Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[O:22]1.CN(C)C=O>[Pd].O>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:14]=3)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:24][C:23]=2[O:22]1
Reactant: CC(C)(C)OC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cncc(-c2ccc3c(c2)OCO3)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
In a flask was placed tert-butyl 5-bromonicotinate (1.00 g, 3.87 mmol), 10% w/w palladium on carbon (210 mg, ˜0.2 mmol Pd), potassium carbonate (1.10 g, 7.96 mmol), 3,4-methylenedioxy-phenyl boronic acid (0.96 g, 5.79 mmol), dimethylformamide (50 mL) and water (250 L). The flask was purged with nitrogen and then heated, with stirring, to 90° C. for 15 hr. The reaction mixture was allowed to cool, diluted with water (350 mL) and extracted with CH2Cl2 (4X). The combined extracts was washed with water, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica (gradient, CH2Cl2 to 50% ether/CH2Cl2) to provide an off-white solid (1.02 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[C:17](Cl)(=[O:19])[CH3:18].C(OCC)(=O)C.O>CN(C=O)C>[C:17]([N:7]1[C:6]2[CH:5]=[CH:4][C:3]([OH:16])=[C:2]([Cl:1])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2Sc2c1ccc(O)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3-hydroxyphenothiazine (2.2 g) in DMF (10 ml) was added 10 ml of acetyl chloride. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate was then added, followed by ice and H2O. The organic layer was separated, dried and evaporated. The resulting residue was purified by chromatography on silica gel to give 1.4 g of 10-acetyl-4-chloro-3-hydroxy-10H-phenothiazine (m.p. 214° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH:18]C(=O)OC(C)(C)C)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+].C(O)(=O)C>C(Cl)Cl.CO>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH2:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(N)n1
Reaction time: 5.5 h

Procedure:
tert-Butyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-ylcarbamate (0.352 g, 0.96 mmol) was dissolved in 2 mL CH2Cl2. tert-Butyl (dimethyl)silyl trifluoromethanesulfonate was added and the solution was stirred for 5.5 hours. N-Ethyl-N,N-diisopropylamine (0.669 mL, 3.84 mmol) was added and the solution was stirred for 0.5 hour. Saturated NaHCO3 (aq) was added and the precipitate was extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford a yellow oil. The oil was dissolved in 10 mL MeOH. Acetic acid (0.20 mL) was added and the solution was stirred for 0.5 hour. The reaction was concentrated in vacuo to afford an off white solid. The solid was purified by flash column chromatography (1:1 EtOAc/hexanes). The fractions containing the desired compound were concentrated to dryness to afford 12-1 as a colorless oil. 1H NMR (CDCl3) δ 6.54 (s, 1H), 6.46 (s, 1H), 5.87 (bs, 2H), 4.65 (s, 2H), 2.73 (q, 2H, J=7.63 Hz), 1.29 (t, 3H, J=7.63 Hz), 0.95 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([NH2:27])[S:26][C:22]=2[CH:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:20]2[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([NH2:27])[S:26][C:22]=3[CH:21]=2)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Product: Nc1nc2ccc(-c3ccc(OCc4ccccc4)c(F)c3)cc2s1

Procedure:
Compound 6-(4-(benzyloxy)-3-fluorophenyl)benzo[d]thiazol-2-amine (W146) was prepared using the general procedure for Suzuki coupling reaction between 4-(benzyloxy)-3-fluorophenylboronic acid (100 mg, 0.4 mmol) and 6-bromobenzo[d]thiazol-2-amine (92 mg, 0.4 mmol), as a white solid (65 mg, 58%). 1H NMR (400 MHz, acetone-d6) δ 7.92 (d, J=2.0 Hz, 1 H), 7.54-7.51 (m, 3 H), 7.49-7.46 (m, 1 H), 7.46-7.40 (m, 4 H), 7.37-7.33 (m, 1 H), 7.30-7.26 (m, 1 H), 6.86 (brs, 2 H), 5.25 (s, 2 H); MS (ESI) m/z 351 (M+H+).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[C:9]([OH:16])[C:8]=2[CH2:17][CH2:18][CH3:19])([O:3][CH3:4])=[O:2].[CH2:20]([C:23]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH2:21][CH3:22]>>[C:1]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[C:9]([O:16][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:32]=[CH:33][C:34]([C:37](=[O:39])[CH3:38])=[C:35]([OH:36])[C:23]=1[CH2:20][CH2:21][CH3:22])[C:8]=2[CH2:17][CH2:18][CH3:19])([O:3][CH3:4])=[O:2]
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Reactant: CCCc1c(OCCCCCBr)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OC)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
Using the procedure of Example 2, 5.25 g (20 mmoles) of 2-carbomethoxy-7-hydroxy-8-propylchromone and 8.24 g (24 mmoles) of 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopentane gave 7.0 g (66%) of the title compound, mp 86°-87° C. Calc: C, 68.69; H, 6.92; Found: C, 68.80; H, 6.89.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][C:8]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].CO.Cl.[C:26](=O)([O:30]CC)[O:27]CC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:26]([OH:30])=[O:27])=[CH:9][C:8]2=[O:18])=[CH:19][CH:20]=1
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Yield: 15 %

