Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]>COC1C=CC(O)=CC=1.C(N(C(CC)C)C1C=CC(N)=CC=1)(CC)C>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]
Reactant: C=C(C)C(=O)OC
Agent: CCC(C)N(c1ccc(N)cc1)C(C)CC
Agent: COc1ccc(O)cc1
Agent: O=C1CCCN1CCO
Product: C=C(C)C(=O)O
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
A 750 ml reactor with Oldershaw column and liquid distributor was initially charged with 280 mg of hydroquinone monomethyl ether (350 ppm), 600 g (6.0 mol) of methyl methacrylate (MMA) and 194 g (1.5 mol) of N-hydroxyethylpyrrolidone, which were stirred at a stirrer speed (anchor stirrer) of 400 rpm and an air supply of 1.5 l/h. Subsequently, 6.37 g (30 mmol; 2.0 mol % based on N-hydroxyethylpyrrolidone) of anhydrous potassium phosphate were added, the vacuum was established (300 mbar) and the suspension was heated (the jacket temperature was adjusted to 120° C. by means of thermostat control). After approx. 20 minutes, the suspension began to boil (t=0 min). During the reaction, distillate was removed continuously (reflux:efflux ratio was 25:1) and the temperature in the bottom rose from approx. 63° C. to 79° C. After 300 min, the reaction was ended and the vacuum was removed. The suspension was cooled and then filtered through a pressure suction filter (30 ml of methyl methacrylate were added to flush the residue). 492 g of crude product were obtained, which were admixed with 200 ppm of N,N-di-sec-butyl-p-phenylenediamine (98 mg) and were distilled with a supply of air. This first removed the excess methyl methacrylate and then afforded the product of value (130° C., 1.3 mbar). 273 g (92%) of N-hydroxyethylpyrrolidone methacrylate (N-(2-(methacryloyl)ethyl)pyrrolidone) were obtained in high purity (GC analysis: 99.6%). The color number was 50 (APHA color number).
Reaction SMILES: B.CSC.[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH:24]C2C=CC=CC=2OC)=O)[CH2:18][CH2:17]1>O1CCCC1>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([CH:22]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:5][CH3:6])[NH2:24])[CH2:20][CH2:21]1
Reactant: COc1ccccc1NC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccccc1C(N)C1CCN(CC2COc3ccccc3O2)CC1
Temperature: 95 °C
Yield: 189.8 %

