Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:46])([CH3:45])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH2:38][NH:39][C:40]([NH:42][CH3:43])=[O:41])=[CH:28][CH:27]=3)[C:15]2=[O:44])=[O:12])[CH2:4][O:3]1.FC(F)(F)C(O)=O>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([CH3:45])([CH3:46])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][NH:39][C:40]([NH:42][CH3:43])=[O:41])=[CH:30][CH:31]=2)[C:15]1=[O:44])=[O:12]
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H]3COC(C)(C)O3)CCc3ccccc32)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H](O)CO)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 137 mg (0.213 mmol) of 3-[[2,2-dimethyl-1,3-dioxolan-4(S)-yl]methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(methylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]-methyl]-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step C) in 2 mL of methanol was added 2.0 mL of 50% aqueous trifluoroacetic acid. The resulting solution was stirred at room temperature for 3 hours at which time the solvent was removed under vacuum to give a solid which was purified by reverse phase medium pressure liquid chromatography on C-8, eluting with methanol/0.1% aqueous trifluoroacetic acid (55:45), to afford 108 mg (70%) of the title compound as a white solid. 1H NMR (200 MHz, CD3OD): δ 1.35 (s, 3H), 1.37 (s, 3H), 2.02-2.22 (m, 1H), 2.22-2.43 (m, 1H), 2.50-2.70 (m,4H), 2.64 (s,3H), 2.94 (dd, 12, 9 Hz; 1H), 3.17 (dd, 12, 3 Hz; 1H), 3.51 (m, 2H), 3.82 (m, 1H), 4.16 (s, 2H), 4.38 (dd, 12, 8 Hz; 1H), 5.03 (d, 15 Hz, 1H), 5.14 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H). FAB-MS: calculated for C34H43N5O5 601; found 602 (M+H, 40%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11].Br[CH:30]([CH3:33])[C:31]#[N:32]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[N:26]([CH:30]([C:31]#[N:32])[CH3:33])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CC(Br)C#N
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C(C)C#N
Temperature: 10 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)—N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to ˜10° C. with an ice bath and 2-bromopropanenitrile (0.813 mmol, 109 mg) was slowly added. The mixture was allowed to warm to RT and it was stirred for 2 h. Solvent was evaporated, DCM was added and the mixture was washed twice with water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and trituration from diethyl ether. 63 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.04-1.12 (m, 3H), 1.77 (d, 3H), 2.42 (s, 3H), 4.23-4.49 (m, 3H), 5.72 (q, 1H), 6.92-6.97 (m, 1H), 7.79-7.85 (m, 2H), 7.95-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.15 (d, 1H).
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[Br:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15]>C(OCC)C.ClCCl.CO>[Br:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH3:3])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (diazomethyl)trimethylsilane (12.87 mL) in diethyl ether was added to an ice-batch cooled solution of 2-(3-bromo-4-fluorophenyl)acetic acid (3 g) in dichloromethane (20 mL) and methanol (5 mL). The mixture was stirred for 10 min. and concentrated in vacuo to give methyl 2-(3-bromo-4-fluorophenyl)acetate (3.20 g) that was
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:27]([CH2:35][CH2:36][F:37])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:14]2)[C@H:10]1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:27]([CH2:35][CH2:36][F:37])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[S:14]2)[C@H:10]1[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Yield: 53.3 %

Procedure:
A solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (1.36 g, 2.06 mmol) in THF (30 mL) was treated with tetrabutylammonium fluoride (1.1 g, 4.2 mmol) for 2 hrs at room temperature. The reaction mixture was quenched with H2O (10 mL), extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 10%-20% ethyl acetate in petroleum ether to provide compound 71 as a pale yellow oil (600 mg, 53%). (ES, m/z) [M+H]+ 546.8; 1H NMR (300 MHz, CDCl3) δ 7.24-7.43 (m, 10H), 6.09-6.11 (d, J=4.2 Hz, 1H), 4.60-4.66 (m, 2H), 4.50-4.54 (m, 1H), 4.46-4.47 (m, 1H), 4.40-4.45 (m, 2H), 4.27-4.39 (m, 2H), 4.12-4.22 (m, 2H), 3.72-3.79 (m, 1H), 3.67-3.71 (m, 1H), 3.55-3.63 (m, 1H), 3.40-3.45 (m, 1H), 1.54 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:13]([O:12][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1cccc(COC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCOc1cccc(CO)n1
Yield: 90.8 %

