Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([N+:10]([O-])=O)[C:6](=[O:9])[NH:7][CH:8]=1)#[CH:2]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:10][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH3:13]
Reactant: C#Cc1c[nH]c(=O)c([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c[nH]c(=O)c(N)c1C

Procedure:
A mixture of 5-ethynyl-4-methyl-3-nitro-2-pyridone (0.18 g, 0.6 mmol) and 10% Pd/C (0.02 g) in ethanol/ethyl acetate (50 mL, 1/1) was hydrogenated at 35 psi in a Parr apparatus overnight. The catalyst was removed by filtration, and the solvents were evaporated to give 3-amino-5-ethyl-4-methyl-2-pyridone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)c1ccc(F)c(N)c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 1-(3-amino-4-fluorophenyl)-ethanone (3 g) in a mixture of MeOH (20 mL) and CH2Cl2 (20 mL) was added in portions NaBH4 (1520 mg) at 0° C. After stirring for 0.5 hours, the reaction mixture was quenched with saturated NH4Cl solution and most of the solvent was removed in vacuo. The residue was extracted with CH2Cl2, and the combined organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give 2.9 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5](=[O:7])[CH:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)[CH2:3]1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:14])[CH2:6][C@H:5]([OH:7])[C@@H:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: Cn1nccc1C1CC(C)(C)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1nccc1[C@H]1CC(C)(C)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of the 4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanone (750 mg, 3.90 mmol) prepared in Example 93d in methanol (8.0 mL), sodium borohydride (150 mg, 3.97 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=97:3) to yield the title compound (390 mg, 52%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:18])[CH3:17])=[C:11]2[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]2=[O:19])(=[O:3])[CH3:2].[CH:21]([N:23]1[CH:32](C(O)=O)[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=O>C(OC(=O)C)(=O)C>[C:16]([O:15][C:12]1[C:11]2[C:10](=[O:19])[C:9]3[C:8]([C:7](=[O:20])[C:6]=2[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1)=[C:32]1[N:23]([CH2:24][C:25]2[C:30]([CH2:31]1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=3)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c2c1C(=O)C=CC2=O
Reactant: O=CN1Cc2ccccc2CC1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(OC(C)=O)c2c1C(=O)c1cn3c(c1C2=O)Cc1ccccc1C3
Temperature: 20 °C
Yield: 41.4 %

Procedure:
5,8-bis(acetyloxy)-1,4-napthalenedione (4.28 g) and 2-formyl-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (1.60 g) in acetic anhydride (65 ml) were heated at 100° C. (20 minutes). The reaction mixture was cooled at about 20° C. (1 h), and the solid was collected by filtration, washed with ether (3×30 ml) and dried in vacuo. The crude product was dissolved in dichloromethane and the solution was loaded onto a column of silica gel (175 g) packed in dichloromethane. The column was eluted with 5% (v/v) ethyl acetate in dichloromethane and fractions containing the major component were evaporated to dryness, and further dried in vacuo at 55° C. to give the title compound as a yellow-green solid (1.34 g), m.p. 228°-232° C. (dec), λmax (in CH2Cl2) 242 nm (ε40,700), 377 nm (ε6,400).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:31])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:32]1([C:35](Cl)=[O:36])CC1.CO.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:31])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:36])[CH3:32]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1)c1ncc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1nc2cnc(N(C)c3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28124.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(trifluoromethyl)benzamide (268 mg, 604 μmol) in pyridine (5 mL) were added N,N-dimethylpyridine-4-amine (23.9 mg, 196 μmol) and cyclopropanecarbonyl chloride (200 μL, 2.20 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction solution were added methanol (10 mL) and 2N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 more hr. The reaction solution was concentrated under reduced pressure, and diluted with ethyl acetate (100 mL) and tetrahydrofuran (10 mL). The diluted solution was washed with water (50 mL), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from ethyl acetate and tetrahydrofuran to give the title compound (compound of Example D2) (301 mg, 97%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][OH:7])[CH3:5])[CH3:2].C(O[K])(C)(C)C.[CH2:14]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[N:6][O:7][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:30])=[CH:28][CH:27]=1)[CH3:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)c1ccc(F)cc1
Reactant: CCOC(C)=NO
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(C)=NOc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 107.3 %

