Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH:2]([OH:4])[CH3:3].[CH3:6][C:7](=[O:11])CCC.[N-:12]=[C:13]=[O:14]>>[OH:4][CH:2]([CH3:3])[CH2:1][NH:12][C:13]([O:11][CH2:7][CH3:6])=[O:14]
Reactant: [N-]=C=O
Reactant: CCCC(C)=O
Reactant: CC(O)CO
Product: CCOC(=O)NCC(C)O
Temperature: 52 °C

Procedure:
999.28 Parts propylene glycol and 434.85 parts 2-pentanone were added to a mixing vessel equipped with a condenser, nitrogen blanket, agitator, and addition funnel. The contents were heated to about 52° C., followed by addition of 1450.97 parts MONDUR MR polymeric isocyanate while keeping the exotherm below 75° C. The addition funnel was next rinsed with 154.87 parts 2-pentanone. The reaction mixture was held at 75° C. for one to two hours until the isocyanate was consumed (thereby forming a beta-hydroxypropyl urethane polymer), then cooled to 60° C. while adding 759.92 parts propylene glycol monomethyl ether (thereby forming a beta-hydroxypropyl urethane solution). The resulting blocked polymeric isocyanate solution was mixed for 30 minutes and stored in a plastic storage vessel.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8](Br)[CH:9]=[C:10]([F:12])[CH:11]=1.[Mg].O>O1CCCC1>[CH2:3]([C:8]1[CH:7]=[C:6]([F:5])[CH:11]=[C:10]([F:12])[CH:9]=1)[CH:2]=[CH2:1]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C=CCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc(F)cc(F)c1
Temperature: 20 °C

Procedure:
A solution of allyl bromide (2.5 g) in dry tetrahydorfuran (10 ml) was added dropwise with stirring to 3,5-difluorobromobenzene (4.0 g) with magnesium (0.5 g) in dry tetrahydrofuran) in dry tetrahydrofuran (40 ml), whilst maintaining the temperature of the mixture at about 20° C. When the addition was complete the mixture was allowed to warm to the ambient temperature (ca. 25° C.) After a period of 18 hours the mixture was poured into water (100 ml) and the resultant mixture extracted with diethyl ether, the extract washed with water, dried over anhydrous magnesium sulphate and the ether removed by distillation at atmospheric pressure. The residual oil was purified by distillation at atmospheric pressure to yield allyl-3,5-difluorobenzene (b.p. 154-155°) as a colourless oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH2:17][CH2:16][NH:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:22]2[NH:32][CH:33]=[C:34]([C:35](=[O:39])[C:36](O)=[O:37])[C:21]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:22]2[NH:32][CH:33]=[C:34]([C:35](=[O:39])[C:36]([N:15]3[CH2:16][CH2:17][C:9]4[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=5)=[N:13][CH:12]=[N:11][C:10]=4[CH2:14]3)=[O:37])[C:21]=12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
Part E: To a solution of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (0.137 g, 0.55 mmol) in DMF (15 mL) at 25° C. was added sequentially 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.151 g, 0.50 mmol), N-methylmorpholine (0.220 mL, 2.00 mmol), and TBTU (0.177 g, 0.55 mmol), and the mixture was stirred at 25° C. for 18 h. The reaction mixture was concentrated under vacuum, and the residue dissolved in hot methanol. The solution was allowed to cool slowly to room temperature. The precipitate was recovered by filtration, washed with methanol, and dried under vacuum to provide 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (0.122 g, 49%) as an off-white solid; HRMS: 496.1835 (M+H)+ [calc'd: 496.1840]; 1H NMR (500 MHz, DMSO-d6) δ 12.44 (br s, 1H), 9.24 (m, 1H), 9.17 (s, 2/3H), 9.08 (s, 1/3H), 8.77 (m, 1/3H), 8.67 (m, 2/3H), 8.34 (s, 2/3H), 8.26 (s, 1/3H), 8.12-8.00 (m, 2H), 7.87 (m, 1H), 7.58 (m, 1/3H), 7.53 (m, 2/3H), 4.92 (s, 4/3H), 4.72 (s, 2/3H), 3.93 (m, 1/3H), 3.91 (s, 1H), 3.85 (s, 2H), 3.70 (m, 2/3H), 3.32 (m, 1/3H), 3.18 (m, 2/3H), 2.50 (s, 2H), 2.49 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([CH:28]=1)[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1>CO.[Pt]>[NH2:29][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:28][C:13]=1[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[CH3:21])=[O:19]
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1

