Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[N+]([C:6]1C=CC=C[C:7]=1[C:8]([O-:10])=O)([O-])=O.[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][SH:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)(C)C>[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][S:35][CH2:6][C@@H:7]([OH:1])[CH2:8][OH:10])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCc1ccccc1
Reactant: [OH-]
Reactant: O=C([O-])c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)[C@H](CSC[C@@H](O)CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (2R)-(−)-glycidyl-4-nitrobenzoate (1.1 eq) and 1M NaOH (1.1 eq) in tBuOH (0.1 M) was stirred at room temperature until complete hydrolysis of nitrobenzoate (30 min) was achieved. To the resulting mixture, a solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-mercaptopropanoate (1 eq) in tBuOH (1 M) was introduced. The reaction was stirred at room temperature for 15 hours, and concentrated en vaccuo to remove tBuOH; then the resulting residue was dissolved in EtOAc. The EtOAc solution was washed three times with H2O then once with brine. The organic layer was dried over anhydrous Na2SO4 then concentrated en vaccuo. The resulting crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-90% EtOAc/Hex to give the title compound as a colorless viscous oil.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:46])([F:45])[C:5]1[CH:6]=[C:7]([C:15]([CH3:44])([CH3:43])[C:16]([N:18]([C:20]2[CH:21]=[N:22][C:23]([N:35]3[CH2:39][C@H:38]([OH:40])[CH2:37][C@H:36]3[CH2:41][OH:42])=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[CH:33]=[O:34])[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO>[F:45][C:4]([F:3])([F:46])[C:5]1[CH:6]=[C:7]([C:15]([CH3:44])([CH3:43])[C:16]([N:18]([C:20]2[CH:21]=[N:22][C:23]([N:35]3[CH2:39][C@H:38]([OH:40])[CH2:37][C@H:36]3[CH2:41][OH:42])=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[CH2:33][OH:34])[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccc(F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccc(F)cc1CO
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 24 mg (0.637 mmol) sodium borohydride in 1 ml methanol were added 100 mg (0.159 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated sodium carbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 78 mg (78%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:3]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Oc2ccc(N)cc2)C1

Procedure:
A solution of 1-methyl-3-(4-nitro-phenoxy)-pyrrolidine•TFA (0.34 g, 1.0 mmol) in ethanol (10 mL) is hydrogenated for one hour at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine•TFA as a black solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][O:25][CH2:28][CH3:29])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCc1cc2c(nc1CC)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-ethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 20, intermediate b), sodium hydride and ethyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:28])[N:13]([CH3:27])[C:14]([C:23]([O:25]C)=[O:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:29][O:30][CH2:31][CH2:32][C:8]2=3)=[CH:4][CH:3]=1.CO.[Li+].[OH-].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:28])[N:13]([CH3:27])[C:14]([C:23]([OH:25])=[O:24])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[C:10]=3[C:9]3[CH2:29][O:30][CH2:31][CH2:32][C:8]2=3)=[CH:33][CH:34]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of methyl 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (0.4 g, 0.869 mmol) in Tetrahydrofuran (THF) (2.77 ml)/Methanol (2.77 ml) was treated with 2M LiOH (3.04 ml, 6.08 mmol) and heated to reflux (80° C. bath). After 18 h, the reaction mixture was cooled to ambient temperature and poured into 1M HCl. The layers were partitioned and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid as a beige solid. A solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid in THF (10 mL) was treated with oxalyl chloride (0.110 ml, 1.303 mmol) and 1 drop of DMF. After 15 min, the reaction mixture was concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield). An ice cold solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield) in 1,2-DME (10 mL) was treated with NaBH4 (0.161 g, 4.34 mmol) and then warmed to ambient temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with MeOH (1 mL) and 1M HCl (˜20 mL). EtOAc was added and the layers were partitioned and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford 5-(4-fluorobenzyl)-8-(hydroxymethyl)-7-methyl-9-(p-tolyl)-3,4,5,7-tetrahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-6(1H)-one (333 mg, 0.770 mmol, 89% yield) as a white solid. The residue was used without further purification. LCMS (m/z) ES+=433 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]=1[N+:20]([O-:22])=[O:21].[CH:23](O)=O>C=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([CH3:23])[CH2:10][CH2:11][C:5]=2[C:4]=1[N+:20]([O-:22])=[O:21]
Reactant: O=CO
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCNCC2c1ccccc1
Agent: C=O
Product: COc1ccc2c(c1[N+](=O)[O-])CCN(C)CC2c1ccccc1

