Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7]>CN(C)C=O>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cccnc2c1Cl
Temperature: 25 °C
Yield: 66.8 %

Procedure:
Phosphorus oxychloride (3.4 mL, 30 mmol) was added to chilled (ice bath) N,N-dimethylformamide (15 mL). The resulting solution was added dropwise to a solution of 3-nitro[1,5]naphthyridin-4-ol (5.73 g, 30 mmol) in N,N-dimethylformamide (35 mL). The reaction mixture was maintained at ambient temperature for 5 hours and then it was poured onto ice. The resulting yellow precipitate was isolated by filtration and then partitioned between dichloromethane (200 mL) and water (150 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and then concentrated under vacuum to provide 4.2 g of crude 4-chloro-3-nitro[1,5]naphthyridine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[S:22][CH:23]=1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[S:22][CH:23]=[C:19]([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[N:20]=1
Reactant: ClCc1csc(-c2ccccc2Cl)n1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2ccccc2Cl)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-(2-chlorophenyl)-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 8.17 (m, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.49 (m, 2H), 7.36 (m, 2H), 6.79 (s, 1H), 6.65 (s, 1H), 5.51 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 432 (M+1) and 434 (M+1, isotope).
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].FC(F)(F)S(O[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])(=O)=O.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=C(Br)CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 3-bromobut-3-en-1-ol (5.2 g, 34.4 mmol) in dichloromethane (69 mL) at rt was added tert-Butyldimethylsilyl trifluoromethanesulfonate (10 g. 37.9 mmol) and DIEA (7.22 mL, 41.3 mmol) and the mixture was stirred at rt for 30 min. The reaction mixture was partitioned between dichloromethane and water, and the crude product obtained from the dichloromethane layer was purified by chromatography eluting with 5-30% EtOAc/Hexanes to give the title compound as a colorless liquid (8.72 g, 95%). 1H NMR (400 MHz, CDCl3) δ 5.66 (1H, s), 5.48 (1H, s), 3.81 (2H, t, J=6.0 Hz), 2.64 (2H, t, J=6.0 Hz), 0.91 (9H, s), and 0.09 (6H, s).
Reaction SMILES: [Br-].[C:2]([C:4]1[C:5]([S:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:6][CH:7]=[C:8]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)#[N:3].C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH2:51]([O:53][C:54]([C:56]1[CH:63]=[CH:62][C:59]([CH:60]=O)=[CH:58][CH:57]=1)=[O:55])[CH3:52]>O>[C:2]([C:4]1[C:5]([S:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[N:6][CH:7]=[C:8]([CH:10]=[CH:60][C:59]2[CH:58]=[CH:57][C:56]([C:54]([O:53][CH2:51][CH3:52])=[O:55])=[CH:63][CH:62]=2)[CH:9]=1)#[N:3]
Reactant: N#Cc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cnc1Sc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C=Cc2cnc(Sc3ccc([N+](=O)[O-])cc3)c(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A mixture of 4.544 g (7.42 mmol) of [3-cyano-2-(4-nitrophenylthio)-5-pyridinylmethyl]triphenylphosphonium bromide, 0.751 g (7.42 mmol) of triethylamine and 50 mL of chloroform was stirred at room temperature for 15 minutes and 1.322 g (7.42 mmol) of 4-ethoxycarbonylbenzaldehyde then were added. After stirring at room temperature for 96 hours, 100 mL of water were added, the mixture was filtered, and the organic layer was separated and washed twice with 100 mL portions of water, dried and filtered. Evaporation of the filtrate under reduced pressure gave a residue which was chromatographed on silica gel. Unreacted aldehyde was eluted with 2:1 petroleum ether:benzene, while the title compound, alternatively named as 2-(4-nitrophenylthio)-3-cyano-5-(4-ethoxycarbonylstyryl)pyridine; was eluted with benzene. Evaporation of the benzene eluate gave 2.82 g (88%) of 3-cyano-2-(4-nitrophenylthio)-5-[2-(4-ethoxycarbonylphenyl)ethenyl]pyridine as a light yellow solid. The product turns from a solid to a gum below 100° C. and then to a clear liquid between 180° and 220° C.; NMR (Me2SO-d6) delta 1.34 (t, 3H, J=6.3 Hz), 4.32 (q, 2H, J=6.3 Hz), 6.73(d, 1H, J=13 Hz), 6.99(d, 1H, J=13 Hz), 7.27(d, 2H, J=9 Hz), 7.74, 7.85, 7.94(dd, 2H, 2H), 8.26, 8.31(dd, 2H, 1H), 8.38(d, 1H, J=1.8 Hz); IR (KBr) 2220, 1707, 1605, 1597, 1575, 1512, 1344, 1295-1277, 1174 cm-1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH:12]1(C(C2CC2)(O)C#C)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:13]1[C:1]2[C:10]3[C:5]([CH:4]=[CH:3][C:2]=2[O:11][CH2:14][CH:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Oc1ccc2ccccc2c1