Procedure:
3-(5-Benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide (0.01 mol) was converted into its corresponding free base. A mixture of the free base (0.01 mol) in methanol (200 mL) was hydrogenated under atmospheric conditions, with 5% Pt/C (2 g) as a catalyst in the presence of 4% thiophene solution (1 mL). After uptake of H2 (3 equiv.), the catalyst was filtered off and the filtrate was evaporated. Toluene was added to the residue, then evaporated again to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:16])=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].C(OC(C1C=NC2=NOC(C)=C2C=1OCC)=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:23][CH3:24])=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2onc(C)c2c1O
Agent: CCOC(=O)c1cnc2noc(C)c2c1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2onc(C)c2c1OCC
Reaction time: 6 h

Procedure:
2.22 g. of 4-Hydroxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 150 ml. of ethanol and 28 g. of potassium carbonate (0.2 mol.). 31 g. of ethyl iodide (0.2 mol.) are added. The mixture is heated with stirring for 6 hours. The hot solution is filtered and the solvent evaporated. The oily residue yields on crystallization with methanol 18.2 g. of 4-ethoxy-3-methylisoxazolo-[3,4-b]pyridine-5-carboxylic acid ethyl ester (73%), m.p. 62°.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[CH3:11][C:12]1[C:13]([OH:19])=[N:14][C:15]([SH:18])=[N:16][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][S:18][C:15]1[N:14]=[C:13]([OH:19])[C:12]([CH3:11])=[CH:17][N:16]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Cc1cnc(S)nc1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(SCc2c(Cl)cncc2Cl)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a mixture of 4-(bromomethyl)-3,5-dichloropyridine (1.0 g, 4.15 mmol) and 5-methyl-2-sulfanylpyrimidin-4-ol (0.38 g, 2.69 mmol) in anhydrous ethanol (25 mL) at 0° C. was added triethylamine (1.67 g, 16.6 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was sonicated and then filtered. The solid was washed with water and hexane to provide 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5-methylpyrimidin-4-ol (0.817 g, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H), 4.66 (s, 2H), 7.99 (s 1H), 8.66 (s, 2H); M+ 302.5.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=[C:16]([CH3:25])[CH:15]=1)/[CH3:4].[OH-].[CH3:28][O:29]C(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:28][O:29][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[C:16]([CH3:25])[CH:15]=2)=[C:7]([C:6]2[O:1][N:2]=[C:3]([CH3:4])[N:5]=2)[CH:12]=1
Reactant: C/C(=N/O)NC(=O)c1ccccc1Nc1cc(C)nn1-c1ccccc1
Reactant: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Nc2cc(C)nn2-c2ccccc2)c(-c2nc(C)no2)c1
Temperature: 25 °C
Yield: 3.7 %

