Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([Sn](CCCC)(CCCC)/[CH:30]=[CH:31]\[CH2:32][OH:33])CCC>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:30]=[CH:31][CH2:32][OH:33])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2Br)ccc(Br)c1OC
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2C=CCO)ccc(Br)c1OC
Temperature: 30 °C

Procedure:
Bis-(tri-tert-butylphosphine)palladium (0.031 g) was added to a degassed solution of methyl 3-bromo-6-(2-bromobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 66, 0.286 g) and 3-tributylstannyl-(Z)-prop-2-en-1-ol (prepared according to Webb et al, Tetrahedron, 2008, 64, 4778, 0.27 ml) in toluene (3 ml) and the resultant mixture was stirred at room temperature for 3 hours then heated at 30° C. for 2 hours. After cooling, the mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl 3-bromo-6-((2-(3-hydroxyprop-1-enyl)benzenesulfonyl)methyl)-2-methoxybenzoate as a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:6]=2[O:5][CH2:4][C:3]1=[O:15]>C(O)C.[Pd]>[NH2:12][C:11]1[C:6]2[O:5][CH2:4][C:3](=[O:15])[N:2]([CH3:1])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CN1C(=O)COc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)COc2c(N)cccc21
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 4-methyl-8-nitro-2 H-1,4-benzoxazin-3(4 H)-one (415 mg, 1.99 mmol) in ethanol (10 mL) was added 10% palladium activated carbon (415 mg) at room temperature, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), followed by washing with ethanol. The filtrate was concentrated under reduced pressure. The resulting residue was dried under reduced pressure to afford the title compound as a gray powder (314 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Li]CCCC.[CH:35](=[O:37])[CH3:36].C(O)(C(F)(F)F)=O>CCOCC.C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26]([CH:35]([OH:37])[CH3:36])=[CH:25][CH:24]=3)[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18]2)[CH2:10][CH2:9]1
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCC(C2(c3ccc(Br)cc3)Oc3ccccc3O2)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(O)c1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(4-bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 277) (742 mg, 1.61 mmol) in Et2O (20 mL) cooled to −78° C. was added BuLi (2.5M in Hexanes, 0.80 mL, 2.0 mmol) and the mixture was stirred at −10° C. for 1 hour. The mixture was cooled to −78° C., acetaldehyde (0.5 mL) was added and the mixture was warmed to room temperature and stirred for 30 minutes. Work-up and purification gave the desired substrate. To the substrate in CH2Cl2 (3 mL) were added H20 (2 drops) and TFA (1 mL) and the mixture was stirred at room temperature for 1 hour to afford 1-[4-(2-piperidin-4-yl-benzo[1,3]dioxol-2-yl)-phenyl]-ethanol as a pale yellow solid (170 mg, 32% over 2 steps) after basic work-up and purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I.CCCCCCC>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:19][CH2:18][Cl:17])[C:9]#[N:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: N#CC(CCCCl)c1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-bromo-2-trifluoromethylphenyl)acetonitrile (2.28 g) in tetrahydrofuran (6 mL) was added to a suspension of sodium hydride (containing 60% in mineral oil, 362 mg) in tetrahydrofuran (12 mL) under ice-cooling. The mixture was stirred at the same temperature for 20 minutes. 1-Chloro-3-iodopropane (0.94 mL) was added dropwise to the reaction solution, and then the reaction solution was stirred at room temperature for 40 minutes. Ice water and heptane were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=49:1→19:1) to obtain 2.67 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][N:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)[S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C(=O)O)cc2)c1
Yield: 35 %

