Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH2:20][CH2:21][O:22][CH3:23])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.COCCN.[CH3:54][C:55]([OH:59])([C:57]#[CH:58])[CH3:56]>>[OH:59][C:55]([CH3:56])([CH3:54])[C:57]#[C:58][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH2:20][CH2:21][O:22][CH3:23])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1
Reactant: COCCNCc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: COCCN
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: COCCNCc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 20 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-(((2-methoxyethyl)amino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with 2-methoxyethanamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (25 mg, 20%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CO.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCN(CC2CCCCC2)C1

Procedure:
To a solution of 600 mg of 3-(benzyloxycarbonyl)amino-N-{((3S)-3-piperidyl)methyl}propanamide in 3 ml of methanol, a solution of 150 mg of sodium cyanoborohydrate and 160 mg of zinc chloride in 8.1 ml of methanol, and 0.30 ml of cyclohexanecarbaldehyde were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate and successively washed with saturated aqueous sodium bicarbonate solution and saturated saline, followed by drying over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 775 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:11])[CH:3]=1.B.C1COCC1.O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([I:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-iodobenzoic acid (5.0 g, 18 mmol) was dissolved in THF (40 mL) and cooled to 0° C. Borane-THF complex (1M in THF) (35 mL, 35 mmol) was added by syringe. The solution was allowed to warm to room temperature and stirred overnight. The reaction was monitored by LCMS and TLC. When the reaction was complete, water was added until gas evolution ceased and then the THF was removed under vacuum. EtOAc (100 mL) was added, and the organic layer was washed with water (3×50 mL), brine (3×50 mL), dried with MgSO4, and concentrated in vacuo resulting in a white solid.
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[C:21]([CH2:2][S:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chilled mixture of 1-chloromethanesulfonyl-naphthalene (19.7 g, 81.8 mmol) and 1-fluoro-4-nitrobenzene (8.7 mL, 82 mmol) in dry THF (197 mL) was dropwise added 1.0M potassium t-butoxide in THF (205 mL, 205 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 1.5 hours. Glacial acetic acid (16 mL, 280 mmol) was then added. After stirring at ambient temperature for 1 hour, 40 minutes, the reaction mixture was concentrated and partitioned in warm ethyl acetate and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. The solid residue was stirred in ether, filtered and dried at 82° C. in vacuo for 1 hour. This yielded 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene as a brown/rust-colored solid (19.9 g, 70.6%): MP: 155-160° C.; Mass Spectrum (−EI, [M−H]−) m/z 344. 1HNMR (300 MHz, DMSO-d6): δ8.50-8.52 (m, 1H), 8.33 (d, 1H, J=8.30 Hz), 8.06-8.14 (m, 2H), 7.97 (dd, 1H, J=7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1H), 7.23-7.26 (m, 1H), 5.23 ppm (s, 2H). Elemental Analysis for C17H12FNO4S: Calcd: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24]([O:26]CC)=O)[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:31].[Cl-]>N.CO>[NH:1]([C:8]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]2[N:15]=[C:14]([C:24]([NH2:31])=[O:26])[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH4Cl (10 mg, 0.19 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et2O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH+: 375.3. This trasformation can also be accomplished using EDCI/HOBT coupling with NH3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15](=[S:17])[NH2:16])[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C(#N)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=2)[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)CC1(COCc2ccccc2)CCC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: c1ccc(COCC2(Cc3nc(-c4ccccc4)cs3)CCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 0.5 g (2.01 mmol) of 2-{1-[(benzyloxy)methyl]cyclobutyl}ethanethioamide in 10 mL of acetonitrile was added 0.39 g (2.01 mmol) of phenacyl bromide and the contents stirred at room temperature for 3 h. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using ethyl acetate:hexane (2:8) as the eluent to afford 0.68 g (97%) of 2-({1-[(benzyloxy)methyl]cyclobutyl}methyl)-4-phenyl-1,3-thiazole as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.96-7.30 (m, 5H), 4.60 (s, 2H), 3.50 (s, 2H), 3.35 (s, 2H), 2.13-1.95 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:19])([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][OH:8].ClC1C=CC=C(C(OO)=O)C=1.[OH2:31].[OH2:32].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>C(Cl)Cl>[F:19][C:2]([F:1])([C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:4][S:5]([CH2:6][CH2:7][OH:8])(=[O:32])=[O:31]
Reactant: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCO)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 65.3 %

