Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][S:25]([CH3:24])(=[O:27])=[O:26])=[O:5]
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.83 h
Yield: 6 %

Procedure:
To a stirred suspension of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (216 mg) in pyridine (2 ml) was added a solution of methanesulfonyl chloride (78.4 mg) in dimethylformamide under ice-cooling, and the mixture was stirred for 50 minutes at the same temperature. The mixture was concentrated in vacuo, and ethyl acetate, methanol and water were added to the residue. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methanesulfonylhydrazino)quinoline (16 mg).
Reaction SMILES: CS(Cl)(=O)=O.Cl[CH2:7][Cl:8].OC[CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]2[O:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]1=[O:23]>C(N(CC)CC)C>[Cl:8][CH2:7][CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]2[O:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]1=[O:23]
Reactant: ClCCl
Reactant: Cc1cc2c(=O)n(CCCO)ccc2o1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(=O)n(CCCCl)ccc2o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methane sulfonyl chloride(0.24 ml) was added to a dichloromethane solution(10 ml) of 5-(3-hydroxypropyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and triethylamine(0.45 ml). The mixture was stirred at room temperature for two days. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:4→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(0.16 g) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)[CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].O>CO.[Fe]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH2:9][CH2:10][C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=2)=[C:14]([NH2:21])[CH:15]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1[N+](=O)[O-])=C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
To a suspension of 7-methoxy-3-(4-methoxy-2-nitrophenyl)-1,2-dihydronaphthalene (600 mg), iron (430 mg) and ammonium chloride (830 mg) in methanol (15 ml) was added water (6 ml), and the solution was stirred for 6 hours at 80° C. The solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (356 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][C:23]1[CH:22]=[N:21][N:20]([CH2:19][C:18]2[C:14]([CH3:13])=[N:15][O:16][C:17]=2[CH3:26])[CH:24]=1)=[O:8])#[N:2]
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2cccc(C#N)c2)cn1
Yield: 15 %

Procedure:
Prepared as in Example 4-8 from 3-cyanobenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 15%. MS M+H calculated 322.6. Found 322.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:26])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid (300 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (e).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 7-fluoro-3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.486 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was then dried in vacuum at 50° C. to obtain the title compound (25.4 mg, yield 14%). LC-MS (ESI) m/z: 380 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 4.52-4.53 (d, J=6.8 Hz, 1H), 5.02-5.04 (m, 1H), 6.73 (s, 1H), 6.82-6.85 (m, 1H), 6.99-7.09 (m, 4H), 7.18-7.22 (m, 2H), 7.69 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)Cl.O.[CH:33](O)=[O:34]>>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][CH:33]=[O:34])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: O=CO
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(OC=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 60 %

Procedure:
4 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate in formic acid were heated to 60° C. for 6 hours and to 65° C. for an additional 3 hours (approx. 80% complete reaction) Methylene chloride and H2O were added to the mixture after transferring to a separation funnel. The methylene chloride layer was washed with water, NaHCO3, water and brine, dried over MgSO4 and its volume reduced to 3.8 g. The product was purified by silica gel chromatography (hexane/ethyl acetate) and identified as the above methyl formoyloxypentanoate ester with an overall yield of 60%.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[CH:25]1([CH:31]=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CC1CCCCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=CC1CCCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.115 g, 0.30 mmol) was reacted with cyclohexanecarbaldehyde (0.336 g, 3.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.
Reaction SMILES: S1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([F:13])[C:10]([C:14]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:15]=3[F:24])=[C:9]([F:25])[CH:8]=2)[CH2:3][CH2:2]1.O[O:27][S:28]([O-:30])=O.[K+]>C(Cl)Cl>[O:27]=[S:28]1(=[O:30])[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([F:13])[C:10]([C:14]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:15]=3[F:24])=[C:9]([F:25])[CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=S([O-])OO
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C3=CCSCC3)cc2F)n1
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3=CCS(=O)(=O)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 6-(4-(3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) in DCM (0.10 M) at rt was added oxone (6.0 equiv.) in one portion. The resulting mixture was stirred at RT overnight, and then refluxed at 40° C. for 4 hrs. 10.0 equiv. of oxone were added and the reaction was allowed to stir at 40° C. over the weekend. The reaction mixture was then diluted with DCM and washed with water the aqueous layer was then separated and extracted with DCM. The combined organic were then dried over MgSO4 and concentrated in vacuo to yield methyl 6-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinate in 100% yield. LC/MS=398.0 (M+H), Rt=0.76 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1>CO>[CH3:1][O:2][C:3]([CH2:4][CH2:5][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)=[O:6]
Reactant: C=CC(=O)OC
Reactant: NCC1COc2ccccc2C1
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CC1COc2ccccc2C1
Reaction time: 16 h
Yield: 95 %