Procedure:
Prepared as in Example 5-5 from 1-(bromomethyl)-3-methoxybenzene and 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 572b). Yield 35%. MS M+H calculated 402.3, found 402.0.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([OH:44])[CH:37]=1)[CH3:33].[Cl:46][C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=1[CH2:54][CH2:55]O>C1COCC1>[CH2:32]([O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH2:55][CH2:54][C:48]2[CH:49]=[CH:50][C:51]([Cl:53])=[CH:52][C:47]=2[Cl:46])[CH:37]=1)[CH3:33]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 10 g (38.3 mmol) of triphenylphosphane in 100 ml of THF were added 6.7 g (3.83 mmol) of DEAD over 5 min at room temperature. After 30 min at room temperature, 5 g (25.5 mmol) of 3-hydroxy-4-methoxybenzoic acid ethyl ester and 4.87 g (25.5 mmol) of 2-(2,4-dichlorophenyl)ethanol were added and the mixture was stirred at room temperature for 12 h. The solvent was removed and the residue was separated by chromatography to give 3.6 g (38%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[C:16]([C:17]2[N:21]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:19]=3[N:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C)C=O>[CH:23]1([CH2:22][N:21]2[C:20]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:19]=3[N:18]=[C:17]2[C:16]2[C:11]([O:9][CH2:8][CH:3]3[CH2:7][CH2:6][CH2:5][CH2:4]3)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3cccnc3OCC3CCCC3)n(CC3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a suspension of sodium hydride (20 mg, 0.51 mmol, 60%) in dry N,N-dimethylformamide (5 ml) at 25° C. was slowly added a solution of cyclopentyl-methanol (30 mg, 0.30 mmol; CAS Reg. No. 3637-61-4) in dry N,N-dimethylformamide (5 ml) and the suspension was stirred for 0.5 h. A solution of 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (90 mg, 0.25 mmol) in N,N-dimethylformamide (5 ml) was then added drop wise to the above solution and further stirred for 16 h at 25° C. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The solvents were removed under reduced pressure. The crude material dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (20-30% ethyl acetate/n-hexane) to afford the title compound as a colorless solid (54%). MS (Turbo Spray): m/z=426.3 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C@H:10]([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[O:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:20][CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1ccc(Oc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCO[C@@H]1CNCC[C@H]1Oc1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of (±)-trans-N-tert-butoxycarbonyl-4-(4-phenoxyphenoxy)-3-(2-methoxy-1-ethoxy)piperidine (2.1 g, 4.7 mmol) in dry dichloromethane (20 ml) and trifluoroacetic acid (1.5 ml) was added. After 2 h the volatiles were evaporated. The residue was triturated with petroleum ether to leave the title compound as an oil. Yield 2.2 g 100%.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:4]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)C1SC(N2CCOCC2)=C(C#N)C1c1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To a solution of ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-yl-2,3-dihydrothiophene-2-carboxylate (0.168 g, 0.45 mmol) in toluene (5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.102 g, 0.45 mmol). The mixture was allowed to stir at 90° C. for 90 min and allowed to cool before filtration through Celite, eluting with toluene. The filtrate was concentrated and the residue was purified by column chromatography. The resulting orange solid was recrystallized from ethyl acetate/40-60 petroleum ether to give ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.11 g, 66%). LCMS: (FA) ES+ 373. 1H NMR (400 MHz, d6-DMSO) δ: 7.28-7.31 (m, 2H), 6.96-7.00 (m, 2H), 4.06 (q, 2H), 3.81 (s, 3H), 3.76-3.79 (m, 4H), 3.59-3.61 (m, 4H) and 1.08 (t, 3H).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:38])[N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:17])=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:38])[N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 17 h
Yield: 41 %

Procedure:
A 4N HCl solution in dioxane (1.5 mL) was added to a stirred solution of 7-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide (0.72 g, 1.40 mmol) in CH2Cl2 (25 mL) and stirred for 17 hours. The resulting suspension was filtered to give 7-amino-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide hydrochloride (0.26 g, 41%) as a white solid. mp 187-189° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.52 (t, J=5.7 Hz, 1H), 7.93 (b, 3H), 7.88-7.67 (m, 3H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 2.91-2.50 (m, 5H), 2.21 (t, J=7.2 Hz, 2H), 2.08-2.04 (m, 1H), 1.57-1.52 (m, 4H), 1.31-1.29 (m, 4H), 13C NMR (CDCl3) δ 172.70, 172.55, 169.77, 167.44, 166.90, 139.54, 134.68, 133.08, 131.47, 127.01, 121.77, 48.82, 38.64, 37.53, 35.00, 30.90, 28.05, 26.73, 25.50, 24.89, 21.95; Anal. Calcd. For C21H27N4O5Cl+0.64H2O: C, 54.95; H, 6.13; N, 12.21; Cl, 7,72. Found: C, 54.56; H, 6.10; N, 11.96; Cl, 8.04.
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]#[N:9]>O>[OH:7][C@@H:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]#[N:9]
Reactant: CCCCCC=O
Reactant: C#N
Solvent: O
Product: CCCCC[C@H](O)C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
1.33 mmol of hexanal (133 mg) were dissolved in 3 ml of water-saturated diisopropyl ether. 1.1 ml of aqueous hydroxynitrile lyase solution (900 IU/ml) were added at room temperature and the mixture was stirred at room temperature for 5 min. 300 μl of anhydrous hydrocyanic acid (7.88 mmol) were then added and the reaction vessel was sealed pressure-tight. After stirring at room temperature for 1.5 hours, the phases were separated, the aqueous phase was extracted three times with 5 ml of diisopropyl ether each time and the combined ether phases were dried using anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude cyanohydrin obtained in this way was subjected to purification by column chromatography. 140 mg of (S)-2-hydroxyheptanenitrile were obtained (83% isolated yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[OH:30])[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]2([NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=1)(=[O:41])=[O:40]
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2O)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2OS(C)(=O)=O)cc1F
Reaction time: 16 h

