Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH2:3][CH2:2]1.Cl.[NH2:11]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([C:4]2[O:9][N:11]=[C:6]([CH3:7])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: CC(=O)CC(=O)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C2CC2)on1
Yield: 81.3 %

Procedure:
A mixture of 1-cyclopropylbutan-1,3-dione (65.3 g), hydroxylamine hydrochloride (36.6 g) and anhydrous potassium carbonate (71.8 g) in ethanol (375 ml) was stirred and heated at reflux for 2 hours. The mixture was cooled and filtered and the filtrate was evaporated to dryness. The residue was distilled under reduced pressure to give 5-cyclopropyl-3-methyl isoxazole containing approximately 20% 3-cyclopropyl-5-methylisoxazole (51.85 g) as a clear oil, b.p. 74° C./12 mm.Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:48]([C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[Cl:61])[NH:57][C:56](=[O:62])[C:55]([C:63]1[CH:68]=[C:67]([CH3:69])[CH:66]=[C:65]([CH3:70])[CH:64]=1)=[C:54]2O)[CH:49]=[CH2:50]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:54]1[C:53]2[C:58](=[CH:59][C:60]([Cl:61])=[C:51]([CH2:48][CH:49]=[CH2:50])[CH:52]=2)[NH:57][C:56](=[O:62])[C:55]=1[C:63]1[CH:68]=[C:67]([CH3:69])[CH:66]=[C:65]([CH3:70])[CH:64]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCc1cc2c(O)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a solution of 6-allyl-7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-1H-quinolin-2-one (960 mg in 30 mL of tetrahydrofuran) at 0° C. was added 615 mg of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and 1.04 g of triphenylphosphine followed by 0.56 mL of diethyl azodicarboxylate and the mixture warmed to room temperature. After 20 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 85:15; then 80:20; then 90:10) to give 1.19 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:32]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CB(O)O
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br)c1ccccc1-n1nccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
A mixture of N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 107; 67 mg, 0.14 mmol), methylboronic acid (CAS number 13061-96-6; 24 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol) and potassium carbonate (aq. 2 M, 271 μl, 0.54 mmol) in 1,4-dioxane (450 μl) was sealed, evacuated and purged with nitrogen and then subjected to microwave irradiation at 140° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water, washing with water, brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:4]([CH2:5][CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:3][N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[Cl:22][C:12]1[CH:13]=[CH:14][C:8]2[NH:7][CH2:6][CH2:5][C@@H:4]3[CH2:3][N:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:1][C@H:10]3[C:9]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCNc3ccccc3[C@@H]2C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CCNc3ccc(Cl)cc3[C@@H]2C1
Temperature: 50 °C

Procedure:
To a solution of Example 389B (172 mg, 0.60 mmol) in N,N-dimethylformamide (1 mL) was added N-chlorosuccinimide (80 mg, 0.60 mmol). The mixture was heated at 50° C. for 2 hours and purified by reversed phase HPLC (0.1% trifluoroacetic acid(aq):acetonitrile) to afford the title compound with a shorter retention time than that of Example 392A.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Solvent: CCOCC
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A solution of 5-Bromo-2-chlorobenzotrifluoride (5 g, 19.2 mmol) in dry diethyl ether (40 ml) was added dropwise at room temperature to a mixture of Mg (470 mg) in dry diethyl ether (20 ml) under a stream of Argon (g). The reaction gave rise to a solution of Grignard's reagent. A solution of 1-benzyl-4-piperidone (1.3 g, 6.88 mmol) in dry diethyl ether (30 ml) was added dropwise via syringe at room temperature. The combined mixture was stirred for 1 hour, and finally quenched with saturated ammonium chloride solution (40 ml). The mixture was extracted several times with EtOAc and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The oily residue was chromathographed on a silica column using EtOAc:toluene (1:1 (v/v)) as eluent affording the title compound (1.6 g, 64%). MS m/z (relative intensity, 70 eV) 369 (M+, 23), 278 (15), 91 (bp), 65 (16), 56 (21).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2-c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product, m.p. 225°-228° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:33][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(-c2ccccc2)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(CBr)cccc1-c1ccccc1
Yield: 92.6 %