Procedure:
To a stirring solution of ethyl-N-hydroxyacetimidate (3.79 g, 36.8 mmol) in anhydrous DMF (150 mL) under Ar was added tBuOK (4.09 g, 36.4 mmol) all at once. After 40 min benzyl-4-fluorobenzoate 17 (7.63 g, 17.9 mmol) was added and the reaction was stirred at room temperature. After 4 h the reaction was diluted with H2O (500 mL), extracted with EtOAc (4×100 mL), and the combined organics were washed with H2O (2×100 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatographic purification over silica (5-10% gradient EtOAc in hexanes) afforded 19 as a clear syrup (6.02 g, 58%). 1H-NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.0 Hz, 3H), 2.12 (s, 3H), 4.20 (q, J=7.0 Hz, 2H), 5.34 (s, 2H), 7.15-7.19 (m, 2H), 7.31-7.35 (m, 2H), 7.36-7.41 (m, 2H), 7.42-7.36 (m, 2H), 8.00-8.14 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.3, 14.4, 63.1, 66.4, 113.4, 122.9, 128.1, 128.1, 128.6, 131.5, 136.3, 163.5, 166.3, 166.4; GC-MS 228 m/z [M-85]+, benzyl-4-hydroxybenzoate C14H12O3 requires 228.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12]([NH2:14])=O)[C:8]=1[C:15]([NH2:17])=O.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[CH3:18][N:19]([CH3:22])[CH:20]=[N:6][C:7]1[S:11][N:10]=[C:9]([C:12]#[N:14])[C:8]=1[C:15]#[N:17]
Reactant: NC(=O)c1nsc(N)c1C(N)=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1snc(C#N)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
10.1 parts of phosphorus oxytrichloride are added dropwise to 30 parts of dimethylformamide at 0° C., and the mixture is then stirred for a further 0.5 hour at this temperature. 3.7 parts of 5-aminoisothiazole-3,4-dicarboxamide are then introduced, a little at a time, into this solution while cooling with ice. The mixture is stirred for a further 2 hours at room temperature, after which it is poured into 100 parts of ice water. The precipitate is filtered off under suction, washed with water and dried to give 3.8 parts (93% of theory) of N,N-dimethyl-N'-(3,4-dicyanoisothiazol-5-yl)-formamidine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:10])=[O:7].O.[C:25]1([CH:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:17]=1)=[O:10])=[O:7]
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(O)cc1
Reactant: CCCCCCC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(Oc1ccc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.24 g of 55% sodium hydride dispersion in mineral oil were added to a solution of 1.63 g of N-(2,6-dichlorobenzoyl)-N'-(4-hydroxyphenyl)urea in 15 ml of dimethylformamide; the reaction mixture was stirred for 20 minutes with external cooling with water until a bright solution was obtained. 1.6 ml of 77% 1-phenylheptylbromide were added to this solution after which the reaction mixture was left to stand at room temperature for approximately 2 days. After pouring the reaction mixture on a mixture of ice water and petroleum ether a crystalline product was obtained which was sucked off, washed with successively water and little isopropanol and dried in air. The desired product was obtained in a yield of 0.87 g; melting point 146°-149° C. The product was identified by means of its NMR spectrum. The following compounds were prepared in a corresponding manner:
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[C:1]([Cl:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(=O)Cl
Reaction time: 16 h
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5.0 grams (0.027 mole) of undecanoic acid in 75 mL of methylene chloride was stirred and 2.8 ml (0.032 mole) of oxalyl chloride and 5 drops of N,N-dimethylformamide were added. Upon completion of addition, the reaction mixture was stirred for about 16 hours, then it was concentrated under reduced pressure, yielding 2.2 grams of undecanoyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzene-sulfonamide (synthesized according to general procedures F and G, 500 mg, 1.17 mmol) in MeOH (5 mL) was added NaBH4 (144 mg, 3.81 mmol) at 0° C. and the mixture was stirred for one hour at room temperature. The reaction mixture was then diluted with EtOAc (50 mL) and the organics were washed with saturated aqueous NH4Cl (50 mL), water (50 mL), and brine (50 mL). The organics were subsequently dried (Na2SO4), concentrated in vacuo, and purified by automated flash chromatography to obtain the title compound as foamy white solid (424 mg) in 84% yield: MS (ES) M+H expected 430.1, found 430.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:7](=[O:9])[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:10])[C@H:20]([C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: COC(=O)CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.4 %