Procedure:
To a solution of the crude N-[(1Z)-N-hydroxyethanimidoyl]-2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]benzamide (257 mg, 0.41 mmol) in THF (3 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent) (145 mg, 0.61 mmol). The flask was flushed with argon and refluxed for 3 h under argon. The reaction mixture was the cooled to rt, filtered through a small plug of silica gel, and the plug was eluted with EtOAc. The filtrate was concentrated under reduced pressure, and the residue purified by preparative TLC on silica gel using EtOAc/Hex (1:2, v/v) to give the title product as a solid (5.5 mg, 4% overall). 1H NMR (400 MHz, CD3CN). δ 2.30 (s, 3H), 2.32 (s, 3H), 3.82 (s, 3H), 6.16 (s, 1H), 7.09 (dd, 1H), 7.21 (d, 1H), 7.38-7.42 (m, 1H), 7.42-7.50 (m, 3H), 7.50-7.58 (m, 2H), 9.46 (br, s, 1H). ES-MS m/z 362.2 (MH+); HPLC RT (min) 3.28.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]#[N:8])([O-:3])=[O:2]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A solution of 3-nitro-4-hydroxybenzonitrile (10 g, 61 mmol) in a mixture of 40 mL of dimethylformamide and 100 mL of acetonitrile was stirred as anhydrous potassium carbonate (10.1 g, 73.2 mmol) and benzyl bromide (10.4 g, 61 mmol) were added. The reaction was heated at 60° C. for about 4 h. The reaction was filtered and the solid was washed with ethyl acetate. The filtrate was washed with water. The organic layers were washed with water and brine, dried and concentrated. The solid was recrystallized from acetone/hexane to give 14 g (90%) of 3-nitro-4-(benzyloxy)benzonitrile, as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C.[ClH:31].CO>>[ClH:31].[NH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(S(=O)(=O)N3CCCC3CO)cc2)n1
Agent: Cl
Solvent: CO
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of {6-[4-(2-hydroxymethyl-pyrrolidine-1-sulfonyl)-phenyl]pyridin-2-yl}carbamic acid tert-butyl ester (15.0 g, 34.6 mmol) in HCl/MeOH (50 mL, 2M) was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was evaporated under vacuum and washed with EtOAc to give (R)-(1-(4-(6-aminopyridin-2-yl)phenylsulfonyl)pyrrolidin-2-yl) methanol hydrochloride (C-2; 11.0 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=8.7 Hz, 2H), 7.93-7.99 (m, 3H), 7.31 (d, J=7.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 3.53-3.57 (m, 2H), 3.29-35 (m, 2H), 3.05-3.13 (m, 1H), 1.77-1.78 (m, 2H), 1.40-1.45 (m, 2H). MS (ESI) m/z (M+H)+ 334.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([NH:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:2].[CH3:25]C(C)=O.[C:29](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([N:15]([CH3:25])[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:2].[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13](=[N:15][N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:14][CH3:29])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=NN=Cc1ccccc1)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 25 mL volume three-necked flask, 300 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6), 1.9 ml of acetone, 386 mg of potassium carbonate and 152 mg of dimethyl sulfate were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the resultant was extracted with ethyl acetate three times. The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=10:1) to give 261 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5) and 28 mg of methyl 2-(2,6-diethyl-4-methylphenyl)-2-oxo-N-(phenylmethylidene)ethanehydrazonate (compound (x-1)).
Reaction SMILES: [CH3:1][N:2]([C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C@H:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].[CH3:20][I:21]>C(OCC)(=O)C>[I-:21].[OH:11][C:7]1[CH:6]=[C:5]([C@@H:3]([N+:2]([CH3:20])([CH3:1])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:4])[CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: C[C@@H](c1ccccc1)N(C)[C@@H](C)c1cccc(O)c1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Product: [I-]
Temperature: 60 °C
Yield: 88.1 %

Procedure:
Mix 5.1 g (0.02 mol) of 3-[(S)-1-(methyl-[(5)-1-phenylethyl]amino)ethyl]phenol (formula V) with 20 ml of ethyl acetate and 11.3 g (0.08 mol) of methyl iodide at room temperature, and heat the mixture to 60° C. for 10 hours. After cooling it to room temperature, filter and dry it to obtain 7.0 g yellow solid with a yield of 88%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[CH:19]=1)=[O:12].N1C=CC=CC=1>C(Cl)Cl>[CH3:34][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=2)[CH:19]=1)=[O:12]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulphonyl chloride (0.46 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-aminobenzamide, pyridine (0.56 ml) and methylene chloride (30 ml) and the resultant mixture was stirred at ambient temperature for 48 hours. The precipitate was isolated, washed in turn with methylene chloride and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (1.64 g); m.p. 239-240° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.03 (s, 9H), 7.24 (m, 2H), 7.45 (m, 5H), 7.59 (m, 1H), 7.71 (m, 1H), 7.27 (m, 1H), 7.77 (d, 1H), 7.82 (d, 1H), 9.94 (br s, 1H), 10.24 (br s, 1H); Mass Spectrum: M−H− 465.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[C@H:10]([C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(=O)CC.O.N>C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]([C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCN1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Product: CCCCN1CCCCC1C(=O)Nc1c(C)cccc1C
Yield: 96.9 %