Procedure:
2-(3,3,4,4,5,5,6,6,6-nonafluorohexylthio)ethanol (50.0 g, 154 mmol) prepared in Synthetic Example 3 was dissolved in methylene chloride (850 ml), and m-chloroperbenzoic acid (m-CPBA) (58.6 g, 340 mmol) was added at 0° C. for 15 minutes with stirring in nitrogen atmosphere. The mixture was stirred at room temperature for one night and then methylene chloride (300 ml) was added to the reaction mixture. The reaction mixture was injected into a mixture of an aqueous saturated sodium thiosulfate pentahydrate solution (100 g) and water (100 ml). An organic layer was removed and an aqueous layer was extracted with methylene chloride (50 ml). Organic layers were joined, washed with a saturated sodium hydrogen carbonate solution (200 ml) and with a saturated saline solution (150 ml), and then dried over magnesium sulfate. A filtrate after filtration was concentrated at reduced pressure. A residue was subjected to a silica gel column chromatography (hexane/ethyl acetate (1/1→1/2)), and fractions having Rf value of 0.41 [Rf value (Thin Layer Chromatography (TLC))=(Migration distance of sample)/(Migration distance of eluting solvent)] were gathered and concentrated at reduced pressure and dried at vacuum to give crystalline 2-(3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)ethanol (35.8 g). Yield: 65.2%.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C>C1COCC1.Cl>[CH3:13][O:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:14])[C:3](=[O:15])[C:2]=1[B:21]([OH:24])[OH:22]
Reactant: COB(OC)OC
Reactant: COc1c(Br)c(=O)n(C)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one (2.7 g, 10.07 mmol) in THF (5 mL) was added n-butyllithium (2.5 M in Hexane, 4.03 mL) under nitrogen atmosphere at −78° C. and the reaction mixture was maintained at this temperature for 1 h. A cooled solution of trimethyl borate (1.35 mL, 12.08 mmol) was added at −78° C., and the reaction mixture was maintained at this temperature for 2 h. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 1M HCl and a white solid precipitated from the solution. The precipitate was filtered, washed with water and EtOAc, then dried under high vacuum to provide (4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (1.5 g, MS: 234.1 [M+H+].)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cc(N2CCOCC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of morpholine (0.604 g, 6.04 mmol) in dry DMSO and NaH (0.251 g, 6.6 mmol) was stirred for 30 minutes at 0° C., after which time 2,4,6-trichloropyridine (1.0 g, 5.50 mmol) was added. This reaction mixture was stirred at room temperature for 4 hours, after which time ice cold water was added to quench the reaction (100 mL). The reaction mixture was then extracted with ethyl acetate, and the extract was washed with 3-4 times water. The organic layer was dried over sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography over 100-200 mesh silica gel. Elution of the column with 20% acetone in hexanes gave the pure product as a colorless solid (0.565 g, yield 44%).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[OH:15]S(O)(=O)=O.N([O-])=O.[Na+]>Cl.O>[OH:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ncc([N+](=O)[O-])c2ccccc12
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Stir a slurry of 1-amino-4-nitroisoquinoline H2SO4 (120 g, 418 mmol) in aqueous HCl (6 N, 2 L) mechanically under nitrogen at 35° C. Add a solution of NaNO2 (72.1 g, 1044 mmol) in water (300 mL) over 1 hour while warming the slurry to 50° C. Heat the mixture an additional 30 minutes then allow to cool to room temperature and stir overnight. Heat the mixture to 50° C., then add a solution of NaNO2 (36 g in 150 mL of water) over 30 minutes. Stir the mixture for 2 hours then heat to 60° C., allow to cool slowly to room temperature over 3 hours. Filter the resulting slurry, and wash the cake with water (3×600 mL). Partially air-dry (180 g). Slurry the wet solid in i-PrOH (1 L) and EtOH (1 L) at reflux, add THF (350 mL) to effect complete dissolution. To the solution add water (400 mL), and cool to 10° C. over 3 hours. Filter and wash with EtOH (2×300 mL), then diethyl ether (3×150 mL). Air-dry overnight to afford 1-hydroxy-4-nitroisoquinoline (62.62 g, 79% yield) as a light brown solid. (ES+): m/z 191 (M++H).
Reaction SMILES: [C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[OH:26])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.[I-].[K+]>C1COCC1.CN(C=O)C>[C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[O:26][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([C:28]3[O:27][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)=[CH:37][CH:38]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@@H]1CCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(C(N[C@@H]2CCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of trans-2-triphenylmethylaminocyclopentanol (4.76 g; 13.85 mmol), is added Nail (60%; 0.83 g; 20.78 mmol) in 100 ml THF and 20 ml DMF. This mixture is stirred for 1 hr. and then 4-(benzoxazol-2-yl)benzyl bromide (3.99 g; 13.85 mmol) is added followed by potassium iodide (pinch). The reaction mixture is stirred for 72 hrs., quenched with water, concentrated in vacuo and flash chromatographed using 9:1; hexane:EtOAc to obtain trans-2-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]cyclopentane which is used directly in the next step.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[C:13]#[N:14].C[O-].[Na+]>[Ni].C(Cl)Cl.CO>[C:15]([N:5]1[C:6]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=2[CH2:13][NH:14][C:3](=[O:2])[CH2:4]1)(=[O:17])[CH3:16]
Reactant: COC(=O)CN(C(C)=O)c1cc(N)ccc1C#N
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CC(=O)NCc2ccc(N)cc21
Reaction time: 12 h
Yield: 34.4 %

