Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(CCCl)c1cc(F)c(F)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
oxalyl chloride (0.39 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (730 mg) in methylene chloride (20 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid chloride. Triethylamine (4.1 mL), methylene chloride (20 mL) and DMF (5 mL) were added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (1.00 g) in THF (25 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid chloride obtained above in THF (5 mL) was added to the reaction solution at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])#[N:2]>C[O-].[Na+]>[CH2:17]([N:16]1[C:1](=[NH:2])[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][CH3:12])[C:8]=2[O:9][CH3:10])[NH:13][C:14]1=[O:15])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNC(=O)Nc1ccc(OC)c(OC)c1C#N
Agent: C[O-]
Agent: [Na+]
Product: CCCCn1c(=O)[nH]c2ccc(OC)c(OC)c2c1=N
Yield: 69.2 %

Procedure:
A mixture of 1-(2-cyano-3,4-dimethoxyphenyl)-3-butyl urea (5.2 g, 18.8 mmol) in 50 ml of 0.5N methanolic sodium methoxide was heated at reflux under nitrogen for 18 hours. The reaction solution was cooled and a precipitate which formed was collected, washed with cold methanol and dried giving 3.61 g (68.4%) of analytical product, mp 165°-168°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Br:30][C:27]1[CH:26]=[CH:25][C:24]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:34]=3)=[CH:3][CH:4]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(-c3cccc(C(F)(F)F)c3)cc2)ccc1OCC(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid (described above) (231 mg, 0.421 mmol), 3-(trifluoromethyl)phenylboronic acid (203 mg, 1.07 mmol), KF (81 mg, 1.39 mmol), Pd2(dba)3 (23 mg, 0.025 mmol) and Pd(P(t-Bu)3)2 (26 mg, 0,051 mmol) was evacuated for air and kept under nitrogen. THF (5 ml) was added and the reaction mixture was stirred at 50° C. overnight. A saturated aqueous NH4Cl (5 ml) solution was added, and the mixture was extracted with methylene chloride (2×20 ml). The combined organic phases were dried an evaporated. The isolated products were further purified on HPLC using acetonitril:water (4:6) increasing to pure acetonitril as eluent. The title product was isolated as an E/Z mixture in 95 mg (37%) yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH2:6][CH2:7][OH:8]
Reactant: OCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: OCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirred solution of 2-(3-thienyl)ethanol (25.0 g, 0.195 mol) in carbon tetrachloride (250 ml) was added N-bromosuccinimide (34.7 g, 0.195 mol) in several portions over a 15 minute period. The mixture was stirred at room temperature for one hour. The succinimide was removed by filtration and the filtrate was concentrated in vacuo at room temperature to give the product as a viscous amber oil (40.2 g) (99%). TLC indicated that the product was pure and mass spectral analysis showed a molecular ion at M/Z 206. NMR supported the structure.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:36])[F:37])=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1C(F)(F)F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-trifluoromethylphenyl isocyanate (0.169 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 148 mg (42.1%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.[Cu]I>[F:28][C:3]1[C:2]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CCCC3=O)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 40.1 %

Procedure:
A suspension of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (221 mg, 0.5 mmol), 2-pyrrolidinone (46 μL, 0.60 mmol), N,N′-dimethylethylenediamine (22 μL, 0.20 mmol), CuI (19 mg, 0.10 mmol), and K3PO4 (212 mg, 1.00 mmol) in 1,4-dioxane (2.0 mL) was stirred at 90° C. under Ar atmosphere. The reaction mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was purified by basic silica gel column chromatography (AcOEt/hexane=50%-100%) to give the title compound (89.4 mg, 40% yield) as an amorphous solid. 1H NMR (300 MHz, CDCl3): δ ppm 2.26 (2H, q, J=7.7 Hz), 2.59 (2H, t, J=8.1 Hz), 3.80 (2H, t, J=7.0 Hz), 3.89 (3H, s), 6.36 (1H, dd, J=15.5, 1.9 Hz), 7.03 (1H, t, J=8.3 Hz), 7.30 (1H, d, J=1.9 Hz), 7.34-7.49 (6H, m), 7.73-7.83 (2H, m). LC-MS (ESI) m/z 446 [M+H]+. Anal. Calcd for C24H20FN5O3.0.2H2O: C, 64.19; H, 4.58; N, 15.59. Found: C, 64.00; H, 4.51; N, 15.56.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]([OH:26])[CH:15]([N+:23]([O-])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]2[CH:27]([CH2:28][O:29][CH3:30])[CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]([OH:26])[CH:15]([NH2:23])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]2[CH:27]([CH2:28][O:29][CH3:30])[CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(Cc1ccccc1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(N)Cc1ccccc1