Reactant: C#CC(O)(C1CC1)C1CC1
Solvent: Cc1ccccc1
Product: C1=Cc2c(ccc3ccccc23)OC1

Procedure:
Acidic alumina (20 grams) was added to a solution of 2-naphthol (4.2 grams, 0.03 moles) and 1,1-Dicyclopropylpropyn-1-o1 (3.08 grams, 0.0226 moles) in toluene (30 cc). The mixture was boiled under reflux for three hours and the alumina removed by filtration. The filtrate was washed sequentially with a dilute (10 percent) sodium hydroxide solution and water. The organic layer was extracted with diethyl ether (2×50 cc), dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure leaving a brown oil which was chromatographed on silica gel using petroleum (b.p. 60°-80° C.) as the eluant. The fraction which exhibited a reversible change from colorless to yellow on exposure to the flash from the flash gun of Example 2 was collected. Petroleum solvent was removed under reduced pressure leaving as a colorless oil 0.3 grams of 2,2-Dicyclopropyl- [2-H-2,1b] naphthopyran (i.e., graphic formula III).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[NH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=1)[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([NH:30][C:28](=[O:29])[C:27]1[CH:38]=[CH:39][N:40]=[C:25]([NH:24][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:14]=2)[CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Yield: 80 %

Procedure:
Following the procedure as describe in Example 6, making non-critical variations as required to replace 2-fluorobenzoyl chloride with 3-(trifluoromethyl)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-(trifluoromethyl)benzamido)-isonicotinamide was obtained as a colorless solid in 80% yield: mp 126-128° C.; 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.82 (s, 1H), 8.41-8.14 (m, 4H), 7.95-7.27 (m, 7H), 7.03 (s, 1H), 4.57 (d, J=5.1 Hz, 2H); MS (ES+) m/z 400.5 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CCOCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([O:12][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1(C)CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)OCc1ccccc1)C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2-dram vial containing a small stirbar was charged with (R)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetic acid (10d) (11 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred at room temperature for 3 h, and then diluted with 10 mL Et2O. The mixture was washed with water (2×10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (7:1 hexanes/Et2O) and analyzed by chiral HPLC analysis: (AS-H, 1 mL/min, 2% IPA/hexanes, 210 nm): tR(minor)=6.84 min, tR(major)=8.13 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1.[CH:21]([O:23][CH2:24][CH3:25])=[CH2:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([O:16][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])[CH3:15])=[CH:17][CH:18]=2)[CH:19]=1
Reactant: CC(O)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 1-(4-(5-bromo-2-chlorobenzyl)phenoxy)propan-2-ol (857 mg, 2.4 mmol) in dichloromethane (20 mL) was added ethyl vinyl ether (1.2 mL, 12 mmol) and pyridinium p-toluenesulfonate (24 mg), and the mixture was stirred at room temperature for 2 h, whereupon starting material had been completely consumed as determined by TLC (eluent PE:EA=1:1). Solid sodium bicarbonate (5 g) was added, and the mixture was stirred for 10 min. Water (25 mL) was added, and the mixture was extracted with ethyl acetate, washed with sodium chloride, and dried over sodium sulfate. The residue was concentrated and purified by column chromatography to obtain intermediate CZ (900 mg, yield 87%) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 7.23-7.30 (m, 3H), 7.09-7.11 (m, 2H), 6.85-6.87 (m, 2H), 4.86-4.94 (m, 1H), 4.10-4.13 (m, 1H), 4.00 (s, 2H), 3.84-3.99 (m, 1H), 3.69-3.72 (m, 1H), 3.50-3.59 (m, 1H), 1.19-1.37 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#N.[OH-:15].[Na+].C[OH:18]>O>[CH3:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([OH:18])=[O:15]