Procedure:
0.40 g (0.00134 mol) 7-methoxy-6-nitro-1 -phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in a mixture of 5 ml formic acid and 4 ml 35% aqueous formaldehyde. The mixture was heated to reflux for 2.5 hours and then evaporated in vacuo. The residue was partitioned between dichloromethane and saturated NaHCO3-solution, the organic layer was washed twice with water and once with brine, dried with NaSO4 and concentrated in vacuo, yielding the compound as a light yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)=[CH:14][CH:13]=4)=[C:9]([C:26]([OH:28])=O)[C:8]=3[CH:29]=2)[CH2:3][CH2:2]1.C1N=C[N:37](C(N2C=NC=C2)=O)[CH:36]=1.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][NH:37][C:26]([C:9]1[C:8]2[CH:29]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:28]
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(Oc4ccc(F)cc4)cc3)c(C(=O)O)c2cc1C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
step 1—To a solution of 28 (0.51 g, 1.07 mmol) in dry DMF (5 mL) was added CDI (0.19 g, 1.17 mmol) and the solution stirred at RT for 2 h. Methyl amine hydrochloride (0.72 g, 10.7 mmol) and DIPEA (1.4 g, 10.7 mmol) were added and the resulting solution heated at 85° C. for 3 h. The solution was cooled and partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 40% EtOAc) to afford 0.426 g of 5-cyclopropyl-2-[4-(4-fluoro-phenoxy)-phenyl]-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (30).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)[CH3:15].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH2:14][CH3:15])=[CH:17][CH:18]=1)[CH2:11]2
Reactant: CCc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 4-ethyl-benzylamine (0.072 mL, 0.5 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.032 g, 28%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.51 (q, 2H), 4.14 (s, 2H), 4.76 (s, 2H), 7.14-7.38 (m, 6H), 7.86 (d, 1H). GC-MS: m/z 377 (M)+, 348 (M−29)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.COC(C)(C)C>[Br:1][C:2]1[C:3]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nc(-n2c(C)ccc2C)nc(N[C@H]2CC[C@H](O)CC2)c1Br
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (1.50 g, 4.99 mmol), trans-4-aminocyclohexanol hydrochloride (1.17 g, 6.24 mmol), and diisopropylethyl amine (2.61 mL, 15.0 mmol) in dimethylacetamide (25.0 mL) was heated at 160° C. in a sealed tube overnight. The reaction mixture was diluted with methyltertbutyl ether (400 mL), washed with saturated ammonia chloride (2×) and brine, dried (MgSO4), filtered, and concentrated. The combined aqueous layers were extracted with dichloromethane (3×150 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0.5-3%) to afford trans-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol (1.76 g, 93%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH:21][C:23]([NH:22][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a round bottom flask was added (1R,2R)—N1-(1-benzylpiperidin-3-yl)cyclohexane-1,2-diamine (3.23 g, 8.05 mmol), THF (30 mL), isocyanatobenzene (0.958 g, 8.05 mmol) and Et3N (5.61 mL, 40.2 mmol). The reaction was stirred at rt for 2 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 ml). The resulting solution was washed with water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with 5% MeOH/CH2Cl2 with NH3) to give the product, 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea (1.4 g, 3.44 mmol, 42.8% yield), as a white solid. Anal. Calcd. for C25H32N4O m/z 407, found: 408.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.15 (m, 9H), 6.97 (q, J=7.15 Hz, 1H), 4.51-4.27 (m, 1H), 3.58-3.34 (m, 2H), 3.23-3.08 (m, 1H), 2.96-2.80 (m, 1H), 2.66 (br. s., 1H), 2.40 (br. s., 1H), 2.29-2.11 (m, 2H), 2.11-1.92 (m, 2H), 1.77-1.57 (m, 5H), 1.57-1.42 (m, 1H), 1.31 (d, J=3.85 Hz, 1H), 1.30-1.05 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].ClCCl.N1C(F)=NC(F)=NC=1[F:29]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:29])[C:10]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=3[C:12](=[O:14])[O:13]2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Product: O=C1OC(F)(c2ccc(Cl)c([N+](=O)[O-])c2)c2c(F)ccc(F)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 2-[(4-chloro-3-nitrophenyl)carbonyl]-3,6-difluorobenzoic acid (7.0 g, 22.00 mmol) at 0° C. in anhydrous dichloromethane (40 mL) pyridine (1.70 ml, 22.00 mmol) was added, followed by the addition of cyanuric fluoride (1.90 ml, 24.20 mmol). The reaction mixture was stirred for 120 minutes at 0° C. Water (35 mL) was added to the reaction mixture and it was stirred for 10 min at 0° C. The resulting slurry was filtered through a pad of Celite and washed with dichloromethane. The filtrate was partitioned with water and the organic layer was washed with water. It was dried over anhydrous sodium sulfate. Filtration and concentration gave a crystalline product. It was collected by filtration and dried in vacuo, to give 3-(4-chloro-3-nitrophenyl)-3,4,7-trifluoro-2-benzofuran-1(3H)-one (5.77 g, 82% yield). MS (EI) for C14H5ClF3NO4: 342 (M−).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[C:9](=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: Cc1ccc(C)cc1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)c1cc(C)ccc1C