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
Cool a mixture of 3-(1-hydroxy-2-nitro-3-phenylpropyl)-7-methoxymethyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.320 g, 0.761 mmol) and nickel (II) chloride (0.150 g, 1.14 mmol) in methanol (10 mL) in a water bath and slowly add sodium borohydride (0.115 g, 3.04 mmol). After 5 min, quench the reaction with water and concentrate. Add ethyl acetate and water, then filter through a filtering agent and wash solid with ethyl acetate. Separate the layers and wash organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (0.243 g, 82%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([NH:12][S:13]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[C:33]([CH:34]=[O:35])=[C:32]([Cl:36])[N:31]=[C:30]3[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])(C)(C)C>>[CH2:37]([C:30]1[N:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:17]3[C:16]([S:13]([NH2:12])(=[O:14])=[O:15])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)[C:33]([CH:34]=[O:35])=[C:32]([Cl:36])[N:31]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
C2HF3O2 (1b): TFA (10 mL, 129.8 mmol) was added to intermediate (1a) (5.0 g, 10.2 mmol). The mixture was stirred at 80° C. for 2 hours. TFA was removed under vacuum and the crude intermediate (1b), as a TFA salt, was used in the next step (5.6 g). Anal. HPLC: retention time=3.4 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C21H22ClN3O3S, 432.11; found 432.2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:36]([CH2:35][CH:34]([OH:38])[C:31]4[CH:32]=[CH:33][C:28]([CH2:27][OH:26])=[CH:29][CH:30]=4)[CH3:37])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccc(CO)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2ccc(CO)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-[4-(hydroxymethyl)phenyl]-2-(methylamino)ethanol (Preparation 93) (69 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/DMF (15 mL/1 mL, dissolved with warming DMF, added with acetonitrile, and then cooled to 0° C. overnight) gave the title compound (92 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:17]O.C(N(CC)CC)C.S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:17][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]=1[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOc1cccc(CO)c1OCCOC
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1cccc(CCl)c1OCCOC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution of (2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (1.12 g, 4.37 mmol) and triethylamine (0.49 g, 4.84 mmol) in dichloromethane (20 mL) was slowly added thionyl chloride (0.78 g, 6.58 mmol) at 0° C. The solution was stirred at 0° C. for 15 min, and then at rt for 3 h. Dichloromethane (80 mL) was added, the solution was washed with water (50 mL), sat. sodium bicarbonate (50 mL), and brine (50 mL), dried with sodium sulfate, and concentrated to give crude 1-(chloromethyl)-2,3-bis{[2-(methyloxy)-ethyl]oxy}benzene (1.15 g, 96% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ7.02 (m, 2H), 6.90 (dd, 1H), 4.72 (s, 2H), 4.27 (m, 2H), 4.14 (m, 2H), 3.77 (m, 2H), 3.73 (m, 2H), 3.46 (s, 3H), 3.44 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.O.NN>CCO.[Pd]>[N:9]1[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:17]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc2cccnc2c2ncccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
This compound was synthesized by the reduction of 5-nitro-1,10-phenanthroline. The procedure was manipulated under argon. To a suspension of 5-nitro-1,10-phenanthroline (2.06 g, 9.0 mmol) and 10% Pd/C (0.280 g) in 90 ml of 95% EtOH, hydrazine hydrate (2.0 ml, 42 mmol) was added dropwise. The mixture was heated for 3 h at 70° C. and then filtered hot through a glass-fiber filter to remove the catalyst. The yellow solution was concentrated to 25 ml and left at 4° C. for 24 hours. The precipitate was filtered off, washed with cold Et2O, and dried under vacuum for 24 hours to give 1.425 g of product (81%). 1H-NMR (DMSO-d6): δ=9.08 (m, 1H), 8.71 (m, 2H), 8.06 (m, 1H), 7.75 (q, 1H), 7.52 (q, 1H), 6.90 (s, 1H), 6.17 ppm (d, NH2). 13C-NMR (DMSO-d6): δ=149.3, 146.2, 144.8, 142.7, 140.5, 132.7, 130.8, 123.2, 122.0, 101.8 ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])C1C=CC=CC=1NC(=O)OC(C)(C)C.FC(F)(F)O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH2:31][C:32]([O-:34])=[O:33])=[CH:25]2.[Li+:37].CC(C)([O-])C.[K+]>>[F:1][C:2]([F:18])([F:17])[C:29]1[CH:30]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][C:26]([CH2:31][C:32]([O-:34])=[O:33])=[CH:25]2.[Li+:37]
Reactant: O=C([O-])Cc1cc2cc(OC(F)(F)F)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li+]
Product: O=C([O-])Cc1cc2cccc(C(F)(F)F)c2[nH]1

Procedure:
The titled compound was prepared from tert-butyl 2-(trifluoromethyl)phenylcarbamate using the procedures described in Example 26, Steps 26b through 26h, except for the use of potassium tert-butoxide instead of potassium hexamethyldisilizane in step 26g. MS (ES+) detects free acid at 244 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[O:62][CH3:63])[C:50]1=[O:64]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[O:62][CH3:63])[C:50]1=[O:64])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4OC)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (23 mg, 0.040 mmol) and Intermediate 62 (14 mg, 0.040 mmol) to give a white solid (10 mg, 31% yield). Anal. Calcd. for C44H54N4O7S m/z 782.4. found: 783.3 (M+H)+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.08-7.33 (10H, m), 6.98-7.08 (2H, m), 6.91-6.98 (2H, m), 5.31 (1H, t, J=4.67 Hz), 5.08-5.18 (1H, m), 4.91-5.02 (1H, m), 4.76 (1H, dd, J=10.17, 6.32 Hz), 4.03-4.35 (4H, m), 3.84-3.96 (1H, m), 3.80 (3H, s), 3.68 (3H, s), 3.29-3.46 (1H, m), 3.04-3.23 (2H, m), 2.65-2.91 (5H, m), 2.30-2.49 (3H, m), 1.90-2.05 (3H, m), 1.57-1.90 (8H, m), 1.41-1.56 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[H-].[Na+].F[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])[CH2:6][CH2:5]2
Reactant: NC(=O)c1ccccc1F
Reactant: Clc1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A slurry was prepared comprising 5-chloroindoline (15.3 gm, 0.1 mole), dimethylsulfoxide (DMSO) [50 ml] and sodium hydride (5.28 gm, 50% in oil, washed with hexane). The slurry was permitted to stir at room temperature for 1 hour. To this a solution of o-fluorobenzamide (15.2 gm, 1.1 eq.) in DMSO (20 ml) was added dropwise with the temperature between 17°-19° C. At the end of addition the reaction mixture was stirred at room temperature for 2 hours, then heated to 75°-78° C. for 16 hours. The reaction mixture was partitioned between methylene chloride (300 ml) and water (250 ml). The aqueous phase was separated and extracted twice with methylene chloride (150 ml). The combined organic solution was washed twice with water, twice with HCl (2N, 100 ml), brine (2×50 ml), dried over Na2SO4, concentrated to about 50 ml. Ether (50 ml) was added. The product was crystallized out upon standing overnight (about 16 hours). The yield was 14.2 gm (52%); m.p. 137°-138° C. Recrystallization from methylene chloride and ether yielded 2-(5-chloro-indolin-1-yl)benzamide (11.82 gm) m.p. 137°-138° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(C)[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1n[nH]c(C)c1Cl
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (Maybridge, 4.41 g, 28.6 mmol) in DMF (14 mL) was added N-chlorosuccinimide (3.86 g, 28.9 mmol). The resulting solution was heated at 60° C. for 3 h and then cooled to room temperature. Water was added until a white precipitate formed, and the solid was collected by filtration washing with water. The solid was dissolved in CH2Cl2, washed with water (2×), dried over MgSO4 and concentrated in vacuo to provide the title compound (5.14 g, 90%) as a white solid. 1H NMR (CDCl3) δ 8.03 (s, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.42 (t, J=7.1 Hz, 3H); MS(ESI+) m/z 188.9 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Benzyl alcohol (3.25 g, 30 mmol) was slowly added to a stirred suspension of sodium hydride (1.15 g, 28.7 mmol) in toluene (50 mL) at room temperature. The mixture was stirred for 30 minutes and then 2,4-difluorobenzonitrile was added all at once and stirring continued overnight. The mixture was quenched with water, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and condensed. The crude product was dissolved in hot ethyl acetate and triturated with hexanes to give 2-(benzyloxy)-4-fluorobenzonitrile (5.4 g, 23.8 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (s, 2H), 6.99 (td, J=8.46, 2.42 Hz, 1H), 7.29-7.51 (m, 6H), 7.86 (dd, J=8.59, 6.44 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:6])[O:5][CH:11]2[CH3:12]
Reactant: CCc1cccc(Cl)c1C(=O)O
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CC1OC(=O)c2c(Cl)cccc21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
5.00 g (0.027 mol) of 2-chloro-6-ethylbenzoic acid in 120 ml of chlorobenzene are introduced into a reaction vessel and heated to 90° C. 0.1 g of α,α′-azoisobutyronitrile is then added, followed by 5.04 g (0.03154 mol) of bromine in 25 ml of chlorobenzene, which is metered in in the course of 10 minutes. The reaction mixture is then stirred for 1 hour at 90° C. to complete the reaction. After the reaction mixture has cooled to 20° C., it is washed with 50 ml of sodium thiosulfate solution (0.1 mol), the organic phase is dried over sodium sulfate and the solvent evaporated off under reduced pressure using a rotary evaporator. The desired target compound is obtained in a yield of 6.1 g and a purity of about 74% (corresponding to 90% of theory).