Procedure:
3.03 g (35.2 mmol) of acrylic acid methyl ester are added to a solution of 2.61 g (16 mmol) of 3-aminomethylchroman in 20 ml of methanol. The reaction solution is stirred for 16 hours at 50° and, after cooling, is concentrated by evaporation in vacuo. 5.1 g (95%) of N,N-bis(2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine are obtained in the form of a reddish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=[N:23][OH:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC2(O)CCCCCC2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCC1(O)CCCCCC1)c1cc(C=NO)ccc1Cl
Yield: 45.9 %

Procedure:
A solution of 2-chloro-5-formyl-N-(1-hydroxy-cycloheptylmethyl)-benzamide (290 mg, 0.94 mmol), hydroxylamine hydrochloride (78 mg, 1.13 mmol) and sodium acetate (223 mg, 2.72 mmol) in methanol (5 mL) and water (5 mL) was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and adsorbed onto silica gel. The residue was purified by chromatography (1:1 ethyl acetate-hexane) to afford the title compound (140 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[NH2:1][C:2]1[C:11](/[CH:19]=[CH:18]/[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c(N)c(Br)cc2c1CCCC2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(N)c(/C=C/C(=O)OC(C)(C)C)cc2c1CCCC2
Temperature: 200 °C
Yield: 30.2 %

Procedure:
A mixture of Example 476A (0.327 g, 1.2 mmol), tert-butyl acrylate (0.203 mL, 1.40 mmol), acetonitrile (1.5 mL), tri(ortho-tolyl)phosphine (0.035 g, 0.12 mmol), palladium diacetate (0.013 g, 0.06 mmol), and triethylamine (0.32 mL, 2.3 mmol) was sealed and heated in a microwave reactor for 10 minutes at 200° C. The reaction mixture was concentrated and purified by flash chromatography (15% ethyl acetate/hexanes) to provide the desired product (0.12 g, 32%); MS (DCI) m/e 332 (M+H)+.
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Br:22])=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.Cl>C(O)C>[Br:22][C:18]1[CH:19]=[C:20]([Cl:21])[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:16][CH:17]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ncc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 78707.6 %