Procedure:
A stirred mixture of (S)-bupivacaine (0.140 g, 0.49 mmol) and propanoic acid (3.5 ml) was heated to reflux under a nitrogen atmosphere for 7 hours. The resulting solution was cooled and then poured into a mixture of distilled water (20 ml) and ethyl acetate (20 ml). Aqueous ammonia (28% w/v) was added until the pH of the aqueous layer was 10. The organic layer was separated and the aqueous layer extracted with ethyl acetate (20 ml). The combined organic extracts were washed with distilled water (20 ml), dried (MgSO4) and concentrated under reduced pressure to give racemic bupivacaine (0.137 g, 98%). ##STR1##
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH:6]([OH:7])[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)n1CCN1CCC(C(O)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 2.6 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione and 120 parts of methanol are added portionwise 2 parts of sodium borohydride. Upon completion, stirring is continued overnight at room temperature. Water is added and the whole is evaporated. The residue is stirred in water. The solid product is filtered off and crystallized from 2-propanone, yielding 1.2 parts of 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 212.8° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([OH:23])=O)[C:18]([CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:21]([C:19]1[C:18]([CH3:24])=[C:17]2[C:13]([C:14]3[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=3[NH:16]2)=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH:20]=1)=[O:23]
Reactant: CN(C)CCN
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)c(C)c3[nH]c4ncc(C)cc4c23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)NCCN(C)C)c(C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid (3.0 g, 73 mmol), N,N-Dimethylethylene diamine (g, mmol), HATU (g, mmol), triethylamine (g, mmol) and DMF (mL) was stirred at room temperature for two days. The reaction mixture was poured over ice affording a precipitate, The resulting suspension was filtered, rinsed with H2O and dried in vacuo to g (%). 1H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 8.28-8.31 (m, 2H), 8.12 (s, 1H), 8.01-8.05 (m, 2H), 7.89 (t, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 3.43 (q, 2H), 2.63 (s, 3H), 2.27 (s, 3H), 2.20 (s, 6H), 1.17 (t, 3H). MS (ES) [m+H] calc'd for C26H30N4O3S, 479; found 479.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:20][CH:17]1[CH2:19][CH2:18]1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCC1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 5-bromonicotinic acid (XXVIII) (1.01 g, 5 mmol) in dry DCM (10 mL) under nitrogen was added oxalyl chloride (0.654 mL, 7.5 mmol) followed by dry DMF (0.1 mL). The solution was stirred at r.t. for 30 min. The solvent was evaporated under vacuum before adding dry pyridine (10 mL) followed by cyclopropylmethanamine (0.39 mL, 4.5 mmol). The solution was stirred at r.t. under nitrogen for 2 h. The solution was poured into ice water, basified with sat. aq. NaHCO3 and extracted with DCM. The combined organic phases were dried over MgSO4, concentrated and dried under vacuum to yield 5-bromo-N-(cyclopropylmethyl)nicotinamide (XXIX) as an off-white solid (0.82 g, 3.2 mmol, 71% yield). 1H NMR (DMSO-d6) δ ppm −0.07-0.07 (m, 2H), 0.15-0.29 (m, 2H), 0.68-0.88 (m, 1H), 2.93 (t, J=6.22 Hz, 2H), 8.20 (t, J=1.88 Hz, 1H), 8.62 (d, J=1.70 Hz, 2H), 8.75 (s, 1H); ESIMS found C10H11BrN2O m/z 254, 256 (M+, M+2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].CC(C)([O-])C.[K+].[CH2:24]([O:26][CH2:27]Cl)[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]([CH2:27][O:26][CH2:24][CH3:25])[C:6]=1[Cl:7]
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (1.0 g, 0.003 mole) is dissolved in 10 mL of dry tetrahydrofuran. To this solution is added potassium t-butoxide (0.37 g, 0.0033 mole) followed by chloromethyl ethyl ether (0.312 g, 0.0033 mole). The mixture is stirred for about 1 hour at room temperature and then poured into a large volume of water precipitating the product. The white solid is collected and dried to give 1.0 g (91%) with mp 128°-130°.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]=[C:7]=[S:8])[CH2:4][CH3:5].Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].C(OCC)C.CCCCCC>CN(C=O)C>[C:14]1([N:13]2[C:11](=[O:12])[CH2:10][S:8]/[C:7]/2=[N:6]\[CH2:3][CH2:4][CH3:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CCCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCC/N=C1\SCC(=O)N1c1ccccc1
Reaction time: 2 h

Procedure:
At rt, NaH (154 mg of 55% dispersion in mineral oil, 3.54 mmol) is added in portions to a solution of n-propylisothiocyanate (596 mg, 5.90 mmol) and the above 2-chloro-N-phenyl-acetamide (1000 mg, 5.90 mmol) in DMF (30 mL). Stirring is continued for 2 h after completion of the addition. The mixture is poured onto EA (150 mL) and is extracted twice with 1 N aq. HCl (200 mL). The aq. layer is neutralised by adding 3 N NaOH followed by sat. aq. NaHCO3, and extracted twice with EA (200 mL). The organic extracts are washed with water (200 mL) and evaporated to give a pale yellow, crystalline solid. This material is suspended in a small amount of diethyl ether/hexane 1:1, filtered, washed with additional diethyl ether/hexane and dried under high vacuum to give 3-phenyl-2-[(Z)-propylimino]-thiazolidin-4-one.