Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[CH2:51]>CN(C)C=O>[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[CH:51][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: C=Cc1ccccc1Cl
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C1Nc2cccc(/C=C/c3ccccc3Cl)c2/C1=C/c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(C=Cc3ccccc3Cl)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (39 mg, 0.116 mmol) (from Example 71 above), triethylamine (65 μL, 0.464 mmol), tri-o-tolylphosphine (7 mg, 0.023 mmol) (Aldrich), palladium(ll) acetate (2 mg, 0.009 mmol) (Aldrich), and 2-chlorostyrene (24 mg, 0.173 mmol) (Aldrich) in 3 mL of dry N,N-dimethylformamide was heated at 85° C. under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 5% ethyl acetate-benzene elution) to yield pure 4-[(E)-2-(2-chlorophenyl)-ethenyl]-1,3-dihydro-(Z)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid. (Yield 27 mg, 67%; mp=257-258° C.).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:8]1[NH:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: O=c1[nH]c2cccc(Cl)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2c(Cl)cccc2[nH]1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Phosphorus oxychloride (10 mL) was added to 4-chloro-1,3-dihydro-benzoimidazol-2-one (0.750 g, 4.45 mmol), and the mixture heated to 80° C. for 48 h. The mixture was cooled to 23° C. and POCl3 removed under reduced pressure. The residue was cooled to 0° C., and cold saturated aqueous NaHCO3 (20 mL) was added cautiously. After stirring at 23° C. for 15 min, the mixture was sonicated and the resulting residue was filtered to yield the titled compound (0.760 g, 92%), which was used in the next step without further purification. MS (ESI/CI): mass calcd. for C7H5Cl2N2, 186.0; m/z found, 187.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.68 (s, 1H), 7.51-7.42 (m, 1H), 7.32-7.25 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH2:37][CH:39]1[CH2:40][O:41]1
Reactant: BrCC1CO1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
N,N-Dimethylformamide (6 ml) was added to 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (189 mg), potassium carbonate (236 mg), and epibromohydrin (234 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59 mg, yield 27%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCc2c[nH]cn2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)c1ccc(C(=CCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
4-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxy-3-phenylpropyl]-1H-imidazole (2,5 g, 6,6 mmol) is dissolved in methylene chloride (50 ml) and thionyl chloride (3,2 g, 26,9 mmol) is added to the solution. The mixture is refluxed for two hours. The solvents are evaporated. 2M sodium hydroxide is added to the residue and the product is extracted into ethyl acetate and dried. The product is convened to its HCl salt with dry hydrogen chloride gas and the solvent is evaporated. Yield 2,14 g, 91%.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[S:13]1[CH:17]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=2[C:21](O)=[O:22])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=2.CN.C(OCC)(=O)C>C1COCC1>[S:13]1[CH:17]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=2[C:21]([NH:3][CH3:1])=[O:22])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(Sc2csc3ccccc23)c(C(=O)O)c1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)ccc1Sc1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (324 mg, 2 mmol) is added to 2-(benzo[b]thiophen-3-ylsulfanyl)-5-methyl-benzoic acid (300 mg, 1 mmol) in mL dry THF and stirred for 2 hours at room temperature. 2.5 mL methyl amine (2M in THF, 5 mmol) is added and the reaction mixture is stirred for 16 hours at room temperature. Ethyl acetate is added and the organic phase is washed with 1 N HCl (aq) and brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: [C:1](=[S:3])=[O:2].[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]>O.C(O)C>[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:1](=[S:3])[OH:2]
Reactant: O=C=S
Reactant: NCCCCN
Solvent: CCO
Solvent: O
Product: NCCCCNC(O)=S

Procedure:
passing carbonyl sulfide gas into a solution of tetramethylene diamine dissolved in a mixture of water and ethanol in equal proportions by weight at a temperature of from about 30° C. to about 45° C. to form N-(4-aminobutyl)thiocarbamic acid or zwitterion thereof; and
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:41].C(N(CC)CC)C>ClCCl>[F:41][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)=[O:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: CC(C)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 9 %

Procedure:
4-Methylvaleric acid (4.30 mmol, 0.543 mL, 0.5 g) was stirred in dichloromethane (5 mL) at 0° C. Oxalyl chloride (21.52 mmol, 1.848 mL, 2.73 g) was added. The reaction mixture allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to give the intermediate 4-methylpentanoyl chloride. A mixture of 4-methylpentanoyl chloride (1.564 mmol, 0.211 g), (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.043 mmol, 0.5 g) and triethylamine (2.086 mmol, 0.290 mL, 0.211 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate, concentrated under vacuum and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (54 mg).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[N-]=C=O>O1CCOCC1.C(N(CC)CC)C>[CH:1]1([NH:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: [H][H]
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNC1CCCCC1
Temperature: -15 °C
Yield: 83.5 %