Procedure:
A solution of 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (18.0g.) in diethyl carbonate (80ml.) was added to a stirred suspension of sodium hydride (15.4g.; weighed as a 60% w/w dispersion in oil, but subsequently washed by decantation with light petroleum, b.p. 40-60° C., to remove the oil) in diethyl carbonate (20ml.). The mixture was stirred under reflux for 11/2 hours, and formed a thick suspension. This was cooled and treated with a small amount of methanol to destroy any remaining sodium hydride. Dilution with ether (400 ml.) gave a suspension from which the solid was filtered. This was suspended in ethanol (180ml.) and brought to pH 3 by addition of hydrochloric acid. Water (600ml.) was added, and the suspension was stirred for 30 minutes before the solid was collected by filtration, washed with water, and well drained. This solid [which comprised diethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylmalonate] was dissolved in ethanol (180ml.), to which was added aqueous 40% w/v sodium hydroxide (20ml.), and the mixture was heated under reflux for 4 hours. The cooled mixture was added to water (600ml.) to give a solution which was brought to pH 3 by addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, drained, and crystallised from ethanol to give 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid, m.p. 208-209° C., in 51% overall yield.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12](=[C:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:13]>ClCCl>[CH3:13][CH:12]1[C:14]2([CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[O:6]1
Reactant: CC=C1CCOCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1OC12CCOCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (1.23 g, 7.13 mmol) was added to a solution of 4-ethylidenetetrahydro-2H-pyran (800 mg, 7.13 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for two hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate then saturated sodium thiosulfate. The layers were separated and the aqueous layer was re-extracted with dichloromethane (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 2-methyl-1,6-dioxaspiro[2.5]octane as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 3.88-3.76 (m, 4H), 2.92 (q, J=5.5 Hz, 1H), 1.91-1.81 (m, 2H), 1.58-145 (m, 2H), 1.30 (d, J=5.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([NH2:23])[CH:10]=1)=[O:8].[CH:24](OCC)=[O:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([NH:23][CH:24]=[O:25])[CH:10]=1)=[O:8]
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reactant: CCOC=O
Product: O=CNc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 10.0 g (32.8 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone and 200 ml of ethyl formate is refluxed with stirring for 24 hours. The reaction mixture is evaporated and the residue is dissolved in methylene chloride, then is washed with dilute HCl and saturated saline solution. The dried organic phase is evaporated to give 4-benzyloxy-3-formamidophenyl 2-pyridyl ketone.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([C:15]([O:17]C)=[O:16])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.Cl>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([C:15]([OH:17])=[O:16])=[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Heat three grams of methyl 5-bromo-3-phenylbenzo[b]thiophene-2-carboxylate in a mixture of 50 ml of methanol and 30 ml of 10% sodium hydroxide, under reflux for 1 hour. Add concentrated hydrochloric acid to yield the title compound as a precipitate. Recrystallize from benzene; m.p. 265°-266°.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]([CH3:14])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)[CH3:5].[BH4-].[Na+].CI.[H-].[Na+]>CO>[CH3:1][O:2][CH2:3][C:4]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:14])[CH3:5]
Reactant: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COCC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester was reduced using sodium borohydride in methanol and the resultant alcohol was alkylated with methyl iodide using sodium hydride as base to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.53 (s, 6H), 3.25 (s, 3H), 3.38 (s, 2H), 7.53 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:26])([OH:25])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:26][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:25][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCC(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCC(c3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
(S)-1-(2-Chloro-4-nitro-imidazol-1-yl)-2-methyl-3-(4-phenylpiperidin-1-yl)propan-2-ol prepared in Example 276 (0.703 g, 1.86 mmol) was dissolved in DMF (5 ml). To the solution, sodium hydride (89 mg, 2.23 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added. The precipitates were filtered off, purified by silica gel column chromatography (n-hexane/acetone=3/1) and recrystallized from ethyl acetate to afford (S)-2-methyl-6-nitro-2-(4-phenylpiperidin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole (0.230 g, yield 36%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH2:12]Cl)[CH2:6]1.[K].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH2:12][N:23]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])[CH2:6]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1CN(Cc2ccccc2Cl)CC(CCl)O1
Agent: [K]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2Cl)CC(CN2C(=O)c3ccccc3C2=O)O1
Temperature: 150 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A mixture of 4-(2-chlorobenzyl)-2-chloromethyl-6-methylmorpholine (19.7 g), phthalimide potassium salt (14.6 g), and dimethylformamide (150 ml) is stirred at 150° C. for 5 hours. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off to give the title compound (26 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1B(O)O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[CH3:9][O:8][C:6]1[C:5]([OH:10])=[C:4]([CH3:11])[N:3]=[C:2]([C:15]2[C:14]([O:13][CH3:12])=[CH:19][C:18]([CH3:20])=[CH:17][C:16]=2[CH3:21])[N:7]=1
Reactant: COc1nc(Cl)nc(C)c1O
Reactant: COc1cc(C)cc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(C)c1-c1nc(C)c(O)c(OC)n1
Temperature: 95 °C