Procedure:
To a solution of 6.85 g (27 mmol) of 2-acetoxymethyl-6-hexyloxypyridine dissolved in 20 ml of ethanol was charged 20 ml of an 8% sodium hydroxide solution, and the mixture was refluxed for one hour. After removal of the ethanol under a reduced pressure, the residue was extracted with ether and separated by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 5.13 g of the desired product (yield 89.9%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:10][C:5]1[CH:6]=[C:7]([C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1C#N
Reaction time: 1 h

Procedure:
A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitrobenzonitrile and 0.81 g of 10% of palladium-on-charcoal in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated under 2.9 bar for 1 hour. The catalyst is filtered off, the filtrate is concentrated and the residue is crystallised from ether/petroleum ether.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:14]1([CH2:17][CH2:18][NH:19][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)NCCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
181 g (1.24 mol) of diethyl oxalate and 500 ml of toluene were placed in a flask, to which 100 g (825 mmol) of 2-phenethylamine was added dropwise at room temperature for 45 minutes. The reaction mixture was heated at 60° C. for two hours, and was further reacted at 75° C. for two hours. The solution was then concentrated at room temperature until the residual quantity of toluene became about 50 ml. The generated precipitation was filtered off and washed with about 50 ml of toluene. 400 ml of hexane was added to the filtrate at 50° C., so as to precipitate crystals. The mixture was further cooled down to 5° C. and stirred for 30 minutes. Then, resulting crystals were filtered, washed with hexane, and dried to obtain 158 g (710 mmol, yield 86%) of ethyl N-(2-phenylethyl)oxamate as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:30])[C:22]([C:24]4[NH:25][C:26](=[O:29])[S:27][CH:28]=4)=[O:23])[C:18](=[O:31])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.CO.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:30])[CH:22]([OH:23])[C:24]4[NH:25][C:26](=[O:29])[S:27][CH:28]=4)[C:18](=[O:31])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=O)[nH]3)[C@H]2SC1
Agent: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(O)n3)[C@H]2SC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3csc(=O)[nH]3)[C@H]2SC1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (5.2 g.), methanol (200 ml.) and 1N sodium hydroxide aqueous solution (10.8 ml.) was dropwise added a mixture of sodium borohydride (0.205 g.) and ethanol (8 ml.) over 10 minutes at 5° to 10° C. with stirring. The mixture was further stirred for 20 minutes at the same temperature, and then a mixture of sodium borohydride (0.01 g.) and ethanol (0.5 ml.) was further added thereto at the same temperature. The mixture was further stirred for 30 minutes at the same temperature, and then the reaction mixture was concentrated under reduced pressure. To the residue was added water (200 ml.), and the solution was washed with ethyl acetate. The aqueous solution was adjusted to pH 5 with 10% hydrochloric acid and washed with ethyl acetate. The solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The remaining aqueous layer was subjected to salting-out and then further extracted with ethyl acetate. The ethyl acetate extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The solvent was distilled off, and the residue was pulverized in diethyl ether, collected by filtration and then dried to give pale yellow powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-hydroxy-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (3.6 g.), mp. 110° to 121° C. (dec.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH2:16].[F-].[Na+].O>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [F-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Yield: 88 %