Procedure:
Borane-dimethyl sulphide complex (1M solution in dimethyl sulphide; 0.5 ml) was added dropwise under nitrogen to a solution of 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide (0.35 g) in dry tetrahydrofuran (25 ml) and then the mixture was heated under reflux for 2 hours. The reaction was cooled and the solvents removed in vacuo. The residue was diluted cautiously with dilute hydrochloric acid (1M; 70 ml) and heated at 95° C. for 1.5 hours. The aqueous mixture was cooled and basified by the addition of aqueous sodium hydroxide solution (2.5M), there the product was extracted into dichloromethane. The organic extract was washed with water, then dried over magnesium sulphate, filtered, and the solvent removed in vacuo to yield 1-[1-(1,4-benzodioxan-2-ylmethyl)piperid-4-yl]-N-(2-methoxyphenyl) methylamine (0.32 g). The procedure was repeated using 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide (1.37 g, prepared in a similar manner to that described above). The products of the two reactions were combined and dissolved in ether. Hydrogen chloride was bubbled through the solution and the resulting solid precipitate collected by filtration (1.2 g). The solid was dissolved in saturated aqueous sodium hydrogen carbonate solution (100 ml) and the resulting oil extracted into ethyl acetate (100 ml). An excess of a saturated solution of oxalic acid in ethyl acetate was added and the solid precipitate was collected by filtration and dried in vacuo at 50° C. to yield 1-[1-(1,4-benzodioxan-2-ylmethyl) piperid-4-yl]-N-(2-methoxyphenyl)methylamine mono-oxalate (0.78 g), m.p. 215°-218° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]/[C:21](=[N:24]\[C:25](=O)[O:26]C4C=CC=CC=4)/[NH:22][OH:23])=[CH:16][CH:15]=3)[C:10]([CH2:34][CH3:35])=[C:9]([CH3:36])[N:8]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]4[NH:24][C:25](=[O:26])[O:23][N:22]=4)=[CH:18][CH:19]=3)[C:10]([CH2:34][CH3:35])=[C:9]([CH3:36])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C/C(=N\C(=O)Oc2ccccc2)NO)cc1
Solvent: Cc1ccccc1
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2noc(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A 50-mL round bottomed flask was charged with Phenyl (NE)-N-[2-[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-1-(hydroxyamino)ethylidene)carbamate (80 mg, 0.15 mmol) and toluene (10 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using 1˜2% methanol in dichloromethane as eluent to give the title compound as a white solid (16 mg, 25% yield over two steps). MW=427.91. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (brs, 1H), 8.57 (brs, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.56 (d, J=3.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.15 (d, J=3.6 Hz, 1H), 3.86 (s, 2H), 2.73 (q, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.10 (t, J=7.6 Hz, 3H).
Reaction SMILES: C[C:2]([C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[CH2:15][CH2:16][CH3:17])[C:3](O)=[O:4].Cl.CN(C)CCCN=C=NCC.[CH:39]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])[CH3:40].C(Cl)(Cl)Cl.CO.[OH-].[NH4+].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:39]([C:42]1[CH:43]=[CH:44][C:45]([S:48]([NH:51][C:3](=[O:4])[CH:2]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=2[CH2:15][CH2:16][CH3:17])(=[O:49])=[O:50])=[CH:46][CH:47]=1)([CH3:41])[CH3:40]
Reactant: CCCc1cc(C#N)ccc1OC(C)(C(=O)O)c1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C#N)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a stirred solution of 2.92 g (8.61 mmol) of the product of Step D in 40 mL of methylene chloride was added 2.31 g (12.05 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.26 g (10.33 mmol)of 4-dimethylaminopyridine, and 1.89 g (9.47 mmol) of 4-iso-propylbenzenesulfonamide. The reaction mixture was stirred overnight and after TLC analysis (80:15:1 chloroform/methanol/ammonium hydroxide) was poured into 1N HCl and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was partially purified with silica gel flash chromatography eluting first with 40% ethyl acetate-hexane and then with 3% methanol-methylene chloride to flush the column. All of the product fractions were contaminated and were chromatographed. The 3.86 g of semi-purified material was dissolved in 15 mL of acetonitrile and 15 mL of water and filtered through a 0.45 μM membrane filter. The compound was purified using a Waters Delta Prep 3000 HPLC by applying the filtered solution to an M1000 Prep-Pak module containing a 47×300 mm 15 mM DeltaPak C18 column and eluting at 50 mL/min first using 50% A (95-5 acetonitile-water) and 50% B (95-5 water-acetonitrile) with 0.1% TFA for 15 minutes and then 70% A (95-5 acetonitile-water) and 30% B (95-5 water-acetonitrile) both with 0.1% TFA. The column effluent was monitored simultaneously at 210 and 277 nM with a Waters model 490 UV-visible detector and the purified fractions were combined in a round bottom flask and concentated in vacuo to afford 1.45 g (38%) of the title compound as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1)#[N:19].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][C:7]1([CH3:16])[C:6]2[CH:17]=[C:2]([C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=3)[C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8]1
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
A mixture of 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine (0.5 g, 1.61 mmol), 3-cyano-5-fluorobenzeneboronic acid (0.39 g, 1.8 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.2 g, 0.161 mmol), and sodium carbonate (0.5 g, 4.83 mmol) in DME (50 mL) and water (25 mL) was subject to a blanket of nitrogen flow for 15 minutes at 50° C. and then was heated at 85° C. under nitrogen for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (200 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (20 mL) and once with brine (20 mL), dried over sodium sulfate and concentrated to a yellow solid. Purification via flash column chromatography (silica gel, 5% ethyl acetate/hexane) gave 3-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]-5-fluorobenzonitrile (0.396 g, 73%) as a white solid: mp 102-103° C.; 1H-NMR (DMSO-d6) δ 8.07 (s, 1H), 7.91 (d, 1H, J=10.7 Hz), 7.7 (d, 1H, J=10.7 Hz) 7.62 (d, 1H, J=1.98 Hz), 7.53 (dd, 1H, J=8.33, 1.98 Hz), 7.05 (s, 1H), 6.87 (d, 1H, J=8.33 Hz), 5.39-5.37 (m, 1H), 1.61 (s, 3H), 1.59 (s, 3H); MS (ES) m/z 349 ([M−H]−).
Reaction SMILES: C(O[CH:5]([CH3:8])[CH:6]=O)(=O)C.[C:9]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:11]1[O:12][C:5]([CH3:8])=[CH:6][C:10]=1[C:9]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(=O)OC(C)C=O
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)Nc2ccccc2)c(C)o1

