Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[CH2:13][OH:14])(=[O:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[CH:13]=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC2C(CO)CCC12
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CCC2C(C=O)CCC12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 6-acetoxy-2-hydroxymethylbicyclo[3,3,0]octane (0.10 g; prepared as described in Reference Example 20 and predominantly in the 2β-configuration) in dry dichloromethane (2.5 ml) was treated with pyridinium chlorochromate (0.22 g) and anhydrous sodium bicarbonate (0.083 g). The resulting suspension was stirred for 150 minutes at the ambient temperature and was then placed directly onto a short column of silica gel and subjected to medium pressure, short column chromatography, eluting with a mixture of ethyl acetate and toluene (1:1 v/v) to give 6-acetoxy-2-formylbicyclo[3,3,0]octane (0.070 g), predominantly in the 2β-configuration.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:14][CH2:15][CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[CH:20]=[CH:19][C:18]1=[O:29]>O.C(N(CC)CC)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[N:17]([CH2:16][CH:15]=[O:14])[C:18](=[O:29])[CH:19]=[CH:20]2
Reactant: COc1cccc2ccc(=O)n(CCO)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc2ccc(=O)n(CC=O)c12
Reaction time: 0.17 h

Procedure:
To 4 mL of a dichloromethane solution containing 0.07 mL of oxalyl chloride, 0.11 mL of dimethylsulfoxide was added dropwise under nitrogen atmosphere at −60° C., and stirred for 10 min. 10 mL of a dichloromethane solution containing 0.14 g of 1-(2-hydroxyethyl)-8-methoxyquinolin-2(1H)-one was added dropwise at the same temperature, and stirred for 12 min. After 0.36 mL of triethylamine was added at the same temperature, it was stirred at room temperature for 1.5 hours, and 20 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (8-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[N:16]([CH3:24])[C:17]([CH3:23])=[C:18]([C:20]([OH:22])=O)[N:19]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:20]([C:18]1[N:19]=[C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:25])[N:16]([CH3:24])[C:17]=1[CH3:23])=[O:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: Cc1c(C(=O)O)nc(-n2ccc(OCc3ccccc3)cc2=O)n1C
Product: Cc1c(C(=O)NCc2ccccc2)nc(-n2ccc(OCc3ccccc3)cc2=O)n1C
Yield: 76 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,5-dimethyl-1H-imidazole-4-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 76% yield: mp 190-191° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 10H), 7.21 (d, J=7.7 Hz, 1H), 6.08 (dd, J=7.7, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.04 (s, 2H), 4.56 (d, J=6.1 Hz, 2H), 3.39 (s, 3H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 163.4, 163.1, 138.6, 138.4, 137.1, 134.7, 133.5, 129.1, 128.8, 128.7, 128.5, 127.8, 127.7, 127.2, 102.7, 97.8, 70.6, 42.7, 30.6, 10.0; MS (ES+) m/z 429.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:16])[C:14]#[CH:15])=[CH:9][CH:8]=1.I[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:29]/[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])/[C:22](=[O:28])[NH:23]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([OH:16])[C:14]#[C:15][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2/[C:21](=[CH:29]/[C:30]2[NH:31][CH:32]=[CH:33][C:34]=2[O:35][CH3:36])/[C:22](=[O:28])[NH:23]3)=[CH:11][CH:12]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)c1ccc(OCCCN(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCCCN(C)C)cc3)c21

Procedure:
Using Method C above, 3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propyne (201 mg, 0.86 mmol) (from Example 22 above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (34 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, to yield rac-(Z)-1,3-dihydro-4-[3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 151 mg, 80%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=1>>[NH2:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])[CH:20]=1
Reactant: Nc1cc(C(=O)O)ncn1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncn1)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (195 mg, clear colorless oil) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (167 mg, 0.58 mmol, Amine-5, single enantiomer) and 6-aminopyrimidine-4-carboxylic acid (80 mg, 0.58 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: C([Li])CCC.O1CCOCC1.[CH3:12][N:13]([CH3:24])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1)=[O:15].Cl.[CH:26]([N:29]([CH:33]([CH3:35])[CH3:34])[CH2:30][CH2:31]Cl)([CH3:28])[CH3:27]>CCCCCC.C(O)C>[CH3:12][N:13]([CH3:24])[C:14]([N:16]([CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:34])[CH:26]([CH3:28])[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1)=[O:15]
Reactant: CN(C)C(=O)Nc1cccc(N)n1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)N(CCN(C(=O)N(C)C)c1cccc(N)n1)C(C)C
Temperature: -25 °C