Procedure:
A mixture of 2-chloro-4-methoxy-6-methylpyrimidin-5-ol (348 mg, 2.0 mmol), 2-methoxy-4,6-dimethylphenylboronic acid (540 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in toluene (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 95° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (50% ethyl acetate in hexanes) yields 4-methoxy-2-(6-methoxy-2,4-dimethylphenyl)-6-methylpyrimidin-5-ol as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH3:26])[C:17]([NH:19]C1C=CC=CC=1)=[O:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>C(O)C>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]([CH3:26])[C:17](=[O:18])[N:19]=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)Nc1ccccc1)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Cn1c(=O)nc(-c2ccccc2)c2cc(Cl)ccc21
Yield: 66.5 %

Procedure:
A mixture of 3.65 g (0.01 mole) of 1-(2-benzoyl-4-chlorophenyl)-1-methyl-3-phenylurea and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of ethanol was stirred and refluxed for 5 days. The reaction mixture was cooled, and the suspended solid was collected on a filter, washed with alcohol, and dried in air to give 1.80 g (63%) of 6-chloro-1-methyl-4-phenyl-2-(1H)-quinazolinone as yellow crystals, mp 289°-291°.
Reaction SMILES: [NH2:1][C@:2]1([CH2:30][OH:31])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[CH2:3]1>C(O)C.[Pd]>[NH2:1][C@:2]1([CH2:30][OH:31])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[CH:9][CH:8]=2)[CH2:3]1
Reactant: N[C@]1(CO)CC[C@@H](c2ccc(OCCc3ccc(OCc4ccccc4)cc3)cc2)C1
Agent: [Pd]
Solvent: CCO
Product: N[C@]1(CO)CC[C@@H](c2ccc(OCCc3ccc(O)cc3)cc2)C1
Yield: 86.2 %

Procedure:
To a solution of ((1R,3R)-1-amino-3-(4-(4-(benzyloxy)phenethoxy)phenyl)cyclopentyl)methanol (250 mg, 0.599 mmol) in ethanol (10 mL) was added Pd/C 10% (20 mg, 0.188 mmol). The mixture was flushed with hydrogen and hydrogenate with a balloon for about 16 hours. The crude mixture was filtered, concentrated and the residue was triturated with ether. The solid was collected and dried under vacuum at 50° C. to give 4-(2-(4-((1R,3R)-3-amino-3-(hydroxymethyl)cyclopentyl)phenoxy)ethyl)phenol (169 mg, 86%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH3:3].NC1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20]C=1O>C1COCC1>[CH3:25][O:24][C:22]1[CH:23]=[CH:3][C:2]2[O:4][C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[CH:7]=3)=[N:16][C:20]=2[CH:21]=1
Reactant: CCOC(=N)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(O)c(N)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2oc(-c3cccc(C(F)(F)F)c3)nc2c1
Reaction time: 8 h

