Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>N1C=CC=CC=1>[F:15][C:4]1[CH:3]=[C:2]([NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 76.5 %

Procedure:
To a solution of ethyl 3-(4-amino-2-fluorophenyl)propanoate (9.89 g, 46.8 mmol) in pyridine (70 mL) was added 2-nitrobenzenesulfonyl chloride (11.4 g, 51.5 mmol) by small portions, and the mixture was stirred at room temperature for 70 hr. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue. The mixture was stirred with heating at 80° C. for 15 min and filtrated through celite. The organic layer in the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane) to give the title compound (14.2 g, yield 76%) as pale-yellow prism crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of (S)-tert-butyl-1-(5-fluoropyridin-2-yl)ethylcarbamate (Method 32; 12.8 g, 53.3 mmol) in DCM (100 ml) was added HCl/dioxane solution (107 ml, 4 N, 428 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed and 50 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (6×400 ml), dried over sodium sulfate and concentrated to give the title compound (7.30 g, 98%) as pale yellow oil. 1H NMR (400 MHz) δ 8.44 (d, J=2.8 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 4.01 (q, J=6.8 Hz, 1H), 1.94 (b, 2H), 1.26 (d, J=6.8 Hz, 3H). MS: Calcd.: 140. Found: [M+1-1]+141.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=CC=C[N:12]=3)NC=2N=CN=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[NH:32][C:26]2[N:27]=[CH:28][N:29]=[C:30](O)[C:25]=2[CH:24]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:16]=[C:11]([CH:9]=[CH:10][CH:3]=1)[NH:12][C:30]1[C:25]2[CH:24]=[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[NH:32][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: Clc1ncnc2[nH]c(-c3ccccn3)cc12
Reactant: Oc1ncnc2[nH]c(-c3ccccn3)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccccn4)cc23)c1
Reaction time: 2 h

Procedure:
4-Chloro-6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidine With the exclusion of moisture, 7.05 g (33.2 mmol) of 6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol and 70 ml of phosphorus oxychloride are heated at boiling for 2 hours. The dark-brown suspension is concentrated by evaporation to a residual volume of 20 ml. The residue is introduced in portions into water, neutralized with solid NaHCO3 and 0.2 liter of ethyl acetate is added thereto. Filtering and washing with hot THF yield the title compound; 1H-NMR (300 MHz, DMSO-d6): 13.2 (sb, 1H), 8.72 (d, J=7, 1H), 8.63 (s, 1H), 8.23 (d, J=11, 1H), 7.97 (t, J=11, 1H), 7.46 (dd, J,=7, J2 =11, 1H), 7.35 (s, 1H). Further product can be isolated from the filtrate and the THF washing solution, which is concentrated by evaporation, by partitioning between ethyl acetate/water and digesting in ethyl acetate/diethyl ether.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([N:5]1[CH2:6][CH2:7][C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:1])[CH2:3][CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
4-Hydroxy-4-phenylpiperidine (0.5 g, 2.8 mmol), benzylbromide (0.5 g, 3 mmol) and potassium carbonate (0.8 g, 6 mmol) were dissolved in DMF (5 mL) and stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with a solution of saturated aqueous sodium carbonate solution then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The resulting solid was recrystallised from pentane to give the title compound as a white solid (0.47 g). LCMS m/z 268.3 [M+H]+. R.T.=2.37 min (Analytical Method 4).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:23])[C:12]=1[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=O>O1CCCC1.[OH-].[Na+]>[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:23])[C:12]=1[CH2:13][CH2:14][CH2:15][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cc1c[nH]c(C)c1CCC(=O)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c(C)c1CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a suspension of lithium aluminum hydride (2.67 g, 70 mmol) in tetrahydrofuran (100 ml) was added dropwise a solution of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-1-morpholin-4-yl-propan-1-one (13.84 g, 59 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred at 80° C. for 1 hour and cooled ins an ice bath. Ice was added to the reaction mixture slowly until gas evolution ceased. A few drops of 2N sodium hydroxide were added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 10.37 g (79%) of 4-[3-(2,4-dimethyl-1H-pyrrol-3-yl)-propyl]-morpholine as a light brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](Cl)[C:3]=1[Cl:10].ClC1C=C(Cl)C=C(Cl)C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[Cl:10]
Reactant: Clc1ccc(Cl)c(Cl)c1Cl
Agent: Clc1cc(Cl)cc(Cl)c1
Product: Clc1ccc(Cl)c(Cl)c1