Procedure:
A solution of 24 parts of α-acetoxypropionaldehyde, 35.4 parts of acetoacetanilide and 2 parts of p-toluenesulfonic acid in 100 parts of benzene is kept for 3 hours at 40° C and then boiled under reflux for 1 hour. Adopting the isolation procedure described in Example 1 there is obtained 41.8 parts of 2,5-dimethylfuran-3-carboxanilide having a melting point of 92° to 93° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].C(O)C.Cl[CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17]>O>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][C:1]#[N:2]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(CC#N)c(C)c1

Procedure:
66 g of sodium cyanide is refluxed in 100 mL water and 140 mL of ethanol with stirring, until a clear solution is formed. 136 g of 2-chloromethyl-1,3,5-trimethylbenzene is slowly added dropwise to this solution and the mixture is refluxed for 3 hours with stirring. It is diluted with 1 L of water and extracted three times with 200 mL of benzene. The combined organic phases are washed with water and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 92 g (72%); bp15: 145° C.-153° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (355 mg, 1.17 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (220 mg, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (348 mg, 64%).
Reaction SMILES: [OH:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[NH:41][N:40]=[N:39][N:18]=1
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1SC[C@H](/C=C/C(O)Cc2ccccc2)N1CCCCCCc1nnn[nH]1
Yield: 62.3 %

Procedure:
To a solution of 4-4 (70 mg, 0.2 mmol) in 0.2 mL toluene was added tributyltin azide (0.27 mL, 1.0 mmol) and the resulting solution was stirred at reflux for 4 hours. Ethyl acetate (100 mL) was added and the solution was quenched with 5% aqueous KF (30 mL) and 1N HCl (30 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 0–5% MeOH/CH2Cl2 to yield 50 mg of 4-5 as a colorless oil. 1H NMR (400 MHz, CD3OD): δ7.29–7.17 (m, 5H), 5.81 (dd, 1H), 5.53 (dd, 1H), 4.38 (q, 1H), 4.33 (q, 1H), 3.45 (dd, 1H), 3.33 (m, 1H), 2.97 (m, 4H), 2.78 (m, 1H), 2.68 (m, 1H), 1.83–1.21 (m, 8H); MS (−ESI): m/z 400.2 (M−1)−.
Reaction SMILES: [Cl-].C(C[P+](C)(C)C)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:19]1([C:25](O)([CH3:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F:29][C:30]1([F:58])[CH2:35][CH2:34][N:33]([C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][C:43]([C:47]([N:49]2[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]2)=[O:48])=[CH:42][CH:41]=3)=[O:37])[CH2:32][CH2:31]1>>[F:58][C:30]1([F:29])[CH2:35][CH2:34][N:33]([C:36]([C:38]2[N:39]([C:25]([CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:26])[C:40]3[C:45]([CH:46]=2)=[CH:44][C:43]([C:47]([N:49]2[CH2:50][CH2:51][N:52]([CH:55]([CH3:56])[CH3:57])[CH2:53][CH2:54]2)=[O:48])=[CH:42][CH:41]=3)=[O:37])[CH2:32][CH2:31]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(C)(O)c1ccccc1
Agent: C[P+](C)(C)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)(C)c2ccccc2)CC1
Yield: 9 %