Procedure:
A solution of cyclohexyl isocyanate (1.25 g.; 0.01 mole) in 100 ml. anhydrous 1,4-dioxane containing two drops of anhydrous triethylamine was mixed with 0.5 gram 10% Pd-on-carbon and shaken at a pressure of 50 p.s.i. of hydrogen on a Parr low pressure hydrogenator. The uptake of hydrogen was complete in two hours. Work up, as in Example 1, gave 1.15 g. of colorless oil containing a trace of isocyanate. The product was purified by slurrying the oil with Skellysolve B, chilling at -15° C. and decanting the supernatant from the crystalline formamide. After drying under high vacuum, the weight of title product was 1.06 g. (83.5% yield). The ir, nmr and glc were identical to an authentic sample.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:18]=[CH:17][N:16]=[C:15]2[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCC1
Temperature: 110 °C
Yield: 14.8 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (1.27 g, 7.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.7 mmol), and potassium carbonate (3.9 g, 28.3 mmol) in DMF (30 ml). The mixture was heated at 110° C. for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/ammonia, (100/8/1) to give an oil which was triturated with ethyl acetate to give 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 15%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:12][CH3:13])=[O:3].[C:14]([O:19][CH2:20]C)(=[O:18])[C:15]([O-])=[O:16].C[O-].[Na+:24].[Na]>CO.CCOCC>[Na+:24].[CH3:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:2]([O-:3])=[CH:1][C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: CCOC(=O)C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 8 h

Procedure:
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous MeOH. The reaction mixture is heated to reflux for 7 hours and left overnight at RT. It is poured into 2 liters of iso ether and left stirring for minutes. The expected product is obtained by filtration, washing with iso ether and drying under vacuum, m=120 g, m.p.=178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[N+:13]([O-])([OH:15])=[O:14]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][N:4]=1
Reactant: COc1ncccc1NC(C)=O
Reactant: O=[N+]([O-])O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ncc([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of N-(2-methoxypyridin-3-yl)acetamide (23 g, 139 mmol) in trifluoroacetic anhydride (TFAA) (90 mL) was added a solution of HNO3 (5.84 mL, 139 mmol) in TFAA (140 mL) dropwise at rt. The reaction was stirred for 1.5 h at rt before being poured into an ice bath with stirring. The precipitated solid was filtered and washed with Et2O (50 mL), then dissolved in EtOAc (1 L) and washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The phases were separated and the organic phase dried (MgSO4), and concentrated in vacuo to yield the title compound as a light yellow solid (21.2 g, 100.4 mmol).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[S:30]([NH2:33])(=[O:32])=[O:31].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[S:30](=[O:32])(=[O:31])[N:33]=1
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 120 °C
Yield: 27.9 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.218 g, 0.75 mmol) was dissolved in pyridine (1.5 mL) and 2-amino-5-iodo-benzenesulfonamide (Example 4a, 0.222 g, 0.75 mmol) was added. The reaction mixture was heated at 120° C. for 16 h, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL, 0.78 mmol) was added an heated for another 4 h. The pyridine was removed in vacuo to afford the crude desired product. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 5%-10% methanol in dichloromethane) afforded the desired product, 4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.110 g, 0.209 mmol, 28% yield) as a white solid. LC-MS (ESI) calcd for C19H19IN4O4S. found 526.02. found 527.20 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[N:12]=1)([CH3:10])([CH3:9])[CH3:8].O>C(O)C>[C:7]([C:11]1[N:12]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[CH:14]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COCCc1cc(Cl)nc(C(C)(C)C)n1
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: COCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of piperazine (45.2 g, 525 mmol) in ethanol (300 mL) was heated to reflux. A solution of 2-tert-butyl-4-chloro-6-(2-methoxy-ethyl)-pyrimidine (20 g, 87 mmol) in ethanol (50 mL) was added dropwise to the above solution. The solution was refluxed for another 3 hrs, cooled to room temperature. Then water was added and the organic layer was extracted with EA (400 mL×3). To the organic layer was added 5% citric acid (1 L), separated, and the aqueous layer was collected and adjusted to alkaline pH>8 with 2 N NaOH. The alkaline aqueous layer was extracted with EA (400 mL×3), and the organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (20 g, 82% yield) as a yellow oil.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8]O)[C:6]#[N:7].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8][Cl:12])[C:6]#[N:7]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C(C#N)=CO
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C#N)=CCl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a suspension of the sodium salt of methylhydroxymethylene-cyanoacetate (19.0 g, 127 mmol) in 200 mL of dichloromethane was added phosphorous pentachloride (26.5 g, 127 mmol) in one portion. The reaction mixture was allowed to exotherm to reflux temperature and then maintained at reflux with stirring for 4 hours. The resulting light yellow suspension was allowed to cool to 23° C. and then poured into 400 mL of cold water. The mixture stirred for 15 minutes and the phases were separated. The aqueous layer was extracted with 100 mL of dichloromethane and the combined organic layers were washed twice with water, dried over magnesium sulfate, and concentrated to 16.8 g of the title compound which was of sufficient purity for use in Example 1. 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 7.58 (s, 0.35H), 8.04 (s, 0.65H).
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[BrH:14]>>[Br:14][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1[nH]c2ccccc2cc1CO
Reactant: Br
Product: O=c1[nH]c2ccccc2cc1CBr
Reaction time: 3 h