Procedure:
A stirred solution of 2-chloro-3-methyl-[1,1'-biphenyl] (0.5 g, 0.0023 mole) in 8 ml of carbon tetrachloride was irradiated and heated to reflux with a 250 watt brooder lamp. A small amount of benzoyl peroxide was added and the reaction mixture refluxed for ten minutes. A second portion of benzoyl peroxide (total 0.01 g) was added, followed by N-bromosuccinimide (0.43 g, 0.0024 mole). The stirred reaction mixture was irradiated for 16 hours, then cooled, and then filtered. The filter cake was rinsed with carbon tetrachloride and the combined filtrates washed with aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 3-bromomethyl-2-chloro-[1,1'-biphenyl] (0.6 g) as an oil.
Reaction SMILES: [Li][CH2:2]CCC.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH:16]=1)[CH:14]=O)([O-:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(N(C)C)=O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH:14]=[CH2:2])[CH:16]=1)([O-:8])=[O:7]
Reactant: [Li]CCCC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: C=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
Methyltriphenylphosphonium bromide (4.97 g, 13.9 mmol) was dissolved in dry THF (30 ml) and a solution of n-BuLi (1.6 M in hexane, 8.69 ml, 13.9 mmol) was added drop-wise. After 15 minutes, 5-nitro-2-(pyridin-2-ylmethoxy)benzaldehyde (3.0 g, 11.6 mmol) dissolved in dry DMA was added. After 1 hour, the reaction was quenched with saturated sodium bicarbonate and the mixture was extracted with ethyl acetate. After evaporation, the crude material was purified on silica gel (20% EtOAc/petroleum ether) to give 2-[(4-nitro-2-vinylphenoxy)methyl]pyridine (1.11 g, 37%); NMR Spectrum: 5.40 (s, 2H), 5.48 (d, 1H), 6.06 (d, 1H), 7.05 (dd, 1H), 7.34 (d, 1H), 7.38 (dd, 1H), 7.55 (d, 1H), 7.87 (t, 1H), 8.18 (dd, 1H), 8.37 (d, 1H), 8.60 (d, 1H); Mass Spectrum: 257 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](Cl)=[O:38]>C(#N)C>[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:38]
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)CC(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added 3,3-dimethyl-butyryl chloride (0.2 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (360 mg, 59% yield): mp, 118-120° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 0.98 (s, 9H, 3CH3), 1.31 (t, J=7 Hz, 3H, CH3), 1.73-1.80 (m, 1H, CH), 2.27 (s, 2H, CH2), 3.03-3.06 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.03 (m, 2H, CH2), 4.18 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=0.8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.49 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H, Ar), 10.55(s, 1H, NH), 11.82 (s, 1H, NH); 13CNMR (DMSO-d6) δ 7.75, 14.70, 15.46, 29.12, 30.53, 34.67, 44.24, 46.62, 51.11, 55.47, 63.80, 111.94, 112.09, 116.78, 117.33, 117.48, 119.25, 131.23, 132.73, 136.98, 142.26, 147.95, 148.56, 166.54, 168.06, 169.34, 171.70; Anal Calcd for C30H37N3O7+0.1H2O: C, 65.11; H, 6.78; N, 7.59. Found: C, 64.87; H, 6.87; N, 7.48.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-methylphenylboronic acid (136 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, then the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (77 mg, yield 100%).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(Cl)(=O)=[O:35])=CC=1.[O-][O-].[Na+].[Na+]>ClCCl.O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [O-][O-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mmol) and p-toluenesulphonyl chloride (2.38 g, 12.5 mmol) are dissolved with stirring in dichloromethane (40 ml), with cooling in ice-water. A solution of sodium peroxide (2.42 g, 31 mmol) in water (30 ml) is added dropwise over 20 minutes. After further stirring overnight the reaction mixture is diluted with dichloromethane and water. The mixture is allowed to separate and the dichloromethane containing layer collected, dried over magnesium sulphate, filtered and evaporated in vacuo. The resulting solid is slurried in water and collected. It is further washed with water and ether to yield (tolyl)diphenylsulphoxonium hexafluorophosphate (0.73 g, 65%) identical to authentic material.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:12]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35](F)[CH:34]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)#[N:13]>CS(C)=O.O>[C:12]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35]([NH:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:34]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCCO
Temperature: 90 °C