Procedure:
34. In a 125 mL flask were mixed 14.11 g. (0.10 mole) of 4-fluoronitrobenzene, 10.22 g. (0.10 mole) of 3-(dimethylamino) propylamine and 5.00 g. (0.12 mole) of dry sodium fluoride. Upon warming, a reaction began, and after an hour the mixture was heated to 150° C. for an hour. The mixture was cooled below 100° and treated with 400 mL water containing 0.10 mole sodium hydroxide at 60° C. for one hour; it was then chilled to solidify the freed amine and the aqueous phase was decanted off. After three water washings and drying, the crude product was dissolved in methyl tertiary butyl ether, filtered and evaporated to dryness, giving 19.69 g. (88% yield) of N-(3-dimethylaminopropyl) 4-nitroaniline, m.p. 60°-61.5° C. A 2.23 g. (0.01 mole) portion of this product was dissolved in 15 mL of acetone and treated with 2.13 g. (0.015 mole) of methyl iodide in a closed vessel. There was an immediate reaction and presently a yellow solid was suddenly precipitated. The mixture was warmed for 1/2 hour at 50° C. cooled, filtered, washed with acetone, and dried; the remaining solid, weighing 3.31 g., m.p. 210°-211.5° C., represented a 90% yield of Dye No. 34.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].[CH:20]([O-])=[O:21].[Na+].C(OC(=O)C)(=O)C.C(O)C>C(O)=O>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][CH:20]=[O:21])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Reactant: O=C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride 1 (Luxen, A., Perlmutter M., Bida, G. T., Van Moffaert, G., Cook, J. S., Satyamurthy, N., Phelps, M. E. and Barrio, J. R. (1990) Remote, semiautomated production of 6-[18F]fluoro-L-dopa for human studies with PET. Appl. Radiat. Isot. 41, 275) (5.3 g, 18.3 mmol) and sodium formate (1.44 g, 21.2 mmol) in formic acid (52 mL) cooled in an ice bath was added acetic anhydride (20 mL) and stirred at room temperature for 3 h. After addition of ethanol (40 mL) the mixture was stirred at room temperature for an additional 3 h and evaporated. The residue was dissolved in ethyl acetate, filtered and the insoluble material was washed with ethyl acetate. The combined filtrates were washed successively with aqueous 10% HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to a yellow syrup. Crystallization of the syrup from ethyl acetate-petroleum ether give a white solid 2 (3.1 g, 61%); m.p. 102°-103° C.
Reaction SMILES: Cl.[Cl:2][C:3]#[C:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:13](=[O:26])[CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][C:16]=2[O:17]C)=[C:7]([CH3:27])[CH:6]=1>CC(C)=O>[Cl:2][C:3]#[C:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH:12]2[C:13](=[O:26])[CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][C:16]2=[O:17])=[C:7]([CH3:27])[CH:6]=1
Reactant: COC1=C(c2c(C)cc(C#CCl)cc2C)C(=O)C(Cc2ccccn2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C#CCl)cc(C)c1C1C(=O)CC(Cc2ccccn2)C1=O
Temperature: 60 °C

Procedure:
Aqueous 2M hydrochloric acid (1.20 ml) is added to a solution of rac-2-(4-chloroethynyl-2,6-dimethylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone (0.120 g, 0.33 mmol) in acetone (1.20 ml), and the reaction mixture is heated at 60°C. for 2 hours. The solution is then concentrated in vacuo, and the crude product is purified by preparative reverse phase HPLC to afford rac-2-(4-chloroethynyl-2,6-dimethylphenyl)-4-pyridin-2-ylmethylcyclopentane-1,3-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h