Procedure:
To 5 g of 3-hydroxymethylcarbostyril was added 50 ml of 47%-hydrobromic acid and the mixture was stirred at 70°-80° C. for 3 hours. After cooled the reaction mixture, the crystals precipitated were collected by filtration and were recrystallized from methanol to obtain 6 g of 3-bromomethylcarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [CH:1]1([C:4]([CH:31]2[CH2:33][CH2:32]2)([C:6]2[S:10][C:9]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]3[C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:23][N:24]=[C:17]3[CH:16]=[CH:15]4)=[N:8][CH:7]=2)O)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:31]1([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:6]2[S:10][C:9]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]3[C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:23][N:24]=[C:17]3[CH:16]=[CH:15]4)=[N:8][CH:7]=2)[CH2:33][CH2:32]1
Reactant: OC(c1cnc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)s1)(C1CC1)C1CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nnc3ccc4cc(Sc5ncc(C(C6CC6)C6CC6)s5)ccc4n23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 10g (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) was added triethylsilane (0.04 mL, 0.24 mmol) and TFA (0.04 mL, 0.49 mmol) at 0° C. After 4 hours at room temperature, additional triethylsilane (0.02 mL, 0.12 mmol) and TFA (0.02 mL, 0.25 mmol) as added at 0° C., and the reaction was stirred for another 3 hours at room temperature. The reaction was washed with saturated aqueous NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the desired product, 10h.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.Cl.[CH3:14]N(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:14][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Suspend 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL). Cool to 0° C. Add methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (18.2 g, 94.8 mmol). Stir the mixture at room temperature for 6 hours, wash with water and brine, and dry over sodium sulfate. Filter the mixture and concentrate in vacuo. Chromatograph the residue on SiO2 (50% ethyl acetate/hexanes) to obtain the desired subtitled intermediate, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CC=CC=1.[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:22](=[O:23])[CH2:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Br)nc(C)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a mixture of 1c (0.364 g, 1.81 mmol) and pyridine (0.158 ml, 2 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.242 g, 1.8 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1d (0.361 g, 1.64 mmol, 91%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14](O)[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24]1(C)[C:25]([S:30](Cl)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14]([S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)=[O:31])[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CO[C@@H]1C=C[C@@H](O)C1)OCC
Reactant: Cc1ccccc1S(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CO[C@@H]1C=C[C@@H](S(=O)c2ccccc2)C1)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trans-1-diethylphosphonomethoxycyclopent-2-en-4-ol (0.4 g; 1.6 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. in an icebath under a nitrogen atmosphere. Triethylamine (0.3 g; 2.9 mmol) was then added followed by a solution of toluenesulfinyl chloride (0.4 g, 2.9 mmol)in CH2Cl2 (2 mL). The reaction mixture was stirred at 0° C. for 1 hr. The ice bath was removed and the reaction mixture concentrated in vacuo. The residual oil was purified by flash column chromotography with 2% methanol/98% dichloromethane as eluent. The product(0.54 g; 87%) was isolated as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([CH3:8])=[CH:4][C:3]=1[OH:9]
Reactant: Cc1ccc(C)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)c(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 2,5-dimethyl phenol (5.0 g, 40.9 mmol) in H2O (150 mL), at room temperature was added tetrabutylammonium tribromide (19.9 g, 41.39 mmol) in CHCl3 (150 mL). The reaction mixture was stirred for 2 h at rt, the organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1:5) to afford 2,5-dimethyl-4-bromophenol as a brown solid (6.2 g, 76%); 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 7.24 (s, 1H), 6.74 (s, 1H), 2.21 (s, 3H), 2.07 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (9:1); Rf=0.52.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].CO>CN(C)C=O>[Si:18]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCC1CC=CCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC1CC=CCC1)(c1ccccc1)c1ccccc1
Reaction time: 22 h

Procedure:
3-Cyclohexene-1-methanol (5.0 g) was dissolved in N,N-dimethylformamide (50 ml), and imidazole (3.93 g) and tert-butylchlorodiphenylsilane (14 ml) were added to stir the mixture for 22 hours. After adding methanol, the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1) to obtain (±)-4-(tert-butyldiphenylsilyloxy-methyl)-1-cyclohexene (16.1 g) as a colorless oil.