Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].Br[CH2:9][CH:10]=[O:11].[OH-].[Na+]>CO>[CH2:1]([NH:7][CH2:9][CH:10]=[O:11])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: CC=CCCCN
Reactant: O=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC=CCCCNCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Hex-4-enylamine (2.0 mole), the diethyl acetal of 2-bromoacetaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 2-hex-4-enylaminoacetaldehyde.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[O:28][S:37]([CH3:36])(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](O)C2=O)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](OS(C)(=O)=O)C2=O)CC1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
tert-Butyl 4-((3R,4S)-4-(benzyloxy)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (525 mg, 1.34 mmol) was dissolved in THF (10 mL) and triethylamine (375 μL, 2.69 mmol) and methanesulfonyl chloride (126 μL, 1.61 mmol) were added to the reaction and stirred for 1 hour. The reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, dried over Na2SO4, filtered and concentrated to afford tert-butyl 4-((3R,4S)-4-(benzyloxy)-3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (623 mg, 1.33 mmol, 98.9% yield) as a white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([OH:18])=O.[NH2:24][CH:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26]1>C1COCC1>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[C:15]=1[C:16]([NH:24][CH:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26]1)=[O:18]
Reactant: NC1CCCNC(=O)C1
Reactant: O=C(O)c1c(F)cccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC(NC(=O)c2c(F)cccc2F)CCCN1
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
1,1'-Carbonyldiimidazole (14.8 g), was added to a solution of 2,6-difluorobenzoic acid (12 g) in THF (200 ml) and followed by stirring for 15 mins. at room temperature. Then to the mixture was added 9.73 g of 3-amino-ε-caprolactam, and the whole was stirred for 5 hrs. at room temperature and the solvent was distilled off under reduced pressure. The residue was washed with methylenechloride to give 3-(2,6-difluorobenzoyl)amino-ε-caprolactam (13.5 g) as crude crystals. The crude crystals and phosphorus pentasulfide (8.96 g) were added to 200 ml of pyridine, and the whole was refluxed under stirring for 24 hrs. After cooling, the mixture was distilled to remove the solvent. To the residue was added a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel and then recrystallized from a mixture of methylenechloride and isopropyl ether to give the title compound (3.19 g, 23.8%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][C:6]([S:9][CH3:10])=[N:7][N:8]=1)#[N:2].C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[CH3:10][S:9][C:6]1[S:5][C:4]([C:3](=[N:15][OH:16])[C:1]#[N:2])=[N:8][N:7]=1
Reactant: CSc1nnc(CC#N)s1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nnc(C(C#N)=NO)s1
Reaction time: 1 h

Procedure:
17.1 g (0.1 mol) of 2-cyanomethyl-5-methylthio-1,3,4-thiadiazole are intially introduced into 75 ml of glacial acetic acid. A solution of 7.8 g (0.11 mol) of NaNO2 in 20 ml of water is added dropwise and the mixture is stirred for 1 hour. 200 ml of water are then added to the solution and the mixture is filtered. The residue is washed with water: 19 g (95% of theory) of end product, melting point >200° C. (decomposition).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][C:34]3[NH:33][CH:37]=[CH:36][N:35]=3)[C:12]=2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: c1c[nH]cn1
Product: CCCCC(=O)c1c(Cc2ncc[nH]2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 3, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with imidazole to give 4-(3,4-dimethoxyphenyl)-2-(1-imidazolylmethyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 156°-157° C.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[N+:7]([C:10]1[CH:18]=[CH:17][C:13](C(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)=O>[Cl-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[OH:5][CH2:4][CH2:3][O:2][C:1](=[O:6])[C:13]1[CH:17]=[CH:18][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(OCCO)c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C