Procedure:
Under a nitrogen atmosphere, n-butyl lithium solution (15.5 ml., 0.025 mole) is added dropwise with stirring to a dioxane (50 ml.) solution of N,N-dimethyl-N'-(6-amino-2-pyridyl)urea (4.5 g., 0.025 mole) at 10° C. Then 2-diisopropylaminoethyl chloride hydrochloride (55.5 g., 0.275 mole) is added followed by another portion of n-butyl lithium (15.5 ml., 0.025 mole). The mixture is heated at reflux over night. Ethanol (30 ml.) is added with cooling and the mixture is filtered and concentrated in vacuo. The residue is treated with ether and is filtered to remove salts. Removal of the ether in vacuo gives 5.1 g. of viscous oil. The crude oil is taken up in hexane, filtered and cooled to -25° C. Filtration gives 1.5 g. of white solid, m.p. 86°-88° C.
Reaction SMILES: [P:1]([O-:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([Br:33])[CH:26]=1.C([O-])(=O)C.[NH4+]>C1COCC1>[Br:33][C:27]1[CH:26]=[C:25]([CH2:24][Br:23])[CH:32]=[CH:31][C:28]=1[CH:29]([P:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[O:2][C:3]([CH3:5])([CH3:6])[CH3:4])[OH:30]
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Reactant: O=Cc1ccc(CBr)cc1Br
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1ccc(CBr)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Di-tert-butyl phosphite (14.8 g, 76.3 mmol, 1.05 eq) was dissolved in 200 ml THF at −78° C. under nitrogen and 72 ml (1.05 eq) of 1.06M Lithium bis(trimethylsilyl)amide in THF was added over 30 min. The mixture was left stirring at −78° C. under nitrogen for 30 min and then added to a solution of the compound of Step 3 (20.2 g, 72.7 mmol, 1 eq) in 200 ml THF at −78° C. The solution was warmed to 0° C. and then poured into 400 ml of half saturated aqueous ammonium acetate. The layers were separated and the aqueous layer was washed with 400 ml isopropyl acetate. The organic layers were combined, dried with sodium sulfate and the solvent removed. The crude solid was then triturated with 15% EtOAc/hexane for 2 hours and 30.4 g (89%) of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(C#N)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.S(=O)(=O)(O)O.[C:18]([O-:21])(O)=[O:19].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]([OH:21])=[O:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: N#CC1(c2ccc(F)cn2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C1(c2ccc(F)cn2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
1-(5-fluoropyridin-2-yl)cyclopropanecarbonitrile (880 mg) was dissolved in ethanol (10 ml) before slow, dropwise addition of 96% sulfuric acid (10 ml). The reaction mixture was allowed to stir at 60° C. for 24 hr. Upon cooling, NaHCO3 was added until pH 8 and then the solution extracted three times with ethyl acetate, the organics were washed with brine and dried over Na2SO4 before concentration in vacuo.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:11][O-:12].[Na+].C(OCC)C.Cl>CO>[CH3:11][O:12][C:7](=[O:9])[CH2:8][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CC(C)(C)CC(=O)O
Temperature: 0 °C
Yield: 67.5 %