Procedure:
A mixture of [acetyl-(5-amino-2-cyano-phenyl)-amino]-acetic acid methyl ester (0.4 g, 1.6 mmol), sodium methoxide (87 mg, 1.6 mmol) and Raney nickel (50 mg) was shaken for 12 hours under a 50 psi H2 atmosphere. The catalyst was removed by filtration and the filtrate was concentrated. Silica gel chromatography (DCM/MeOH 9:1) gave 1-acetyl-8-amino-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one (120 mg, 0.55 mmol, 34%): 1H NMR (300 MHz, CD3OD) δ 7.12 (d, 1H), 6.7 (m, 2H), 5.35 (d, 1H), 4.37 (d, 1H), 3.80 (d, 1H), 3.49 (d, 1H), 1.93 (s, 3H); MS (m/e) 220 (M+1).
Reaction SMILES: [H][H].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19]CC2C=CC=CC=2)=[CH:14][C:13]=1[Cl:27])(=[O:5])[CH3:4]>[Pd].C(O)C>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([Cl:27])=[CH:14][C:15]([OH:19])=[CH:16][C:17]=1[Cl:18])(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl

Procedure:
This compound was prepared in a manner analogous to that set forth in Step D of Example 1, using excess hydrogen gas, 33.0 grams (0.086 mole) of 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butyl acetate and 0.05 gram (catalyst) of 10% palladium on carbon in 350 mL of ethanol. The yield of the subject compound was 25.4 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)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>[Cl:12][C:13]1[N:18]=[C:17]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1
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: CC#N
Product: COc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C
Yield: 98 %

Procedure:
To a solution of 4-methoxyphenylboronic acid (3.0 g, 19.7 mmol) and 2,4-dichloropyrimidine (5.9 g, 39.0 mmol) in dry acetonitrile (120 mL) was added a 0.4 M solution of Na2CO3 (120 mL) followed by Pd(PPh3)4 (400 mg, 0.35 mmol). The suspension was degassed and heated at 90° C. for 16 h, cooled down and concentrated to produce a precipitate which was collected by filtration, washed with water, dried and purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 5/95) to afford the title compound 17 (4.25 g, 19.3 mmol, 97% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[S:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCOc1ccc(C=O)cc1
Product: CCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-ethoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 76%).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[CH:10]\[CH2:11][CH3:12])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:41]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([C:9](=[O:8])[C@H:10]([OH:41])[CH2:11][CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC[C@@H](O)C(=O)c1cccc(Cl)c1
Yield: 85.2 %

Procedure:
Compound 10j was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)but-1-enyloxy)dimethylsilane (9j, 3.7 g, 0.013 mol), AD-mix-β (17.5 g), and CH3SO2NH2 (1.2 g, 0.0126 mol) in tert-butyl alcohol-water (45 mL:45 mL). The reaction was quenched with sodium sulfite (12.5 g). After purification by column chromatography on silica gel, 2.2 g (79%) of the title product was isolated: [α]20D +31.4° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.91-7.88 (m, 1H), 7.81-7.75 (m, 1H), 7.62-7.56 (m, 1H), 7.45 (t, 1H, J=7.8 Hz), 5.06-4.98 (m, 1H), 3.60 (d, 1H, J=6.5 Hz), 2.04-1.87 (m, 1H), 1.70-1.51 (m, 1H), 0.94 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3) δ 201.4, 135.8, 135.7, 134.2, 130.6, 128.9, 126.9, 74.5, 29.1, 9.2. C10H11ClO2.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12][OH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(Br)s2)=NO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)s2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
[3-(5-Bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-yl]-methanol (10.7 g, 40.6 mmol) was added to anhydrous dichloromethane (200 ml) followed by addition of triethylamine (7.9 ml, 56.9 mmol). The solution was cooled to 0° C. followed by dropwise addition of methane sulfonyl chloride (3.8 ml, 48.7 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (9 g).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][N:28]=[C:27]2[NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)=[C:37]([Cl:49])[CH:36]=1>C(Cl)Cl>[Cl:49][C:37]1[CH:36]=[C:35]([NH:34][C:27]2[C:26]3[C:31](=[CH:32][CH:33]=[C:24](/[CH:23]=[CH:22]/[CH2:21][NH:20][C:1](=[O:4])[CH3:2])[CH:25]=3)[N:30]=[CH:29][N:28]=2)[CH:40]=[CH:39][C:38]=1[O:41][C:42]1[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CN)cc34)cc2Cl)cn1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)NC/C=C/c1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c2c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A mixture of 14.4 μL (0.25 mmol) of acetic acid and 40.3 mg (0.33 mmol) of dicyclohexylcarbodiimide in 2 mL of methylene chloride were stirred for 10 minutes and treated with 100.3 mg of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine. The reaction was allowed to stir at room temperature overnight. The precipitate which formed was filtered and chromatographed on silica gel, eluting with 6-10% methanol/chloroform to afford 106 mg of the title compound; mp 254-256° C.; 1H NMR (d6 DMSO): δ 9.88 (s, 1), 8.58 (s, 1), 8.48 (m, 1), 8.20 (m, 3), 7.95 (m, 1), 7.83 (m, 1), 7.71 (d, J=8.7 Hz, 1), 7.24 (m, 2), 7.19 (d, J=8.7 Hz, 1), 6.61 (d, J=16.2 Hz, 1), 6.48 (m, 1), 3.90 (m, 2).