Procedure:
Proceeding as in Example 1, but substituting 4-methoxy-4-oxobutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 125, methyl 4-((2S,4R)-4-benzyl-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-1-yl)-4-oxobutanoate (8.3 mg, 27.4%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.90 (s, 1H), 7.54-7.60 (m, 2H), 7.28-7.32 (m, 2H), 7.16-7.24 (m, 5H), 6.93-7.02 (m, 4H), 4.45 (m, 1H), 3.64-3.68 (m, 1H), 3.57 (s, 3H), 3.10-3.11 (m, 1H), 2.66 (m, 2H), 2.54 (m, 2H), 2.47 (m, 2H), 19.2 (m, 2H). MS (EI) for C29H29FN2O5. found 505.5 (MH+).
Reaction SMILES: [NH2:1][S:2]([CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:3])=[O:4])=[O:29])[N:22]=1
Reactant: CN(C)C(=O)c1ccccc1CS(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2C(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 0.48 g of the compound of Example 18 and 0.54 g of N-(4,6-dimethoxypyrimidin-2-yl)carbamic acid, phenyl ester in 25 ml of acetonitrile was added 0.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was stirred overnight at room temperature. Ice (25.0 g) was added; the aqueous mixture acidified with concentrated hydrochloric acid and then extracted with two 75 ml portions of methylene chloride. The organic solution was washed with water, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Trituration of the oily residue with 1-chlorobutane gave 0.42 g of 2-[[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl]-N,N-dimethylbenzamide, m.p. 141°-143°; IR (nujol): 1700 and 1600 cm-1 ; NMR (CDCl3): δ 2.93-3.13 (6H, N(CH3)2, 2 singlets), 3.83 (6H, OCH3, s), 5.0 (2H, CH2, s) and 5.76 (1H, CH, s).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.C(#N)CCCCCCCCCC.N[CH:27]([OH:29])[CH3:28]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:1]([C:12]1[O:29][CH2:27][CH2:28][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(N)O
Reactant: CCCCCCCCCCCC#N
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCC#N
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCC1=NCCO1
Yield: 64.3 %