Procedure:
In effect, when using a single tetrachlorobenzene or a mixture of tetrachlorobenzenes, it has been found that 1,3,5-trichlorobenzene is formed in admixture with 1,2,4-trichlorobenzene and an equivalent amount of pentachlorobenzene. The pentachlorobenzene formed in this manner reacts with 1,2,4-trichlorobenzene to yield a mixture of tetrachlorobenzenes. The formation of pentachlorobenzene is restricted, while maintaining the production of 1,3,5-trichlorobenzene, by introducing 1,2,4-trichlorobenzene into the reaction medium.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](OCC)=[O:32])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(OCC)C>[CH2:7]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][OH:32])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(CCO)cc1
Reaction time: 2 h

Procedure:
A mixture of 1.0 g. of lithium aluminum hydride in 20 ml. of dry ethyl ether is stirred at room temperature as a solution of 5.0 g. of ethyl (4-hexadecylaminophenyl)acetate in 15 ml. of dry ethyl ether is slowly added. When the addition is complete, the reaction is stirred for an additional 2 hours and then quenched with 10% aqueous ammonium chloride. The mixture is filtered through celite, the phases are separated, and the ether is evaporated to provide 2-(4-hexadecylaminophenyl)ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Yield: 89.9 %

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (24 g, 77.4 mmol) in ethanol (400 mL) was added sodium hydroxide (4.02 g, 100.6 mmol), water (11 mL) and the mixture was stirred at reflux condition for 6 h. Ethanol was distilled off and residue was diluted with water, extracted with ethylacetate (40 mL) adjusted aqueous layer to PH-3 with 1N HCl and extracted with ethyl acetate (3×250 mL), finally organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. The crude was washed with pet ether, filtered the solid and dried to afford desired product 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (20.6 g, 89.8%). 1H NMR (DMSO-d6, 400 MHz): δ 1.407 (d, J=6.4 Hz, 6H), 2.296 (s, 3H), 4.754-4.819 (m, 1H), 7.455 (s, 1H), 7.472 (s, 1H), 7.938 (s, 1H), 12.950 (brs, 1H). LCMS (ES+) m/z=296.15 (M+H).
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[O:8][C:7](=[O:19])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:21]1[O:22][C:7]2([NH:6][C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C@H:9]([CH2:10][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[O:8]2)[O:19][CH2:20]1
Reactant: OCCO
Reactant: CC(C)CCC(=O)CC[C@@H]1OC(=O)N[C@H]1CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CCC(=O)CC[C@@H]1OC2(N[C@H]1CC(C)C)OCCO2
Yield: 79 %

Procedure:
A mixture of the product from Example 27 (2.5 g, 9.3 mmol), ethylene glycol (7.5 mL) and p-toluenesulfonic acid (60 mg) in toluene (100 mL) was heated at reflux with a Dean-Stark trap for 8 hours. The cooled mixture was washed with aqueous NaHCO3 and dried over MgSO4. Evaporation of the solvent gave a residue which was flash chromatographed on silica gel eluting with 65/35 hexane-ethyl acetate to give 2.3 g (79%) of product. NMR (300 MHz, CDCl3, ppm): 0.85-0.95 (4d, 12H), 3.5 (m, 1H), 3.95 (s, 4H), 4.15 (m, 1H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[CH2:1]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCCCCCC
Reactant: O=Cc1ccc(Br)cc1
Product: CCCCCCCCCCc1ccc(C=O)cc1
Yield: 94.4 %