Procedure:
0.9 g of potassium carbonate and 3.3 ml of 3-amino-1-propanol are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 1 and a half hours in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (70/30 by volume), so as to give 0.7 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)-amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C(OCC)(=O)C>[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:25])([O-:20])=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a stirred solution of 13.81 g. (0.1 mole) of m-nitroaniline in 100 ml. of dry ethyl acetate is added 11.13 g. (0.11 mole) of triethylamine. To the solution is added a solution of 18.56 g. (0.1 mole) of m-nitrobenzoylchloride in 100 ml of ethyl acetate. The mixture is refluxed for 6.5 hours. The reaction mixture is allowed to stand at room temperature overnight. The precipitate is removed by filtration. The filtrate is evaporated to dryness in vacuo. The residue is recrystallized from absolute ethanol. There is obtained 5.79 g. of yellow needles that melt at 188°-189°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20]([C:22]1([NH2:25])[CH2:24][CH2:23]1)=[O:21]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:25][C:22]3([C:20]([O:19][CH3:18])=[O:21])[CH2:24][CH2:23]3)=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride according to the procedure of Example 154 as a gum; MS (ES) m/z; 317.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([Li])CCC.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][NH:7]2
Reactant: COc1cccc2[nH]ccc12
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c[nH]c2cccc(OC)c12
Reaction time: 2 h

Procedure:
To a solution of 2.94 gm (20 mmol) of 4-methoxyindole in 150 ml of tetrahydrofuran was added slowly 13 ml of n-butyl lithium (1.6M in hexane; 20 mmol) followed by the slow addition of 20 ml of zinc chloride (1.0M in ethyl ether; 20 mmol) at 0-5° C. The cooling bath was removed and the solution stirred for 2 hours and then treated with 2.1 ml (25 mmol) of ethyl bromoacetate for 19 hours, diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/10-50% ethyl ether to give starting material (40%) and then product, 2.3 gm, 50%, as an oil. 1H NMR (CDCl3) δ: 1.25 (t, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 4.10 (q, 2H), 6.45 (d, 1H), 6.90 (d, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 8.00 (br s, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(C)cc1
Agent: N
Product: Cc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-4-methylbenzene (Apollo, 58 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.43 (s, 3H), 7.30 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.60 (dd, J=7.6, 4.6 Hz, 1H), 7.81 (d, J=8.5 Hz, 2H), 8.36 (dt, J=8.2, 1.8 Hz, 1H), 8.66 (dd, J=4.9, 1.5 Hz, 1H), 9.09 (d, J=3.1 Hz, 1H) ppm; MS (DCI/NH3) m/z 237 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[NH2:26][CH2:27][C:28]([O:32][CH3:33])([O:30][CH3:31])C>C1COCC1>[CH3:31][O:30][CH:28]([O:32][CH3:33])[CH2:27][NH:26][C:16](=[O:18])[C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: COC(C)(CN)OC
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C., i-butylchlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxypropane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aqueous HCl (2×2 L), washed with sat. NaHCO3 (2 L) and Na2CO3 (2 L), and washed with brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+. 1H NMR (CD3OD 300 MHz): δ 7.35-7.30 (m, 5H), 5.08 (s, 2H), 4.45-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.34-3.25 (m, 8H), 2.10-1.90 (m, 1H), 0.94-0.91 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[NH:30][C:29](=[O:32])[CH2:28]2>>[Br:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[NH:30][C:29](=[O:32])/[C:28]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 73.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b obtained from step 1 of Example 4 as starting materials to obtain (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 50 (51 mg, yield 73.2%) as an orange solid.