Procedure:
Ethylene carbonate (20 g., 0.22 mole), 4-Nitrobenzoic acid (38 g., 0.2 mole), and tetraethylammonium chloride (2.0 g., 0.04 mole) were placed in a one liter round bottom flask and heated at 140° C. with stirring until evolution of CO2 stopped. The reaction was cooled to room temperature and dissolved in one liter of ethyl acetate. The solution was washed with water and dried over MgSO4. The drying agent was removed by filtration. The volume was reduced in-vacuo and the 2-hydroxyethyl-4-nitrobenzoate obtained as a pale yellow solid. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][CH:25]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=2)=[CH:28][CH:29]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: Cn1cc(Cl)cc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
A solution of 3-bromo-5-chloro-1-methyl-2-pyridone (660 mg, 2.97 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (1.7 g, 2.99 mmol) in DMF (30 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). Tetrakis(triphenylphosphine)palladium (140 mg, 0.20 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 140 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in 1:1 ether:ethyl acetate (60 mL). The solution was washed with water (3×10 mL) and brine (1×10 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 150 g of silica gel eluting with 7:3 ethyl acetate:hexane to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (670 mg, 54%). LRMS-Electrospray: m/z 863 (2M+Na), 858 (2M+NH4), 443 (M+Na), 438 (M+NH4), 421(M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]=[C:36]1[NH:41][C:40]2[CH:42]=[CH:43][C:44]([S:46](Cl)(=[O:48])=[O:47])=[CH:45][C:39]=2[C:38](=[O:50])[O:37]1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][N:11]1[S:46]([C:44]1[CH:43]=[CH:42][C:40]2[NH:41][C:36](=[O:35])[O:37][C:38](=[O:50])[C:39]=2[CH:45]=1)(=[O:47])=[O:48])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2c(=O)o1
Product: O=c1[nH]c2ccc(S(=O)(=O)N3C[C@H](SC(c4ccccc4)(c4ccccc4)c4ccccc4)C[C@H]3COCc3ccccc3)cc2c(=O)o1

Procedure:
In analogy: (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine and 2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-sulfonyl chloride [Ferrini et al. Eur. Pat. Appl. No. 800220] gave (2S,4R)-6-(2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione, MS: 689(M−H−), which was deprotected (following Method 3) to give (2S,4R)-6-(2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione, MS: 447 (M−H−).
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(CCC(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a stirred solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate (0.28 g, 0.72 mmol) in dioxane (6 ml) was added lithium hydroxide monohydrate (0.18 g, 4.3 mmol) and water (3 ml). The mixture was stirred at room temperature for 8 hr. It was concentrated under reduced pressure, neutralized with 5% HCl, extracted with EtOAc, and dried over MgSO4. The solvent concentrated and purified by silica gel flash column chromatography dichloromethane/methanol (8:2) to give the product (0.09 g, 35%). 1H NMR (300 MHz, CDCl3) δ 7.77 (br, NH)), 7.19 (d, 1H), 6.91 (d, 1H), 4.04 (m, 2H), 3.68 (m, 2H), 3.16 (m, 1H), 3.06 (t, 2H), 2.85 (m, 1H), 2.74 (m, 3H), 2.18 (m, 1H), 1.98 (m, 3H), 1.35 (d, 6H), 0.94 (t, 3H); ESI (+) MS m/e=360 (MH+), ESI (−) MS m/e=358 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>O>[Cl:1][C:2]1[C:3]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1

Procedure:
5-Chloro-3H-benzooxazol-2-one (10.0 g, 59 mmol) was added in portions to chlorosulfonic acid (30 mL) at −20° C. with stirring. The mixture was stirred at room temperature for 2.5 hours and at 70° C. for 1.5 hours. The cooled reaction mixture was poured slowly into iced-water (300 mL) and stirred for 1 hour. The precipitate was collected and washed with water. The dried precipitate was stirred in chloroform (500 mL) for 3 hours at room temperature, filtered off and dried to give 12.3 g of a pale pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:15]
Reactant: O=C(Cl)c1cnoc1-c1ccc(Cl)cc1Cl
Reactant: COCCOCCO
Product: COCCOCCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 96 %

Procedure:
5-(2',4'-Dichlorophenyl)-4-isoxazolecarbonyl chloride (2.0 g.; 0.007 mol.) was covered with 2-(2'-methoxyethoxy) ethanol and the solution was heated on a steam cone for 2 hours. After esterification, the excess 2-(2'-methoxyethoxy) ethanol was extracted into water. The insoluble oil was dissolved in ether, dried with anhydrous magnesium sulfate and concentrated to yield 2-(2'-methoxyethoxy)ethyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (2.4 g.; 96% yield) as an oil having the following analysis:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][CH2:9][O:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:13]>C(#N)C>[O:13]=[C:12]1[CH2:11][O:10][CH2:9][CH2:8][N:14]1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)COCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
43.4 g (133 mmol) of caesium carbonate are added to a solution of 26.6 g (88.8 mmol) of ethyl {4-[2-(2-chloroethoxy)acetylamino]phenyl}acetate in 100 ml of acetonitrile, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is tittered, and the filtrate is evaporated, giving ethyl [4-(3-oxomorpholin-4-yl)phenyl]acetate as a yellowish oil; ESI 264.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O1CCOCC1>[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][N:36]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[C@H:35]([CH3:39])[CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1c1ccc(C#N)cn1
Yield: 42.2 %