Procedure:
Undecyl cyanide in Example 1 was substituted with 18.13 g (108.4 mmoles) of undecanenitrile and allowed to react with 7.5 ml (121.3) mmoles of aminoethanol in presence of cadmium acetate dihydrate (667 mg; 2.5 mmoles) in 1-butanol under identical reaction conditions. The reaction mixture was worked up following Example 1 and the residue was distilled at 118°-120°/1.2 mm to give 14.72 g (64.3%) of 2-decyl-2oxazoline.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][O:14][C:15]2[C:16](=[O:24])[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[NH:19][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:26]1([CH2:25][O:24][C:16]2[C:15]([O:14][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:20][N:19]=[C:18]([C:21]([O:23][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:22])[CH:17]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.5 g (156 mmol) of potassium carbonate was added to a suspension of 29.4 g (120 mmol) of 1,4-dihydro-5-(phenylmethoxy)-4-oxo-2-pyridinecarboxylic acid in 350 ml of N,N-dimethylformamide (DMF) and stirred for 1 hour at room temperature. 31 ml (264 mmol) of benzylbromide was added and the mixture was heated at 100° C. under stirring for 25 hours. After cooling to room temperature, the DMF was distilled off in vacuo and the residue triturated with ethyl acetate with short heating to 60° C. 40 g of inorganic salts were filtered off, the filtrate was concentrated to ca. 75 ml and chromatographed on silica gel with ethyl acetate:petroleum ether 90:10 as eluent. Yield: 35.5 g; melting point 116.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=O)=[CH:4][CH:3]=1.C(O)C[OH:21]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:13]([C:14]([O:16][CH2:17][CH2:18][OH:21])=[O:15])[NH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC=C(C=O)c1ccc(Cl)cc1
Reactant: OCCO
Solvent: O
Product: O=C(OCCO)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
2-(4-Chlorophenyl)-3-carbethoxymethylaminoacrylaldehyde (73.6 g.) was refluxed in 300 ml. of ethylene glycol for 10 minutes. The reaction mixture was cooled, diluted with 1 liter of water, product extracted into chloroform, treated with activated carbon and evaporated to solids. Trituration with ether gave crude product (8 g.). An additional quantity of crude product (7.5 g.) crystallized from the aqueous phase which had been standing. Recrystallization of the combined crude solids from chloroform gave 2-hydroxyethyl 4-(4-chlorophenyl)pyrrole-2-carboxylate (5 g., m.p. 128°-130° C.). The ether and chloroform mother liquors were combined and evaporated to yield an additional 40 g. of crude product.
Reaction SMILES: N1(O)CCOCC1.[CH3:8][CH:9](NC(C)(C)C)[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:11].Cl.ClC1C=C(C(=O)CC)C=CC=1.[Br-:36].[Br-].O1CCOCC1>O1CCOCC1.O>[Br:36][CH:9]([CH3:8])[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:11]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: [Br-]
Agent: CCC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: ON1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: CC(Br)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride) may be synthesized by the following process. To 3′-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2 h at ambient temperature and poured into a mixture of ice and water (500 mL). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3′-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300 Mhz, CDCl3); δ 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:32]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][C@H:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][CH:27]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCCOc2ccc(Cc3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol (910 mg, 2.29 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (667 mg, 3.44 mmol) and triphenylphosphine (901 mg, 3.44 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (867 mg, 3.44 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 680 mg (yield: 51.5%)
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:21]=[C:22]([C:26]3([O:31][CH3:32])[CH2:30][CH2:29][NH:28][CH2:27]3)[CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C(Br)C#C>>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:20]2[CH:21]=[C:22]([C:26]3([O:31][CH3:32])[CH2:30][CH2:29][N:28]([CH2:3][C:1]#[CH:2])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: COC1(c2cccc(Sc3ccc(C(C)=O)cc3)c2)CCNC1
Reactant: CCN(C(C)C)C(C)C
Agent: C#CCBr
Product: C#CCN1CCC(OC)(c2cccc(Sc3ccc(C(C)=O)cc3)c2)C1
Yield: 14 %

Procedure:
Using an analogous procedure to that described in Example 3 except that diisopropylethylamine was used in place of potassium carbonate, 3-[3-(4-acetylphenylthio)phenyl]-3-methoxypyrrolidine was reacted with 2-propynyl bromide to give 3-[3-(4-acetylphenylthio)phenyl]-3-methoxy-1-(prop-2-ynyl)pyrrolidine as a gum in 14% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:23][CH2:24][CH2:25][O:26][CH3:27].C(Cl)(=O)C([Cl:31])=O>C1COCC1.CN(C=O)C>[Cl:31][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=2)[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:8]=1
Reactant: COCCOc1cc2c(=O)[nH]c(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cc2c(Cl)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Yield: 67.9 %

Procedure:
To a suspension of 7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-one (1.65 g, 4.46 mmol) in anhydrous THF (30 mL) was added oxalyl chloride (1.3 mL, 14.7 mmol) and 2 drops of DMF. The mixture was refluxed for 2 h, upon which the mixture was concentrated in vacuo, taken up in CHCl3 (100 mL) and washed with sat. NaHCO3 (3×50 mL), water (2×50 mL) and brine (1×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline (1.18 g, 3.03 mmol, 68%). HPLC retention time 9.55 mins.