Procedure:
The title compound was synthesized in analogy to example 74, from (cyanomethyl)trimethylphosphonium chloride (prepared according to Tetrahedron Lett. 1996, 37 (14), 2459-62), potassium bis(trimethylsilyl)amide, 2-phenyl-2-propanol and (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), to give the desired product as a yellow foam (9%).
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2].[H-].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:30]=1[CH:31]=O)([O-:28])=[O:27].C(OCC)(=O)C>C1COCC1>[C:1]([C:3](=[CH:31][C:30]1[CH:33]=[C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27])[CH:4]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C(C#N)C(CCC(=O)O)C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(CCC(=O)O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentanoic acid (2.68 g, 7.7 mmol) in THF (300 mL), sodium hydride (60%, 1.24 g) was added portionwise at room temperature. 2-Nitro-5-phenoxy-benzaldehyde (1.9 g, 7.7 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the resulting solution washed with saturated aqueous NH4Cl solution. The organic phase was separated, dried with MgSO4, and filtered. The filtrate was evaporated in vacuo to yield an oil which was triturated with heptane to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:31]3[CH2:30][CH2:29][N:28]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:27]=4[N:18]=[CH:19][CH:20]=[CH:21]5)[CH2:33][CH2:32]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: Clc1ccc(N2CCNCC2)c2ncccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1ccc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-chloro-8-(piperazin-1-yl)quinoline (Step 3) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a beige solid; MP. 201-203° C.; MS (ES) m/z (relative intensity) 459 (M+H)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N+:16]([O-:18])=[O:17])=[C:8]([C:12]([O:14]C)=[O:13])[NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.C(OCC)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N+:16]([O-:18])=[O:17])=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1[nH]c2cc(OC)ccc2c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c([N+](=O)[O-])c(C(=O)O)[nH]c2c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-methoxy-3-nitroindole-2-carboxylate (step 1) in ethanol (10 ml) and water(5 ml) was added K2CO3 and the mixture was stirred for 4 hr at 40° C. The mixture was acidified with 2N HCl and extracted with ethyl acetate (20 ml×2). The organic layer was washed with brine (10 ml) and dried (MgSO4). Removal of solvent gave product as an oil. tlc: Rf=0.1 (50% ethyl acetate in hexanes)
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[C:8]([F:16])[CH:9]=3)=[O:13])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 61.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-fluorobenzoic acid (223 mg) described in Preparation Example 26 and 1-(3,5-dimethylpyridin-2-yl)piperazine (164 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (229 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl>C(O)C>[NH2:18][CH:16]([C:13]1[N:12]=[N:11][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15][CH:14]=1)[CH3:17]
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)OC(C)(C)C)nn2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Yield: 79.8 %

Procedure:
To a stirred solution of 1,1-dimethylethyl [1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]carbamate (Intermediate 46) (3.00 g, 8.69 mmol) in ethanol saturated with hydrogen chloride (30 mL) was stirred overnight at room temperature. The resulting mixture was reduced under vacuum, partitioned between ethyl acetate and saturated sodium bicarbonate solution and the mixture filtered to give a solid residue. The aqueous layer was re-extracted with ethyl acetate (5×) and the combined organic layers dried with magnesium sulfate, filtered and reduced under vacuum. The residue was purified by chromatography on silica gel eluting with 50% ethyl acetate in petrol to afford a solid which was combined with the initial solid to give 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (1.70 g) as a yellow solid. 1H NMR (CDCl3): δ8.35 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.34 (s, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.33 (q, J=6.7 Hz, 1H), 3.82 (s, 3H), 1.51 (d, J=6.7 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([CH3:12])[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:13][C:6]1([CH3:14])[N:7]([CH3:12])[C:8]([CH3:10])([CH3:11])[CH2:9][N:4]([CH2:3][CH2:2][O:1][CH2:16][CH:18]2[CH2:19][O:20]2)[C:5]1=[O:15]
Reactant: CN1C(C)(C)CN(CCO)C(=O)C1(C)C
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CN1C(C)(C)CN(CCOCC2CO2)C(=O)C1(C)C

Procedure:
Following the procedure described in Example 7, 80 g (0.37 moles) of 1-(2-hydroxyethyl)-3,3,4,5,5-pentamethyl-piperazin-2-one are reacted with 118 g (1.28 moles) of epichlorohydrin in the presence of 13 g (38 mmoles of tetrabutylammonium hydrogen sulfate and 16.4 g (0.41 moles) of sodiumhydroxide dissolved in 41 ml of water.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.N[C:14]([CH3:18])=[CH:15][C:16]#[N:17].[ClH:19]>>[ClH:19].[NH2:17][C:16]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[N:10]=[C:14]([CH3:18])[CH:15]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CC(N)=CC#N
Agent: Cl
Product: Cc1cc(N)n(-c2cccc(C(F)(F)F)c2)n1

Procedure:
3-Trifluoromethylphenyl hydrazine (Tetrahedron, 1960, 69) (25.0 g.) was reacted with 3-amino-2-butene nitrile (12.7 g.) as described in Example XLIII to give 36.1 g. product as HCl salt, mp 222°-226°.