Reactant: CO
Reactant: [OH-]
Reactant: Cc1cccc(C#N)c1-n1nccn1
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(=O)O)c1-n1nccn1
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.4 g, 7.82 mmol) in MeOH (15 mL) was added a 4N aqueous solution of NaOH (10 mL). The resulting mixture was heated to 90° C. After 15 h the reaction mixture was cooled to ambient temperature then diluted with water (50 mL). The aqueous layer was acidified to pH2 and extracted with EtOAc (50 mL) three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (SiO2, gradient DCM to 10% MeOH/1% HOAc/DCM) to yield the title compound (1.3 g, 78%). 1H NMR (500 MHz, CDCl3): 7.90 (d, J=7.7, Hz, 1H), 7.83 (s, 2H), 7.57-7.53 (m, 1H), 7.49 (dd, J=9.7, 5.8 Hz, 1H), 2.10 (s, 3H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: Fc1ccc(CNC2CCCC2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(Cc1ccc(F)cc1)C1CCCC1
Yield: 90.3 %

Procedure:
6.1 g (0.05 mol) of phenyl isocyanate were added dropwise to a solution of 9.65 g (0.05 mol) of N-4-fluorobenzyl-N-cyclopentylamine in 80 ml of anhydrous methylene chloride, while cooling with ice and stirring. The mixture was stirred for 30 minutes at room temperature and for 30 minutes at 40° C., the solvent was stripped off in vacuo, and the residue was recrystallized from acetonitrile. 14.1 g of N-4-fluorobenzyl-N-cyclopentyl-N'-phenylurea of melting point 120° to 121° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:54]=[CH:53][C:6]2[N:7]=[C:8]([S:10]([C:13]3[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:45])=[O:44])=[O:39])[CH:14]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:55][CH2:56][C:57]1[C:62]([CH3:63])=[C:61]([O:64][CH3:65])[C:60]([CH3:66])=[CH:59][N:58]=1.ClC1C=C(C=CC=1)C(OO)=[O:72].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:54]=[CH:53][C:6]2[N:7]=[C:8]([S:10]([C:13]3[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)(=[O:25])=[O:26])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:44])=[O:45])=[O:39])[CH:14]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:55]([CH2:56][C:57]1[C:62]([CH3:63])=[C:61]([O:64][CH3:65])[C:60]([CH3:66])=[CH:59][N:58]=1)=[O:72]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2nc(S(=O)(=O)c3ccc(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c3)[nH]c2c1SCc1ncc(C)c(OC)c1C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2nc(S(=O)(=O)c3ccc(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c3)[nH]c2c1S(=O)Cc1ncc(C)c(OC)c1C
Reaction time: 0.67 h
Yield: 37.1 %

Procedure:
2-(4-Tolylsulfonyl)ethyl 4-[{5-methoxy-([4-methoxy-3,5-dimethyl(2-pyridyl)]methylthio)benzimidazolyl}sulfonyl]-2-(2-[4-tolylsulfonyl]ethoxycarbonylmethoxy)phenoxyacetate (Intermediate A20, 4.8 g, 0.0054 mol) was dissolved in 20 mL of tetrahydrofuran, and the solution was left in a freezer for 40 min. A solution of 3-chloroperoxybenzoic acid (1.3 g, 0.0075 mol) in 6 mL of tetrahydrofuran was cooled for 30 min. The two were combined and left in the freezer for 16 hr. The mixture was then poured into a rapidly stirring mixture of 5% aqueous sodium metabisulfite and ethyl acetate. The layers were separated, and the organic layer was washed with 2 portions of 2.5% aqueous sodium bicarbonate and with saturated aqueous sodium chloride. The solution was filtered through 1PS paper and concentrated at aspirator pressure. The residue was separated on a column of flash silica gel (2:1 ethyl acetate:hexanes→ethyl acetate) to yield 2.0 g (41%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].Cl.[NH2:33][OH:34]>C(O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=[N:33][OH:34])[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: NO