Procedure:
A solution of compound 13 and compound 12 (850 mg, 6.13 mmol) in THF (10 mL) was heated to reflux and allowed to stir overnight. The reaction mixture was allowed to cool and the THF evaporated (in vacuo). The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and treated with activated carbon Norit A. The mixture was filtered through Celite 521, and evaporated (in vacuo) and the residue was purified using column chromatography (20% Ethyl acetatelhexanes) to afford compound 10 as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([Cl:11])=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc2ncnc-2c(Cl)[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
An ice-cold solution of 2,6-dichloro-1H-purine (1.89 g, 10 mmol) in THF (10 mL) was treated with NaH (60% in oil, 440 mg, 11 mmol), stirred at 0° C. for 30 min, treated with ethyl bromoacetate (1.22 mL, 11 mmol), stirred at room temperature for 2 h, poured into sat. NaHCO3, extracted with EtOAc and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Heptane:EtOAc (2:1)] to give the title compound (1.46 g, 53%) as a white solid: IR νmax (Nujol)/cm−1 3106, 2985, 2955, 2924, 2854, 1734, 1598, 1557, 1374, 1341, 1298, 1156 and 884; NMR δH (400 MHz, CDCl3) 1.31 (3H, t, J7.0 Hz), 4.29 (2H, q, J7.0 Hz), 5.01 (2H, s), 8.17 (1H, s).
Reaction SMILES: [ClH:1].[O:2]([CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.N1CCCCC1.Cl>CO.CO.C(Cl)Cl.C(Cl)Cl.CCCCCC.[Pt]=O>[ClH:1].[O:2]([CH2:9][CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)[OH:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC(COc1ccccc1)c1ccccn1
Agent: O=[Pt]
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCCCCC
Solvent: CO
Product: OC(COc1ccccc1)C1CCCCN1
Yield: 25.5 %

Procedure:
A solution of α-phenoxymethyl-2-pyridinemethanol hydrochloride (20.22 g, 0.08 mole) in 425 ml of methanol was hydrogenated for 2.5 hr in the presence of 1 g of platinum oxide at room temperature. TLC analysis (in 5% methanol-methylene chloride) showed that all the pyridine compound had been converted to the piperidine derivatives. Removal of methanol furnished an oil. The oil was dissolved in methylene chloride-hexane mixture and treated with ethereal hydrogen chloride. The resulting salt was triturated with acetone and recrystallized from methylenechloride-hexane-diethyl ether to give 5.28 g (25.5% of a white crystalline solid, m.p. 165°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][OH:31])=[NH:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[C:32](Cl)(=O)[CH2:33][CH2:34][CH3:35]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[N:29]=[C:32]([CH2:33][CH2:34][CH3:35])[O:31][N:30]=4)[CH2:26][CH2:27]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)c(F)c1
Reactant: CCCC(=O)Cl
Product: CCCc1nc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5F)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-N-hydroxy-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.58 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-5-(methanesulfonyl)benzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)benzamide. MS (Q1) 420.95 (M)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13](B(O)O)=[CH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:18]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[C:33]([N:39]=2)=[N:34][C:35](Cl)=[CH:36][CH:37]=3)=[C:26]([F:40])[CH:25]=1.C(Cl)Cl>O1CCOCC1.O>[O:20]1[CH2:21][CH2:22][CH2:23][O:18][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[C:33]([N:39]=2)=[N:34][C:35]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH2:14])=[CH:36][CH:37]=3)=[C:26]([F:40])[CH:25]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2nc(Cl)ccc2s1
Reactant: C=C(B(O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1ccccc1)c1ccc2sc(-c3ccc(C4OCCCO4)cc3F)nc2n1
Temperature: 80 °C

Procedure:
A slurry of (amphos)2PdCl2 (0.0333 g, 0.0470 mmol), potassium carbonate (0.442 g, 3.20 mmol), 1-phenylvinylboronic acid (0.306 g, 2.07 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[4,5-b]pyridine (0.330 g, 0.941 mmol) in 4.5 mL dioxane and 1 mL water was flushed with argon and sealed, and heated to 80° C. overnight. The reaction mixture was cooled and treated with water and DCM. The aq. Layer was extracted with DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was suspended in 2 mL MTBE and filtered, rinsing with 1 mL MTBE, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[4,5-b]pyridine as a gray solid. MS (ESI) m/z: calculated: 418.1; Observed: 419.0 (M++1).