Procedure:
Solid Na2CO3 (50 mg, 0.47 mmol, 1.5 eq) is added to a solution of 6-chloronicotinonitrile (50 mg, 0.36 mmol, 1.2 eq), 1-benzyl-4-((R)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) in DMF (1 mL) and dioxane (2 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 180° C. (high absorption setting) for 30 minutes. The reaction mixture is concentrated, dichloromethane is added and is washed with water then brine. The organic fraction is dried over sodium sulfate, and is evaporated under reduced pressure, then purified by flash chromatography (50%-90% EtOAc/Hexane) to afford the title compound as a white solid (55 mg, 42% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[O:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]1)[C:5](O)=O.O=S(Cl)Cl.[NH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[O:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]1)[C:5]#[N:26]
Reactant: N
Reactant: CCCCCC1COC(c2ccc(C(=O)O)cc2F)OC1
Solvent: O=S(Cl)Cl
Product: CCCCCC1COC(c2ccc(C#N)cc2F)OC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
As described in Example 9 4.44 gms. of 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoic acid are converted by SOCl2 into the acid chloride. After removing excess SOCl2 the residue obtained is added to aqueous ammonia and stirred for 4 hours at 20° C. The precipitated acid amide is filtrated by suction and dried. For conversion into the nitrile it is dissolved in 50 ml of pyridine and 10 ml of POCl3, then stirred at 20° C. for 20 hours and evaporated. Thus 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzonitrile is obtained.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:17]([NH2:21])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC(C)CN
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)C

Procedure:
In a DMF solution containing 2.0 g of Boc-Ile-OH, 0.82 ml of isobutylamine, 1.27 g of HOBt and 2.06 g of DCC were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture, after filtration, was treated similarly to that in Example 50 (Process 2),except for the crystallization solvent (hexane) to give 1.44 g of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C@H:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=2[N:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH:29]=O)[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH2:29][NH:13][C@H:10]1[CH2:11][CH2:12][C@H:8]([N:7]3[C:6]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=4[N:4]=[C:3]3[CH3:2])[CH2:9]1)[CH2:23]2
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](N)C1
Agent: Cl
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](NCC2Cc3ccc(Cl)cc3C2)C1

Procedure:
This compound was prepared from trans-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine hydrochloride and 5-chloro-indan-2-carbaldehyde using the same reductive amination method described in previous example. 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C24H28ClN3 (m/e) calcd 393.1972, obsd 394.2 (M+H).
Reaction SMILES: O[C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:3]=[C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=[O:12])[C:7]1([CH3:15])[CH3:14])[C:4]#[CH:5]
Reactant: C#CC(C)(O)C1CC(CC(=O)O)C1(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC(=C)C1CC(CC(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of Example 29A (253 mg, 1.2 mmol) in 5 mL of CH2Cl2 was added triethylsilane (250 μL, 1.6 mmol), followed by trifluoroacetic acid (116 μL, 1.6 mmol). The resulting mixture was stirred at room temperature for overnight. Volatile organics were removed in vacuuo and the residue was evaporated with toluene (2×10 mL). The resulting title compound was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:30][CH2:31]Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC(N(C)C)=O>[C:17]([O:30][CH2:31][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 74.1 %

Procedure:
In 100 ml of dimethylacetamide were dissolved 19.51 g (0.15 mol) of 5-fluorouracil and 75.90 g (0.75 mol) of triethylamine. To this mixture was added dropwise at room temperature 41.05 g (0.165 mol) of chloromethyl laurate and the mixture was reacted together for 20 hours. After completion of the reaction, the triethylamine and dimethylacetamide were removed by distillation and the residue was poured into 400 ml of water. The mixture was stirred, filtered and washed with water whereby crystals were obtained which were then recrystallized from 200 ml of ethanol to obtain 38.06 g of 1-lauroyloxymethyl-5-fluorouracil having a melting point of 113.7~114.2° C. in a yield of 74.2%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][C:11]=1[CH3:42])(=[O:3])[CH3:2].[BH4-].[Na+]>CC(O)C.O>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][C:11]=1[CH3:42])[CH3:2]
Reactant: CC(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
To a solution of 10-[(2′-acetyl-2-methyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 29 (0.122 g, 0.220 mmol) in 2-propanol (5 mL) and water (1 mL) was added sodium borohydride (0.0092 mg, 0.242 mmol) and the reaction mixture stirred at room temperature under nitrogen for 24 hours. The reaction was quenched by the addition of 2 M hydrochloric acid (10 mL) and then washed with diethyl ether (20 mL). The aqueous phase was basified by the addition of 2 M sodium hydroxide and the resulting milky suspension extracted with ethyl acetate ( 2×30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a colorless syrup. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from diethyl ether/hexane to afford the title compound (0.061 g, 50%) as white solid.