Procedure:
Paraxylene (1 mL), methacryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (140 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:6]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nccc1-c1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.00 g), 4-iodobenzotrifluoride (4.03 g), bis(triphenylphosphine)palladium(II) dichloride (312 mg), potassium carbonate (2.65 g), ethanol (10 mL) and dimethylformamide (20 mL) was stirred at 75° C. for 2 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=4:1 to 3:1), so as to obtain the title compound (3.70 g) in the form of a brownish-red solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2.O[Li].O>C1COCC1.O>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH:17]=[CH:16][CH:15]=2
Reactant: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(=O)O)c21

Procedure:
Using Method F above, (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester (40 mg, 0.11 mmol) (from Example 7 above) was hydrolyzed with LiOH.H2O (92 mg, 2.19 mmol) in THF (3 mL) and water (3 mL) for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid. (Yield 31 mg, 81%).
Reaction SMILES: [F:1][CH:2]([F:50])[C:3]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:38]=[N:37]3)[N:31]=2)[C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)=[CH:9][CH:8]=1.[H][H]>CCOC(C)=O.[Pt]=O>[F:50][CH:2]([F:1])[C:3]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:38]=[N:37]3)[N:31]=2)[C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C(F)F)c3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C(F)F)c3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a degassed solution of the title compound from Example 7 Step E (115 mg, 0.17 mmol) in EtOAc (5 mL) was added platinum oxide (22 mg). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 45 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 701.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.01-7.92 (m, 2H), 7.68 (dd, J=8.0, 6.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (dd, J=12.5, 8.5 Hz, 4H), 6.94 (t, 2JH-F=55.5 Hz, 1H), 4.57 (s, 2H), 4.40 (q, J=7.0 Hz, 2H), 4.34-4.16 (br m, 2H), 2.90-2.72 (br m, 2H), 2.68-2.60 (m, 1H), 1.86-1.74 (m, 2H), 1.66-1.56 (m, 2H), 1.49 (s, 9H), 1.40 (t, J=7.0 Hz, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:31])([F:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:54]1([C:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]([F:71])([F:70])[F:69])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[O:29]=[C:27]([N:57]1[CH2:58][CH2:59][N:54]([C:60](=[O:61])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]([F:71])([F:69])[F:70])[CH2:55][CH2:56]1)[CH2:26][NH:25][C:23]([C:20]1[CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([F:10])([F:31])[F:30])[NH:22][N:21]=1)=[O:24]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 69.3 %

Procedure:
DIPEA (137 mg, 0.18 mL, 1.06 mmol) was added to a stirred solution of {[5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (95 mg, 0.30 mmol) in DMF (2 mL). HOBT (47 mg, 0.34 mmol) and EDCI (67 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (90 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 115 mg (68.45% yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.52%. 1H NMR (DMSO-d6): δ 13.6 (m, 1H), 8.2 (m, 1H), 7.7 (m, 4H), 7.6 (m, 3H), 7.5 (m, 1H), 6.7 (m, 1H), 4.2 (d, 2H), 3.7 (m, 1H), 3.5 (m, 3H), 3.4 (m, 2H), 3.0 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([C:15]2[CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=[CH:19][CH:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][C:9]1[C:10]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[NH2:21])=[N:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc(N)c1
Yield: 100.4 %

Procedure:
A suspension of 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)-nitrobenzene (332 mg) in ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 150 mg) under a hydrogen atmosphere for 4 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)aniline (303 mg).