Procedure:
Water (7 ml) and 4N aqueous solution of sodium hydroxide (7 ml) were added at room temperature to a solution of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.00 mg) in ethanol (14 ml) and stirred at 80° C. for five hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (29 ml) was added. The precipitated solid was collected by filtration to give the titled compound (723 mg) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1.[C:45](Cl)(=[O:50])[CH2:46][CH:47]([CH3:49])[CH3:48]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:45](=[O:50])[CH2:46][CH:47]([CH3:49])[CH3:48])[C:9]2[CH:10]=[C:11]([CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)CC(C(=O)O)c1cc(Nc2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CC(=O)N(c1ccc(Cl)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
To a solution of 2-[5-(4-chloro-phenylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (51.1 mg, 0.11 mmol), sodium acetate 40 mg, 1.1 mmol) and toluene (0.5 mL) was added isovaleryl chloride (60 μL, 0.55 mmol) and the resulting mixture was stirred at RT for 48 hr. The mixture was treated with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried with MgSO4, filtered and the solvent was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (gradient 0% to 30% EtOAc/heptane) to afford 16.3 mg (27%) of the title compound as a solid. 1H-NMR (CDCl3; 300 MHz): δ 7.6-7.7 (m, 4H), 6.98-7.45 (m, 7H), 3.7 (m, 1H), 2.2 (m, 2H), 2.0 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.25 (bs, 1H), 0.85-1.0 (m, 12H). Mass spectrum (ESI, m/z): Calcd. for C30H31ClF3NO3, 546.03 (M+H), found 548.26, 546.29.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[C:81]([F:84])([F:83])[F:82])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27]([NH:68][C@H:69]([CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[C:81]([F:82])([F:83])[F:84])[CH2:70][C:71]([OH:73])=[O:72])=[O:28])[CH:5]=1)[CH2:2][CH3:3]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1C(F)(F)F
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2C(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)-phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 0.257 mmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-trifluoromethylphenyl)butanoic acid.HCl (14.6 mg, 51.4 μmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (21.1 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H29F3N8O3, 619.23; found 619.6.
Reaction SMILES: C(=O)([O-])O.[Na+].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:15]([NH2:25])(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:12]([O:11][C:9]([C:8]1[N:25]=[C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][CH:7]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
Synthesis was performed as described by Panek et al. (J. Org. Chem., vol. 61, p. 6496 (1996)). Sodium hydrogencarbonate (22.8 g) and ethyl bromopyruvate (10.5 mL) were added to a solution of cinnamamide (10.0 g) in tetrahydrofuran (250 mL) at room temperature, and the mixture was heated under reflux for 48 hours. After the reaction mixture was left to cool to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), and trifluoroacetic acid anhydride (30 mL) was added to the solution at 0° C. The mixture was gradually heated to room temperature, and was stirred for 63 hours. Saturated aqueous sodium hydrogencarbonate (500 mL) and ethyl acetate (150 mL) were added to the reaction mixture to partition the mixture. The aqueous layer was extracted with ethyl acetate (150 mL), and the organic layers were combined. The combined organic layer was washed with saturated brine (150 mL), dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→3:1), to thereby give the title compound (10.9 g).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:40][C:37]1[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
A solution of 5.5 g (21.72 mmol) of 1,1′-azodicarbonyl-dipiperidine, in solution in 15 ml of dry toluene, is added, under argon at 20° C., dropwise, to a solution of 3 g (14.48 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 2.37 g (21.72 mmol) of 4-pyridylcarbinol and 5.45 ml (21.72 mmol) of n-tributylphosphine in 200 ml of toluene. The mixture is stirred at 20° C. for 48 h. The reaction mixture is subsequently concentrated under reduced pressure. The residue is purified by silica column chromatography (eluent: heptane/ethyl acetate). 3.2 g of the expected product are thus isolated, which product is used as it is in the subsequent synthesis.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C.O>[C:13]([NH:17][C:18]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: COc1ccc(C(N)CO)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(CO)NC(=S)NC(C)(C)C)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 1.3 g of 2-amino-2-(4-methoxyphenyl)-1-ethanol and 1.46 cm3 of tert-butyl isothiocyanate in 12 cm3 of absolute ethanol for 21 hours at a temperature in the region of 20° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 10 cm3 of water. A crystalline precipitate forms, which is filtered off, washed with 3 times 5 cm3 of diethyl ether and dried under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.32 g of N-(tert-butyl)-N′-[1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea are obtained in the form of a white solid melting at 127° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[O:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: O=C1CCCC1
Product: C1CCC2(C1)NCCO2

Procedure:
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methoxy-4-nitrophenylimino)-3-(cyclopentyl)-1,3-thiazolidine.