Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[CH2:14]([SnH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[C:10](=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)/[C:11]([NH2:13])=[O:12])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COc1ccc(CCC(N)=O)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(OC)cc1)C(N)=O
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
3-(4-methoxyphenyl)propionic acid amide (10.3 mg, 0.059 mmol) prepared in Reference Synthetic Example 3 was dissolved in tetrahydrofuran (500 μl) in nitrogen atmosphere, tetrakistriphenylphosphine palladium (1.4 mg, 0.0012 mmol) was added under cooling with ice, and a tetrahydrofuran solution of tri-n-butyltin hydride (20 μl, 0.074 mmol) was dropwise added. After stirring for 10 minutes, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired compound (E)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (18.6 mg, 68%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.Cl.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][NH2:20].CN(C)C(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C.O>[N+:8]([C:7]1[C:2]([NH:20][CH2:19][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cccnc1NCc1cnccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a stirred solution of 25.4 parts of 2-chloro-3-nitropyridine, 29.5 parts of 2-pyrazinemethanamine dihydrochloride and 235 parts of N,N-dimethylacetamide were added 67.8 parts of sodium carbonate. The reaction mixture was stirred for 1.5 hours at 100° C. The reaction mixture was poured into water and 4-methyl-2-pentanone. The whole was filtered twice over diatomaceous earth and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.6 parts (10%) of N-(3-nitro-2-pyridinyl)-2-pyrazinemethanamine (int. 27).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CN(C1C=CC=CN=1)C>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cccc(CO)c1Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(COS(C)(=O)=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(2-Chloro-3-dimethylamino-phenyl)-methanol (0.50 g, 2.69 mmol) was placed in a round bottomed flask with dichloromethane (10 mL) and cooled to 0° C. Triethylamine (0.68 g, 6.73 mmol), methanesulfonylchloride (0.23 mL, 2.97 mmol), and dimethylaminopyridine (0.02 g) were added and the reaction was allowed to warm and stir at rt over 3 h. The reaction was diluted with dichloromethane (20 mL) and washed with 1N Hydrochloric acid (10 mL), 10% aqueous sodium bicarbonate (10 mL), and water (10 mL). The organics were dried (MgSO4) and concentrated to afford methanesulfonic acid 2-chloro-3-dimethylamino-benzyl ester.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:15]>CO>[C:1]([O:5][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[O:15])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CCC(=O)OCC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Propionic acid (1.5 mL, 20 mmol) was added over a period of 30 min to a stirred suspension of Cs2CO3 (3.30 g, 10 mmol) in MeOH (20 mL). The reaction mixture was concentrated and the residue was suspended in DMF (25 mL), to which was added 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (5.00 g, 18 mmol). The mixture was stirred at 25° C. for 16 h, and then partitioned between H2O (100 mL) and EtOAc/hexane (20/100 mL). The organic layer was separated, washed with water (3×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl propionate. LCMS: [M+1]+=271.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([OH:22])=O)=[C:7]([CH2:25][CH2:26][CH3:27])[CH:6]=1)([O:3][CH3:4])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH:53][C:20](=[O:22])[CH2:19][C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[C:10]=2[O:9][C:8]2[CH:23]=[CH:24][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][C:7]=2[CH2:25][CH2:26][CH3:27])(=[O:51])=[O:52])=[CH:46][CH:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)O)ccc2c1OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccc2c1OCO2
Temperature: 50 °C

Procedure:
To the product of Step A (57.2 mg, 0.154 mmol) in dry THF (0.75 mL) was added CDI (76.0 mg, 0.469 mmol) and the reaction heated to 50° C. for 2.5 hr. To this solution was added a solution of p-t-butylphenyl-sulfonamide (131.7 mg, 0.618 mmol) and DBU (92.1 μL, 0.594 mmol) in dry THF (0.75 mL). The reaction continued to be stirred at 50° C. monitoring by thin layer chromatography until all of the mono-acid was consumed (approx. 3 hr). The reaction was concentrated in vacuo and the residue was taken up in 50:50/Et2O:EtOAc. The organic phase was washed with 10% citric acid (2×), water and brine then dried over MgSO4, filtered and the solvent removed. Purification was accomplished by radial chromatography eluting with 3:2/Hex:EtOAc. Yield=74.3 mg (0.131 mmol, 85%) rf=0.32 (80:10:1/CHCl3 :MeOH:NH4OH) FAB mass spectrum, m/e 590.0 (M+Na calculated for C30H33 NSO8 590). See Drummond, J. T.; Johnson, G. Tetrahedron Lett., 1988, 29, 1653.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Yield: 27.8 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 0.22 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), methane sulfonamide (63 mg, 0.66 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (30 mg, 28%) as a light yellow solid: LC/MS m/e calcd for C29H34N2O3S (M+H)+: 491.67, observed: 491.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (8.00 g) in anhydrous DMF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g) in anhydrous DMF (200 ml), and the resulting mixture was stirred at room temperature for 80 minutes. To the reaction solution, 2-iodopropane (4.03 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Sodium hydride (1.08 g) was added to the reaction solution and thereafter 2-iodopropane (4.03 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 6 hours. Water was added to the reaction solution and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed 4 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane, cyclohexane/ethyl acetate=50/1). The obtained solid was recrystallized from hexane to obtain N-(4-iodophenyl)-N-isopropylpyrimidin-2-amine (7.06 g). NMR (H1, CDCl3): δ 1.14 (3H, s), 1.16 (3H, s), 5.12-5.19 (1H, m), 6.52 (1H, t, J=4.6 Hz), 6.88-6.92 (2H, m), 7.74-7.77 (2H, m), 8.29 (2H, d, J=4.6 Hz)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.ClCCl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CNc3ccccc32)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(C2CNc3ccccc32)c1
Temperature: 0 °C