Reactant: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc2c(cc1N1CCC(=NO)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (30 mg) and hydroxylamine hydrochloric acid salt (10 mg) were dissolved in ethanol (5 ml) and stirred at 60° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (20 ml). The organic layer was washed with 10% brine and concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (23.5 mg, yield 74%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:42])[CH:14]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[N:15]2[C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:26]2[C:27]([O:34][CH3:35])=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(#N)C.O>[CH:36]1([CH:14]([N:15]2[C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:26]2[C:27]([O:34][CH3:35])=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:13]([NH:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCOC(=O)C1CCC(NC(=O)C(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)C2CCCCC2)c(OC)n1
Temperature: 100 °C

Procedure:
To a solution of 4-{2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetylamino}-cyclohexanecarboxylic acid ethyl ester (350 mg, 0.60 mmol, 1.0 equiv) in a mixture of acetonitrile/water (2:1, 5 mL) was added a solution of aqueous 6 M NaOH (0.3 mL, 1.80 mmol, 3.0 equiv) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. The solvent was removed under reduced pressure and the crude reaction mixture adjusted to pH=3 by addition of a solution of 1 M HCl and the aqueous layer extracted with a mixture of dichloromethane/isopropanol (4:1). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified over a short silica column eluting with a gradient of dichloromethane/methanol yielding 0.31 g (93%) of the title compound. MS (ES+): 558 (M+H).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C([Zn]CC)C.ICI.[CH3:16][CH2:17][O:18][C:19]([C@@H:21]1[CH2:25][CH:24]=[CH:23][N:22]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC>[CH2:17]([O:18][C:19]([C@@H:21]1[CH2:25][C@H:24]2[C@H:23]([CH2:1]2)[N:22]1[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:20])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CC=CN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: ICI
Product: CCOC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C. a solution of TFA (104 mmol, 2.0 eq) in DCM (50 mL) is added dropwise to a solution of diethylzinc (104 mmol, 2.0 eq) in hexane (104 mL) and DCM (100 mL). After 30 min a solution of diiodomethane (104 mmol, 2.0 eq) in DCM (50 mL) is added slowly to the white suspension. The mixture is stirred for 10 min and treated with a solution of (S)-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (52 mmol, 1.0 eq) in DCM (50 mL). After 5 min the mixture is allowed to reach RT, stirred for additional 2.5 h, cooled to 0° C. and treated slowly with TEA (18 mL). After 14 h a sat. aqueous NaHCO3 solution is added and the mixture is filtered through Celite. The residue is washed with DCM (100 mL) and the layers are separated. The organic layer is washed twice with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (heptane/EtOAc 9/1) to give the desired product as a pale yellow oil. LC-MS (basic): tR=0.90 min; [M+H]+=256.3.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])=[CH:14][C:13]2=[O:26])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:28]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:59][C@@H:60]([CH2:90]O)[CH2:61][N:62]1[CH:66]=[CH:65][C:64]([NH:67]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:63]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:67][C:64]2[CH:65]=[CH:66][N:62]([CH2:61][C:60]([OH:59])([CH3:90])[CH3:28])[N:63]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc(F)c3F)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (125 mg, 0.34 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (195 mg, 1.0 mmol) and N,N-diisopropylethylamine (220 mg, 1.7 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (157 mg, 1.1 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl US2008021032 Example 80, 53 mg, 0.34 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (68 mg, 40%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.81-1.08 (m, 3H), 1.14 (s, 6H), 1.16-1.32 (m, 2H), 1.65-1.96 (m, 8H), 3.64 (br. s., 1H), 3.92 (s, 2H), 4.12 (d, J=18.0 Hz, 1H), 4.34 (d, J=18.0 Hz, 1H), 4.89 (dd, J=8.8, 6.8 Hz, 1H), 5.00 (s, 1H), 6.67 (d, J=1.5 Hz, 1H), 7.01-7.15 (m, 3H), 7.28 (d, J=1.5 Hz, 1H), 8.64 (br. s., 1H).