Procedure:
General procedure G was used to couple 1-decene (8.1 mmol) to 4-bromobenzaldehyde (5.4 mmol) to yield 1.25 g (5.1 mmol) of the title product after column chromatography. Spectral data was consistent with previously reported compounds.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)([O-:18])=[O:17]>C(#N)C>[N+:16]([C:19]1[CH:27]=[CH:26][C:25]2[C:21](=[CH:22][N:23]([CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[N:24]=2)[CH:20]=1)([O-:18])=[O:17]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 g (62.0 mmol) 1-(2-chloroethyl)-pyrrolidine hydrochloride and 12.9 g (93.0 mmol) K2CO3 are added successively to a solution of 5.00 g (31.0 mmol) 5-nitroindazole in 100 mL acetonitrile. The reaction solution is stirred for 2 h at RT and refluxed for a further 5 h. After the solution has cooled the insoluble salts are filtered off and the solvent is eliminated i.vac. The residue is taken up in EtOAc and water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. A 4:1 mixture of 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole and 5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole is obtained. The purification is carried out by column chromatography on Alox (PE/EtOAc 3:2).
Reaction SMILES: [C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:13]=3)[C:8]=2[CH:7]=[C:6]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)[CH:5]=1)(=[O:3])[NH2:2]>CCO.[Pd]>[C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:13]=3)[C:8]=2[CH:7]=[C:6]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)CC1
Reaction time: 24 h
Yield: 64.2 %

Procedure:
tert-Butyl 4-(1-carbamoyl-7-(morpholine-4-carbonyl)-9H-carbazol-3-yl)-5,6-dihydropyridine-1(2H)−carboxylate (Example 390, 159 mg, 0.290 mmol) was dissolved in EtOH (50 ml) in a 500-ml PARR flask. The flask was flushed with nitrogen, than palladium (10% on carbon, 96 mg, 0.090 mmol) was added, the flask flushed with nitrogen again, then transferred onto PARR shaker and hydrogenated for 24 hours under 60 psi of hydrogen. The reaction mixture was filtered through a 0.45 uM nylon filter and concentrated in vacuum. 94.3 mg crude tert-butyl 4-(1-carbamoyl-7-(morpholine-4-carbonyl)-9H-carbazol-3-yl)piperidine-1-carboxylate (colorless film) was isolated. 44.3 mg of the crude were purified by preparative HPLC to give 21.5 mg tert-butyl 4-(1-carbamoyl-7-(morpholine-4-carbonyl)-9H-carbazol-3-yl)piperidine-1-carboxylate. MS m/e+=507, m/e−505 consistent with [M−H]− and [M+H]+. 1H NMR (CD3OD) δ ppm 8.21 (s, 1H), 8.20 (d, 1H, J=8.0), 7.86 (d, 1H, J=1.5), 7.67 (s, 1H), 7.26 (dd, 1H, J=8.0, 1.5), 4.29 (bd, 2H, J=13.3), 3.90-3.50 (b, 8H), 2.95 (m, 3H), 1.96 (br. d. 2H, J˜12), 1.79 (dq, 2H, J=4.1, 12.6), 1.51 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[N:10]([S:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=23)[CH:24]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: N#Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1c(C#N)cnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of Example 236A (2 g, 6.29 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (1.284 g, 7.55 mmol), sodium hydrogencarbonate (1.586 g, 18.88 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (0.276 g, 0.378 mmol) in 80 mL N,N-dimethylformamide and 20 mL water was degassed with nitrogen and heated at 100° C. for 3 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica-gel flash chromatography (AnaLogix IntelliFlash 280) eluting with dichloromethane afforded the title compound. MS (ESI+) m/z 408 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[C:10]1(=[O:27])[N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17]C2=O)[C:13](=[O:22])[C:12]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:11]12.C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][O:7][C:9]1[CH:15]([N:14]2[C:10](=[O:27])[C:11]3[C:12](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:13]2=[O:22])[CH2:20][CH2:19][CH2:18][N:17]=1
Reactant: O=C1NCCCC1N1C(=O)c2ccccc2C1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCCC1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
To a solution of 13.474 g (91.1 mmol) of trimethyloxonium tetrafluoroborate in 294 mL of anhydrous dichloromethane was added 22.25 g (91.1 mmol) of (+/−)-3-phtalimidopiperidin-2-one (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20) and the resulting mixture was stirred at room temperature for 12 h. The mixture was hydrolyzed with a saturated aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, dried over sodium sulfate and the solvent was evaporated to afford 23.22 g (99%) of pure product as a yellow oil. The compound was used as such in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](Cl)(=O)[C:16](Cl)=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:15][CH3:16])=[O:10])=[C:7]([CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(C)(C)C)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round bottom flask was charged with acid 101a (630 mg, 3.3 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (4.9 mL, 9.8 mmol, 2.0M solution in CH2Cl2) followed by DMF (1 drop). After the reaction was stirred at room temperature for 8 h, it was concentrated. To the residue was added Et2O (25 mL) and the mixture was concentrated. This repeated to removed any excess oxalyl chloride. The residue was dissolved in CH2Cl2 (15 mL) and EtOH (15 mL). After the reaction was stirred at room temperature for 30 min, it was concentrated. The residue was dissolved in EtOAc (15 mL) and this organic phase was washed with aqueous HCl (15 mL, 1M), H2O (15 mL), brine (15 mL), dried with Na2SO4 and concentrated. The crude 101b (660 mg, 91%) was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[S:9][C:10]3[CH2:11][N:12](C(OCC)=O)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:3][CH:2]=1.[OH-].[K+].[ClH:24]>>[ClH:24].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[S:9][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCc2nc(Cc3ccncc3)sc2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: c1cc(Cc2nc3c(s2)CNCC3)ccn1
Temperature: 0 °C