Procedure:
A 3.0 g portion of the (+)-3-(3-methoxyphenyl)indoline obtained in Reference Example 4 was dissolved in 30 ml of dichloromethane, and this solution was added dropwise to 40 ml of a boron tribromide dichloromethane solution (1 mole/liter) at -70° C. After stirring the solution at room temperature overnight, ice water was added, the pH was adjusted to 9 with sodium bicarbonate, and the mixture was extracted with a chloroform/ethanol mixed solvent. After drying and concentration, ether was added to the residue to precipitate crystals which were then collected by filtration to obtain 2.7 g of 3-(3-hydroxyphenyl)indoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34](=[O:38])[NH:35][CH2:36][CH3:37])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].FC(F)(F)C(O)=O>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:23]([C:24]4[S:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:28]=4)=[CH:22][C:21]([NH:33][C:34]([NH:35][CH2:36][CH3:37])=[O:38])=[N:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cn3C(COC)COC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCNCC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 72 %

Procedure:
Tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate (Example 139, 260 mg, 0.33 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (195 mg, 1.68 mmol) was added to the mixture and it was stirred for 30 h at room temperature. The reaction mixture was concentrated, and the pH was adjusted to 8 with saturated sodium bicarbonate solution to give solid compound which was filtered and dried to afford 160 mg (72%) of 1-{5-[1-(1,3-dimethoxypropan-2-yl)-4-oxo-3-(piperazin-1-ylcarbonyl)-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea.
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.O[CH2:31][C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1>>[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]([CH2:31][C:32]5[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=5)[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: Cn1cncc1CO
Product: Cn1cncc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-thiazolidine-2,4-dione 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 5-hydroxymethyl-1-methyl-1H-imidazole following General Procedure J.
Reaction SMILES: [N:1]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:2]1.Br[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][CH2:8][C:7]([NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([CH:23]2[CH2:27][CH2:26][N:25]([C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)[CH2:24]2)[CH2:2]1)=[O:22])=[O:21]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNC2)C1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)C2)cc1
Yield: 29.7 %

Procedure:
A slurry of N-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide (50 mg, 0.13 mmol), methyl 4-bromobenzoate (35 mg, 0.16 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), cesium carbonate (64 mg, 0.19 mmol) and R-BINAP (8 mg, 0.013 mmol) in toluene was heated at 100° C. overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, methyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate (20 mg, 30%) as a white solid. 1H-NMR (CDCl3) δ: 1.60-1.76 (m, 1H), 1.86-2.04 (m, 1H), 2.08-2.25 (m, 1H), 2.20-2.44 (m, 2H), 2.60-2.78 (m, 2H), 2.84-3.00 (m, 2H), 3.18 (q, J=8.7 Hz, 1H), 3.32 (q, J=7.5 Hz, 1H), 3.40-3.54 (m, 2H), 3.82 (s, 3H), 4.10 (m, 2H), 4.40-4.56 (m, 1H), 6.44 (d, J=8.7 Hz, 2H), 6.54 (d, J=2.4 Hz, 1H), 7.20-7.35 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.97 (d, J=7.8 Hz, 1H), 8.07 (s, 1H). MS m/z: 519 (M+1)
Reaction SMILES: COC(C[C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:11][CH2:10][N:9]([CH3:12])[C:8](=[O:13])[C:7]1=[CH2:14])=O.[OH-].[K+].CO.O.C(Cl)(Cl)Cl>CO.O>[CH3:12][N:9]1[CH:10]=[CH:11][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([CH3:14])[C:8]1=[O:13]
Reactant: C=C1C(=O)N(C)CCC1(CC(=O)OC)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cccc(-c2ccn(C)c(=O)c2C)c1
Reaction time: 20 h
Yield: 19.6 %