Procedure:
Combine 3,3-dimethylglutaric anhydride (1.00 g, 7.03 mmol) and sodium methoxide (2.5 mL, 14.1 mmol, 30 wt % in methanol) in methanol (20 mL) and heat at reflux for 3 h. Cool the reaction to room temperature and pour into ice water (100 mL). Add diethyl ether (25 mL) and adjust the pH of the mixture to pH=2 with 2 N HCl (10 mL) and separate the layers. Extract the aqueous layer with diethyl ether (25 mL) and combine the organic layers, dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford 3,3-dimethylpentanedioic acid monomethyl ester as a colorless oil (0.827 g, 68%): 1H NMR (CDCl3, 300 MHz) δ 1.14 (s, 6H), 2.46 (s, 2H), 2.48 (s, 2H), 3.67 (s, 3H), 10.9 (br s, 1H); APCI MS (Negative mode) m/z 173 [C8H14O4−H]−.
Reaction SMILES: [C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23]3)[CH2:13][CH:12]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>CO.[C].[Pd]>[C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:13][CH:12]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1C=CCCC1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.30 g) was dissolved in methanol (10 ml), 10% palladium carbon (0.10 g) was added, the mixture was stirred for 2 hours under hydrogen atmosphere. Palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, to thereby obtain 0.29 g of the titled compound (Yield 96%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:14](=[O:29])[CH2:13]1.Br[CH2:31][C:32]([N:34]([CH:43]([CH3:45])[CH3:44])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:33].O>C1COCC1.CN(C=O)C>[O:11]=[C:12]1[N:18]([CH2:31][C:32]([N:34]([CH:43]([CH3:45])[CH3:44])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[O:33])[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:14](=[O:29])[CH2:13]1
Reactant: O=C1CC(=O)N(c2ccccn2)c2ccccc2N1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
1.6 mL (1.6 mmol, 1.0 equiv) of 1M NaN(TMS)2 in THF is added dropwise to a solution of 0.40 g (1.6 mmol, 1.0 equiv) of 2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine in 20 mL of DMF at 0° C. After 15 min, a solution of 0.47 g (1.6 mmol, 1.0 equiv) of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 3 mL of DMF is added dropwise and the resulting green solution is stirred at 0° C. for 25 min. The reaction mixture is poured into 100 mL of H2O and extracted with EtOAc (×2). The organic extract is washed with H2O and brine, dried over MgSO4 and concentrated to a brown oil. Purification by silica gel flash chromatography using EtOAc as eluent gave 0.35 g of the title compound as a light yellow foam: 1H NMR (CDCl3, 300 MHz) δ8.4-6.8 (m, 12H), 5.04 (m, 1H), 4.44 (d, 1H, J=17), 3.94 (d, 1H, J=17), 3.80 (s, 3H), 3.65 (d, 1H, J=12), 3.49 (d, 1H, J=12), 1.11 (d, 6H, J=7); low resolution MS (FAB) m/e 459 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.O>[OH:7][CH:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([O:11][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: CC(C)(C)CC(O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CC(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
743 mg (2.28 mmol) of caesium carbonate were added to a solution of 667 mg (4.56 mmol) of 2-hydroxy-4,4-dimethylpentanoic acid (racemate) in 8.7 ml of methanol and 1.7 ml of water The reaction mixture was stirred at RT for 60 min and the solvent was then removed under reduced pressure. The residue was dried under high vacuum (4 h) and then taken up in 10 ml of dimethylformamide. At 0° C., 516 μl (4.33 mmol) of benzyl bromide were slowly added dropwise. The reaction mixture was stirred at RT for 12 h, the reaction was terminated by addition of 25 ml of water and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 584 mg (54% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[N+:29]([O-])=O.[CH2:33](O)C>[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:13](=[O:32])[C:14]2[C:15](=[CH:16][CH:17]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:19]=2)[N:29]=[CH:33]1
Reactant: CCO
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCN(C(C)C)CC3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(C(C)C)CC4)cc3c2=O)c1
Reaction time: 16 h

