F)cc1
Product: [Cl-]

Procedure:
In a manner similar to that previously described, 4.2 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-imidazole, 1.7 parts of 2-chloro-4'-fluoroacetophenone and 40 parts of methylene chloride are mixed together and stirred at reflux temperature for 15 hours. Thereafter, the solvent is evaporated under reduced pressure and the residue triturated in 4-methyl-2-pentanone. The solid is recovered by filtration and crystallized from acetonitrile to obtain a purified 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-3-(p-fluorobenzoylmethyl)-imidazolium chloride product, mp. 181° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([N:10]([C:19]([O:21]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[N:5]2.[C:27]1([C:33]2[N:37]=[C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[S:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([NH:10][C:19]([N:41]1[CH2:42][CH2:43][N:38]([C:36]3[S:35][N:34]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:37]=3)[CH2:39][CH2:40]1)=[O:21])=[N:5]2
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1ccc2nccn2n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc2nccn2n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A mixture of bis(2,2,2-trichloroethyl) imidazo[1,2-b]pyridazin-6-ylimidodicarbonate (295 mg, 0.609 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.106 ml, 0.609 mmol) in dimethylsulfoxide (2.0 ml) was stirred at 70° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 212 mg (85.7%) of the desired product as a solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][N:17]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH:18]2[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46].Cl>C(Cl)Cl.N1C=CC=CC=1>[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45]([NH:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][N:17]([S:32]([C:35]([F:37])([F:36])[F:38])(=[O:34])=[O:33])[CH:18]2[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:46]
Reactant: NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Reactant: O=C(Cl)Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
To a suspension of p-toluenesulfonic acid salt of benzyl 7-amino-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (800 mg.) in methylene chloride (8 ml.) was added pyridine (146 μl). After stirring at -55° C. for 5 minutes, 2-(2-thienyl)acetyl chloride (290 mg.) was added thereto, and then the mixture was gradually allowed to warm to 0° C. over a period of 1.5 hours. This mixture was poured into chilled dilute hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with water (×2), a dilute aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, successively. Drying over magnesium sulfate and removal of the solvent left an amorphous solid (800 mg.), which was chromatographed on silica gel (10 g.) with a mixed solvent of methylene chloride and ethyl acetate (95:5 to 90:10 by volume) to give benzyl 7-[2-(2-thienyl)acetamido] -8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (667 mg.).
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:27]1[CH2:28][CH2:29][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][C:26]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1csc2ccc(NN)cc12
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CN(Cc1ccccc1)CC4

Procedure:
The compound is formed analogously to that described in Example 5, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 23 g of 1-benzyl-4-piperidone. Melting point: 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH:37](=O)[CH3:38]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: CC=O
Product: CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:44])[C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([N:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH3:44])=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Reactant: CN(C(=O)CC(=O)O)c1ccc(F)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(C=O)cn4)sc23)c(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To intermediate 38 (0.35 g, 0.86 mmol) in dry DMF (25 mL) was added 3-((4-fluorophenyl)(methyl)amino)-3-oxopropanoic acid (44) [U.S. 2007/0004675 A1] (0.36 g, 1.7 mmol) [Met-036], and EDCHCl (0.33 g, 1.7 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated. The crude product was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), and heated to reflux for 3 h. It was then cooled and concentrated. The residue was then partitioned between ethyl acetate and water, the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated to produce intermediate 45 (0.27 g, 57% yield). MS (m/z): 559.2 (M+H).
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[CH:25]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13].Br[CH2:30][C:31]([O:33]CC)=[O:32]>C(OCC)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To methylmagnesium bromide solution (3 mol/L in diethyl ether, 0.4 mL) stirred under nitrogen at 0° C. was added a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (354 mg) in diethyl ether (5 mL) dropwise. The reaction mixture was stirred at 0° C. for 30 mins. Ethyl bromoacetate (0.13 mL) in toluene (15 mL) was added dropwise. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated ammonium chloride solution; the organic layer was separated and the solvent was evaporated off. The residue was dissolved in tetrahydrofuran (5 mL) and sodium hydroxide (40 mg) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. Evaporated off the organic solvent, extracted with ether (100 mL), the water layer was separated and acidified with HCl (1 M) to pH around 1. The solid was filtered and purified by Mass Directed Auto Prep to afford [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]acetic acid (E31) (86 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.74 (2H, s), 4.87-4.93 (1H, m), 7.22 (1H, t), 7.40 (1H, d), 7.45 (1H, d), 7.78 (1H, d), 7.95 (1H, d), 8.21 (1H, dd), 8.37 (1H, d), 10.91 (1H, s), 12.19 (1H, br s). MS (ES): C21H18ClN3O4 requires 411; found 412.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[ClH:1].[CH3:23][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)nc2ccccc12
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCN1c1nc(N(C)c2ccccc2)nc2ccccc12
Product: Cl
Yield: 54 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.4 g of the compound (4.52 mM) prepared in Example 2 and 15 ml of dimethyl-formamide, 1.1 ml of N-methylaniline(10.1 mM) was added, 1.02 g of the title compound was prepared.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[CH:11][C:10]([S:23]([C:26]1[CH:27]=[C:28]([CH:44]=[CH:45][CH:46]=1)[C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38]OS(C)(=O)=O)[CH2:33][CH2:32]1)=[O:30])(=[O:25])=[O:24])=[CH:9][C:8]=2[CH3:47])(=[O:3])[NH2:2].[NH2:48][CH2:49][C@@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C.O>CS(C)=O>[Si:52]([O:51][CH:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[CH2:49][NH:48][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][N:31]([C:29]([C:28]2[CH:27]=[C:26]([S:23]([C:10]3[CH:11]=[C:12]4[C:7](=[C:8]([CH3:47])[CH:9]=3)[N:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:13]4[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)(=[O:25])=[O:24])[CH:46]=[CH:45][CH:44]=2)=[O:30])[CH2:32][CH2:33]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCOS(C)(=O)=O)CC5)c4)cc23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCNCC(O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)CC5)c4)cc23)c1
Reaction time: 1 h

Procedure:
To a solution of Intermediate 138 (360 mg, 0.53 mmol) and Intermediate 2 (209 mg, 0.53 mmol) in 3 mL DMSO, DIEA (276 μL, 1.59 mmol) was added at 50° C. The reaction mixture was stirred for 1 h and water was added. The solid was collected by filtration and purified with prep HPLC to give the title compound. ES/MS calcd. for C48H58N7O8Ssi+ 920.4. Found m/z=920.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3].O=S(Cl)Cl.[CH3:20]O>>[CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([O:11][CH3:20])=[O:10])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CCOc1cc(Cl)c(C(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: C=CCOc1cc(Cl)c(C(=O)OC)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of compound 21 (17.0 g, 58.0 mmol) in MeOH (380 mL) was added dropwise SOCl2 (21.1 mL, 291 mmol) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then, stirred at 0° C. for 14 hours. The mixture was concentrated in vacuo and poured into aq. saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude product 39 (17.7 g, 99%) as a white solid.