Procedure:
N-[(1R)-1-(3,3′-difluoro-2′-hydroxy-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide (0.040 g, 0.093 mmol) and triethylamine (0.019 g, 0.187 mmol) were dissolved in CH2Cl2 (2 mL) and cooled to −78 C. To this solution was added methanesulfonyl chloride (0.012 g, 0.103 mmol) and the reaction was allowed to stir for 16 hours. The reaction was concentrated under reduced pressure, diluted with methanol and purified by reverse phase chromatography using a gradient from 95/5H2O/CH3CN to 5/95H2O/CH3CN. Product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: C21H19F5N2O5S requires: 507.1076, found: 507.1002. 1H NMR (400 MHz, (CD3)2SO) δ 9.79 (s, 1H), 8.30 (d, J=7.5 Hz, 1H), 7.44-7.54 (m, 3H), 7.30-7.39 (m, 3H), 5.23 (qn, J=7.5 Hz, 1H), 2.99 (s, 1H), 1.4.2 (d, J=7.5 Hz, 3H), 1.32-1.38 (m, 2H), 0.92-1.06 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][N:16]1[CH2:17][CH2:18][CH:14]([C:6]2[NH:7][C:8](=[O:13])[C:9]3[C:4]([CH:5]=2)=[C:3]([CH3:2])[CH:12]=[CH:11][CH:10]=3)[CH2:15]1
Reactant: OCCCBr
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCCO)C3)cc12

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one hydrochloride (501 mg) and 3-bromo-1-propanol (991 μl), 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (216 mg) was obtained.
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:40])[F:41])=[CH:39][CH:38]=3)=[O:36])[CH2:20][CH2:21]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]1(CN2CCN(C(=O)c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
(S)-2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (2.36 mg, 0.882 mmol) was suspended in methylene chloride (10 ml). To the suspension, triethylamine (1 ml, 7.17 mmol) was added. To the solution, 4-(trifluoromethyl)benzoyl chloride (193 mg, 0.926 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-(4-trifluoromethylphenyl)methanone (264 mg, yield 68%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][O:12][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)nc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Yield: 16 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 1.43 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.83 ml of tributylphosphine, 0.773 g of 1,1'-(azodicarbonyl)dipiperidine and 80 ml of benzene were used, to give 0.3 g of the title compound, melting at 97°-102° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:38])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:38])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1)=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(OCCCCCCCCCCCOC(=O)c1cc(O)ccc1O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 56.6 %

Procedure:
2.78 g (18.0 mmol) 2,5-dihydroxybenzoic acid was dissolved in 36 ml dimethylformamide. 2.96 ml (19.8 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) was added dropwise in the course of 15 minutes. The reaction temperature rose to 30° C. and 8.83 g (19.8 mmol) 3,5-dinitrobenzoic acid 11-bromoundecyl ester was subsequently added in one portion. The mixture was then heated at 80° C. for 2 hours. The reaction mixture was cooled and then partitioned between dichloromethane and 1N hydrochloric acid; the organic phase was washed twice with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using Toluene yielded 5.28 g (57%) 3,5-dinitrobenzoic acid 11-[2,5-dihydroxybenzoyloxy]undecyl ester as yellow powder.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:11]([O:24]C)=[N:12][C:13]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[N:14][C:15]=1[CH3:16].I[CH3:28]>>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[C:13]1[N:12]([CH3:28])[C:11](=[O:24])[C:10]([NH:9][C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:26])=[C:15]([CH3:16])[N:14]=1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)c1nc(C)c(Nc2c(C)cc(C)cc2C)c(OC)n1
Reactant: CI
Product: CCCN(CCC)c1nc(C)c(Nc2c(C)cc(C)cc2C)c(=O)n1C
Temperature: 140 °C
Yield: 29 %

Procedure:
N5-Mesityl-4-methoxy-6-methyl-N2,N2-dipropylpyrimidin-2,5-diamine (9.0 mg, 0.025 mmol) was dissolved in iodomethane (2 mL). The solution was heated in a sealed tube for 6 h at 140° C. The solution was cooled and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 2.6 mg (29% yield) of the desired compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[N:17]2[C:13]([S:14][CH:15]=[CH:16]2)=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(=S)=S.ClCCl>[C:5]([C:12]1[N:11]=[C:10]([CH3:9])[N:17]2[CH:16]=[CH:15][S:14][C:13]=12)(=[O:7])[CH3:6]
Reactant: Cc1ncc2sccn12
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: ClCCl
Product: CC(=O)c1nc(C)n2ccsc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Aluminum chloride (6.96 g) was added to a solution of 4.33 ml of acetyl chloride in 40 ml of carbon disulfide. A solution of 1.20 g of 5-methylimidazo[5,1-b]thiazole in 40 ml of dichloromethane was added dropwise thereto. The mixture was stirred at room temperature for 24 hr. The reaction solution was poured into 40 g of ice. Dichloromethane (100 ml) was added thereto. Sodium carbonate (32 g) was added to the mixture with stirring. The insolubles were removed by filtration, and washed with dichloromethane. The filtrate was concentrated under the reduced pressure. Ethyl acetate (20 ml) was added thereto. The resultant crystal was collected by filtration. The filtrate was purified by column chromatography on silica gel (dichloromethane:methanol=20:1). The purification product was combined with the above collected crystal to give 1.45 g of 7-acetyl-5-methylimidazo[5,1-b]thiazole.