Procedure:
To a 0° C. cooled solution of 4-nitrobenzaldehyde in DCM (40 mL) was added Na(OAc)3BH (10.526 gm, 49.66 mmol) and the reacton was stirred for 10 min. To the reaction mixture was added N-methylpiperazine (9.93 g, 99.3 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 h. The progress of the reaction was monitored by TLC and upon completion of the reaction, the mixture was partitioned between DCM (20 mL) and water (15 mL) and the organic layer was separated, washed with water (2×15 mL), dried over sodium sulphate, filtered and the solvent was removed under reduced pressure to give crude residue. Washing with ether gave 1-methyl-4-(4-nitrobenzyl)piperazine (4 g). 1H NMR (CDCl3, 200 MHz) δ: 8.19 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 3.59 (2H, s), 2.47 (8H, bm), 2.29 (3H, s); m/e=236 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:6]1.[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O.O>[N:18]([CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:6]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C(=O)OC)n(CCCBr)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)n(CCCN=[N+]=[N-])n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-1 (1.0 g, 3.45 mmol) in 10 ml DMSO was treated with NaN3 (0.883 g, 13.8 mmol) and mixture stirred at 25° C. for 5 h. Next, the reaction mixture was diluted with 100 ml of H2O and then extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 ml) and brine (1×100 ml), dried over Na2SO4 and evaporated to give 5-2 as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]#[N:26])=[CH:4][N:3]=1.[OH-:27].[Na+].OO.O>CCO.CS(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]([NH2:26])=[O:27])=[CH:4][N:3]=1
Reactant: Cc1cn(-c2ccc3c(N)ncc(C#N)c3c2)c2c1C(=O)CC(C)(C)C2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cn(-c2ccc3c(N)ncc(C(N)=O)c3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A suspension of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile (0.066 g, 0.19 mmol) in EtOH/DMSO (3:1, 2 mL) is treated with an aqueous solution of NaOH (1 M, 0.03 mL) and H2O2 (30%, 0.1 mL). The reaction mixture is stirred at RT for 2 h. The reaction mixture is treated with H2O (20 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-20% MeOH/CH2Cl2) affords 0.02 g (29%) of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carboxylic acid amide. LC/MS m/z=363 [M+H]+, RT=1.93 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([C:23](=[O:42])[C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]5[C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:35]=[N:34][CH:33]=5)[CH:25]=4)=[N:22][C:17]3=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.C(OCC)C>[CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]([C:26]2[CH:25]=[C:24]([C:23]([C:21]3[NH:20][C:18]4=[N:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=[C:17]4[N:22]=3)=[O:42])[CH:29]=[CH:28][C:27]=2[C:30]#[N:31])=[CH:33][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)c4ccc(C#N)c(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)c2nc3ccc(N4CCNCC4)nc3[nH]2)cc1-c1cncc2ccccc12
Yield: 34.5 %

Procedure:
4-[2-(4-cyano-3-isoquinolin-4-yl-benzoyl)-3H-imidazo[4,5-b]pyridine-5-yl]piperazine-1-carboxylic acid tert-butyl ester solution (16 mg, 0.029 mmole) in 2 M HCl ethylether (2 ml) was stirred at room temperature for 1 hour. Solvent was removed. Solid was washed with ether for three times and purified by using HPLC (20% to 100% acetonitrile in water with 0.1% NH4OH) to afford product (4.6 mg, 25%) as a yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 2.86 (m, 4H), 3.55 (m, 4H), 6.73 (d, J=9.03 Hz, 1H), 7.59 (d, J=8.03 Hz, 1H), 7.66 (m, 2H), 8.00 (d, J=9.03 Hz, 1H), 7.97 (d, J=8.03 Hz, 1H), 8.07 (d, J=8.03 Hz, 1H), 8.50 (s, 1H), 8.72 (s, 1H), 8.77 (d, J=8.03 Hz, 1H), 9.31 (s, 1H). HR-MS m/z 460.1896 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:38])[C:15](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:16][CH2:17][CH3:18])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:38])/[C:15](/[CH2:16][CH2:17][CH3:18])=[CH:9]/[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8])[CH3:12]
Reactant: CCCC(C(=O)OCC)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C=O
Product: CCC/C(=C\c1ccccc1C=O)C(=O)OCC

Procedure:
(E)-3-(2-Formylphenyl)-2-propyl 2-propenoic acid ethyl ester as a colourless oil was prepared from o-phthalaldehyde and 2-(triphenylphosphoranylidene)pentanoic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCOCC1.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN(C)CCO
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 1.5 h

Procedure:
A suspension of 9.0 g of 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylic acid in 240 ml of dioxane was treated in succession with 6.7 ml of 2-(dimethylamino)ethanol, 15.7 g of 1H-1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 263 mg of 4-dimethylaminopyridine, whereupon the mixture was heated to boiling under reflux for 80 minutes under argon, treated with 1.58 g of 1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate and heated for a further 1 hour. The mixture was then left to cool and the separated crystals were filtered off under suction. After stirring with 890 ml of methylene chloride, 475 ml of water and 70 ml of saturated sodium hydrogen carbonate solution for 90 minutes the organic phase was separated and evaporated. The residue was dissolved in 100 ml of methanol, whereupon the solution was acidified with ethereal hydrochloric acid, filtered and the product was precipitated by cooling in an ice bath. There was obtained 2.9 g of 2-(dimethylamino)ethyl 4,6dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 225°-228°.