Procedure:
A solution of ethyl 2-(pyridin-4-ylmethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (3.7 mmol) in a 3.5 N potassium hydroxide solution (7 ml) was heated under reflux for 3 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then cooled to 0° C. and acidified with concentrated hydrochloric acid. The solid which precipitated was filtered out and dried. The product was obtained in the form of the HCl salt. The desired product was obtained in a yield of 35%.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:31]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([N:25]([CH2:37][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CCN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)CCN(CC1CCCCC1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(3-methyl-butylamino)-propionamide mono-hydrochloride (1.0 g, 2.3 mmol, Example 2) and cyclohexanecaboxaldehyde (0.28 g, 2.3 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.73 g, 3.4 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (25 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (20% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.70 g (58%) of the pure titled compound as a white foam; mp 70-81° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.[OH:16][C@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:23]2[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C@H:17]([OH:16])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:24]2)[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(Cl)nc3cc(C(=O)O)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2,4-dichloroquinazoline-7-carboxylic acid (0.45 g, 1.9 mmol) in CH2Cl2 (20 mL) was added (R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (0.37 g, 1.9 mmol) and triethylamine (0.52 mL, 3.7 mmol). The reaction mixture was stirred overnight at room temperature and then purified via silica gel chromatography using 0-10% MeOH/CH2Cl2 to obtain 2-chloro-4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-quinazoline-7-carboxylic acid (0.58 g, 77%). LC/MS: m/z 407.3 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:25])[C:16]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][N:11]3[C:10]3[CH:9]=[CH:8][C:7]([N+:26]([O-])=O)=[CH:6][C:5]2=3)[CH:14]=1.[OH-].[Na+]>S(=O)(=O)(O)O.[Cu]>[NH2:26][C:7]1[CH:8]=[CH:9][C:10]2[N:11]3[CH:17]=[C:16]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[C:15](=[O:25])[C:13]4[CH:14]=[C:2]([Cl:1])[CH:3]=[C:4]([C:5]=2[CH:6]=1)[C:12]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc([N+](=O)[O-])cc3c3cc(Cl)cc1c32
Agent: [Cu]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1ccc2c(c1)c1cc(Cl)cc3c(=O)c(Cc4cccnc4)cn2c31
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
2-chloro-10-nitro-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (1.86 g) obtained in Example 272 was dissolved in conc. sulfuric acid (11 ml) and copper (995 mg) was added to the solution. The mixture was heated to 50° C. in a hot water bath and stirred for 30 minutes. After allowing to cool, the reaction mixture was poured into ice water, then the solution was adjusted to pH 10 with 1 N aqueous solution of sodium hydroxide. The precipitated crystals were recovered by filtration, and washed with water and ether in succession to obtain the title compound (1.37 g, 80%).