Procedure:
A suspension of methyl 4-methyl-3-{[5-(4-isopropylpiperazin-1-yl)-2-nitrobenzoyl]amino}benzoate (10.7 g) and 10% palladium on carbon (0.3 g) in ethanol (200 ml) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and was concentrated to c.a. 100 ml. To this solution was added triethylorthoformate (4 ml) and glacial acetic acid (0.35 ml) and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was evaporated, redissolved in ethyl acetate, washed with saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated to give methyl 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate as a foam (7.57 g); NMR Spectrum: (DMSOd6) 1.00 (d, 6H), 2.15 (s, 3H), 2.59 (m, 4H), 2.68 (m, 1H), 3.24 (m, 4H), 3.85 (s, 3H), 7.45 (d, 1H), 7.60 (m, 3H), 7.95 (m, 1H), 8.00 (m, 1H), 8.05 (d, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[NH:32][C:31](=[O:33])[C:30]([CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:29][N:28]=2)=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:1]1([S:7]([N:28]2[CH:29]=[C:30]([CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:33])[N:32]=[C:27]2[S:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(SCCCCCCCCc2ccc(Cl)cc2)ncc1Cc1cccnc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=c1nc(SCCCCCCCCc2ccc(Cl)cc2)n(S(=O)(=O)c2ccccc2)cc1Cc1cccnc1
Reaction time: 8 h
Yield: 18.5 %

Procedure:
Benzenesulfonyl chloride (41 mg) was added to a solution of 2-(8-(4chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one (103 mg) in pyridine (0.5 ml), and the mixture stirred overnight. Evaporation of the pyridine followed by chromatography (silica, 0-2% methanol in dichloromethane) gave 1-phenylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one (25 mg). 1H-NMR (CDCl3) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.56(2H, t), 2.92(2H, t), 3.87(2H, s), 7.08(2H, d), 7.15-7.8(7H, m), 7.95(2H, m), 8.29(1H, s) and 8.35-8.7(2H, bm).
Reaction SMILES: C(N)(=O)C.C=O.O.[C:8]([OH:11])(=[O:10])[CH3:9].N(CC(O)=O)CC(O)=O.[C:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:23])[CH3:22]>COCCOC>[C:21]([N:24]([CH2:25][C:26]([OH:28])=[O:27])[CH2:9][C:8]([OH:11])=[O:10])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CC(=O)NCC(=O)O
Agent: C=O
Agent: CC(N)=O
Agent: O=C(O)CNCC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 125 °C
Yield: 93 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (6.5 g, 0.36 mole), acetic acid (16.8 g, 0.28 mol, 0.19 g/mL of DME), DME (90 mL) and Co2 (CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 125° C. for 30 min. HPLC analysis of this stream gave a 93% yield of (XVI), 1% (XIV), and 4% (XVIII).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH:14]1([CH2:17][O:18][C:19]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=O)[CH2:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:21]/[C:20]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=1[O:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OCC1CC1

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g, 4.181 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (1.29 g, 6.255 mmol) in the presence of sodium ethoxide (0.56 g, 8.361 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 424 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.35-0.40 (m, 2H), 0.60-0.79 (m, 2H), 1.30-1.40 (m, 1H), 3.82-3.90 (m, 5H), 6.90 (d, J=7.8 Hz, 1H), 7.04-7.12 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.62-7.72 (m, 3H), 8.48 (d, J=15.6 Hz, 1H), 8.95 (d, J=7.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:49]([C:46]2[CH:47]=[N:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=2)(=[O:50])=[O:51])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (129 μL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 6-methoxypyridine-3-sulfonyl chloride (129 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:6) to give the title compound as a pale-yellow oil (yield 247 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[F:17][CH:18]1[CH:23]([OH:24])[CH2:22][CH2:21][NH:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[F:17][CH:18]1[CH:23]([OH:24])[CH2:22][CH2:21][N:20]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:16])[CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2c1
Reactant: OC1CCNCC1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(O)C(F)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.18 g of (7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 0.1 g of 3-fluoropiperidin-4-ol, 0.14 mL of acetic acid was added, the mixture was stirred at room temperature for 1 hour, thereto was added 0.18 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 30 minutes. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.22 g of a brown oily substance, 1-(2-(3-fluoro-4-hydroxypiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one.