Procedure:
To methyl ester 28 of Example 10 (1.20 g, 3.97 mmol) dissolved in CH3OH (5 mL, 0° C.) was rapidly added KOH (775 mg, 11.9 mmol) in 5 mL of 1/1 CH3OH/H2O. After 20 h at 25° C., CHCl3 (20 mL) and H2O (20 mL) were added, the separated aqueous layer was extracted with CHCl3 (20 mL) and the combined organic phases were dried and evaporated to give 178 mg (20%) of 1,3-dimethyl-4-(3'-methoxyphenyl)-2-pyridone (this arises from unreacted allylic alcohol under the alkaline hydrolysis conditions): NMR δ7.20 (m, 2H), 6.86 (m, 3H), 6.07 (d,J=7 Hz, 1H), 3.81 (s, 3H), 3.57 (s, 3H), 2.10 (s, 3H): IR (neat) 1640 cm-1 (broad); mass spectrum m/e (rel intensity) 229 (63), 228 (100). Anal. Calcd for C14H15NO2 : C, 73.3; H, 6.6; N, 6.1. Found: C, 73.0; H, 6.6; N, 6.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:17][CH:18]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([CH:8]=1)[CH2:2][N:17]1[CH:18]=[C:14]([CH3:13])[CH:15]=[C:16]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: CCOC(=O)c1cc(C)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Vigorously stir a solution of 2-(bromomethyl)-4-chloro-1-nitro-benzene (25.02 g, 99.88 mmoles) in DCM (200 mL), and to this add a solution of ethyl 4-methyl-1H-pyrrole-2-carboxylate (15 g, 97.92 mmoles) in DCM (200 mL). Then add 30-hydrated tetra-n-butylammonium hydroxide (0.508 g) and cool the stirred mixture under nitrogen to 5° C. using an external ice-bath. Add 25% aq. sodium hydroxide (200 mL) dropwise over 15 minutes observing the internal temperature rise to 10° C. Stir and allow to warm to room temperature. Stir at room temperature for 3.5 h. Add further 50% aq. sodium hydroxide (20 mL) and stir at room temperature for a further 1 h. Stop the stirring and allow the layers to separate. Transfer to a separating funnel and wash the organic layer with 1N hydrochloric acid (200 mL), observing the pH of this layer to be acidic using indicator paper. Next wash the organic layer with water (600 mL) and then brine (600 mL) and finally dry over Na2SO4. Filter the mixture and remove the solvent in vacuo at 40° C. to give an orange oil. Purify by passing through a silica gel pad with iso-hexane/ethyl acetate (gradient eluting from 10 to 20%) to give ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate as a yellow oil (33 g, quantitative). MS (m/z): 322.98 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=O)[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O>C(O)C>[Cl:1][C:2]1[C:3]([C:12](=[N:30][O:29][CH2:27][CH3:28])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCON
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
To 214 mg of the N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-oxoethyl]phthalimide prepared in Step 2 in Synthetic Example 6 in 3 ml of ethanol, 84 mg of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), and the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 111 mg of the desired product as a brown resinous substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.Cl.[F:14][C:15]([F:20])([F:19])[C@H:16]([NH2:18])[CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:18][C@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: C[C@@H](N)C(F)(F)F
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc(F)c(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2,5-difluorobenzoyl chloride (29.6 mg, 0.140 mmol) (Oakwood, Cat. #: 001628) was added to a solution of (2R)-1,1,1-trifluoropropan-2-amine hydrochloride (20.0 mg, 0.134 mmol) (SynQuest Lab, Cat. #: 3130-7-R1) in methylene chloride (4.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 min., then worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=288.0/289.9.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:28])[CH2:8][CH2:9][CH:10]=[C:11]([C:23](OCC)=[O:24])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.[H-].[Al+3].[H-].[H-].C(OCC)(=O)C>CCOCC>[OH:24][CH2:23]/[C:11](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:10]/[CH2:9][CH2:8]/[C:7](/[CH3:28])=[CH:6]/[CH2:5][OH:4]
Reactant: CCOC(=O)C(=CCCC(C)=CCOC(C)=O)CCC=C(C)CCC=C(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO

Procedure:
The ester thus obtained was further reduced by aluminum hydride (prepared from 760 mg of lithium aluminum hydride and 880 mg of aluminum chloride) in 7 ml of ether. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the precipitate was filtered off. The filtrate was evaporated to dryness, yielding 3.5 g of the desired product.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18]1C=C([CH:22]=[C:23]([F:25])[CH:24]=1)N)([CH3:16])([CH3:15])[CH3:14]>ClCCl.O>[C:13]([O:17][C:18]1[CH:11]=[C:12]([N:8]=[C:1]=[S:2])[CH:22]=[C:23]([F:25])[CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Oc1cc(N)cc(F)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
1,1′-Thiocarbonyldiimidazole (423 g, 2.37 mol) was dissolved in dichloromethane (3200 ml). The mixture was stirred under N2 atmosphere while a solution of 3-tert-butoxy-5-fluoroaniline (435 g, 2.37 mol) in dichloromethane (800 ml) was added slowly within 2 h. Then the mixture was kept stirring at 20° C. for 16 h. The mixture was diluted with water (3000 ml). The separated dichloromethane phase was washed again with water (3000 ml) before dried with anhydrous Na2SO4 for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to remove solvent to give 1-tert-butoxy-3-fluoro-5-isothiocyanato-benzene (499 g). 1H-NMR (400 MHz, CDCl3): 6.63-6.68 (m, 3H), 1.37 (s, 9H).