Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[N:10]=[C:9]([C:27]#[N:28])[C:8]=2[N:7]=[CH:6]1.CN(C)C=O.[OH-].[Li+].Cl>O>[C:27]([C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:4][C:3]([OH:29])=[O:2])[C:13]=2[CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[N:10]=1)#[N:28]
Reactant: CCOc1ccc(-c2cc3c(ncn3CC(=O)OC)c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cc3c(ncn3CC(=O)O)c(C#N)n2)cc1C(F)(F)F
Yield: 94.9 %

Procedure:
To a solution of [4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]-pyridin-1-yl]-acetic acid methyl ester (110 mg, 0.27 mmol) in a 1:1 mixture of dimethylformamide (2 ml) and water (2 ml) was added lithium hydroxide (19 mg, 0.81 mmol) dissolved in 200 μL of water. An additional 2 ml of dimethylformamide was added to aid solubility. The mixture was stirred at room temperature for 30 minutes before acidification to pH 1 with 2N HCl solution and filtration. The solid obtained was washed with ether before dissolving in acetone and concentration under reduced pressure to remove residual organic solvents and afford [4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-acetic acid (100 mg). 1H NMR (DMSO): δ 8.76 (s, 1H) 8.64 (s, 1H) 8.37 (m, 3H) 7.43 (d, 1H) 5.31 (s, 2H) 4.27 (q, 2H) 1.38 (t, 3H); MS m/z 391.7 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].[CH2:13](C([SnH3])=C(CCCC)CCCC)[CH2:14]CC>O1CCOCC1.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>[F:12][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([F:8])[C:2]=1[CH:13]=[CH2:14]
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Yield: 76.5 %

Procedure:
A solution of 2-bromo-1,3-difluoro-4-nitrobenzene (0.20 g, 0.84 mmol), tributylvinylstannane (0.27 mL, 0.924 mmol) and Pd(PPh3)4 (48.6 mg, 0.042 mmol) in dioxane (4 mL) was heated at 150° C. for 1 h using microwave irradiation. The cooled reaction mixture was concentrated in vacuo, the resulting residue was purified by column chromatography (Si—PCC, eluant 2-10% EtOAc in cyclohexane) affording the title compound as a pale orange oil (0.119 g, 77%). 1H NMR (CDCl3, 300 MHz): 8.01-7.93 (1H, m), 7.03 (1H, dt, J=9.2, 1.9 Hz), 6.71 (1H, dd, J=18.0, 12.0 Hz), 6.15 (1H, d, J=18.0 Hz), 5.77 (1H, d, J=12.0 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F
Temperature: 80 °C
Yield: 76 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 116, step 8), 3-fluoro-4-methoxycarbonyl-phenylboronic acid (320 mg, [CAS Reg. No. 505083-04-5]) and dichloro(1,1′-bis(diphenyl-phosphino)ferrocene)palladium(II)dichloromethane adduct (39 mg) were dissolved in dioxane (9 mL) and water (5 mL). To the reaction mixture was added 2.0 M aqueous Na2CO3 (0.81 mL). The mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (440 mg, 76%). MS (m/e)=555.2 [(M+NH4+)+], MS (m/e)=506.1 [(M−CH3O−)+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reaction time: 1 h

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a cooled, stirred suspension of 0.69 g of sodium hydride (50% in mineral oil) in 50 ml of anhydrous dimethylformamide under nitrogen. After 1 hour at 20° C., 0.8 ml of n-butyl bromide was added. Stirring was continued for an additional 18 hours at room temperature. The reaction mixture was poured over a 10% HCl--ice mixture, then extracted three times with 250 ml ethyl acetate. The organic layer was washed five times with 200 ml water, dried and evaporated to dryness. The residue was purified on a silica column (200 g) eluting with hexane:ethyl acetate (9:1). Crystallization from acetone-hexane gave 1.52 g of N-n-butyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (mp 101°-103° C.).
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C1COCC1.CO>C1COCC1>[NH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([C:2]2([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCC#N)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
Into a 50 mL 3 neck flask with stirrer, borane-THF complex (2 mL, 1M solution) was added syringe wise to 2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile (125 mg, 0.37 mmol) in THF (10 mL) while stirring at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred overnight. 3 mL of 1:1 THF/Methanol solution was then added by syringe with severe foaming. After the foaming subsided, the solution was concentrated under reduced vacuum to yield 85 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron® and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield the intermediate title compound (35 mg) as an oil. Ion spray M.S. 341.4 (M*−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:16][CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:16][CH3:17])[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:10][C:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC1(c2ccc(Cl)cc2)CCNCC1(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1(C)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 37.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-methyl-piperidin-3-ol (206 mg, 1.24 mmol) in acetonitrile/water (4:1, 20 mL) was added potassium carbonate (171 mg, 1.24 mmol) followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (417 mg, 1.12 mmol). The mixture was stirred at rt 40 h and concentrated. The product residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (100% methylene chloride−90% methylene chloride/10% methanol gradient) to afford the titled compound (232 mg, 35%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:4]=[N:3]1.Cl[C:17]1[N:25]=[C:24]2[C:20]([N:21]=[C:22]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]3)[N:23]2[CH3:26])=[C:19]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:18]=1>>[CH3:26][N:23]1[C:22]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]2)=[N:21][C:20]2[C:24]1=[N:25][C:17]([N:11]1[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)=[N:18][C:19]=2[N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1
Reactant: Cn1nccc1-c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1nccc1-c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 319. LCMS m/z: 571.3 (MH+)
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)([O-:24])=[O:23].[BH3-]C#N.[Na+]>CO.CC(O)=O>[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](COc1ccc(C(=O)OCc2ccccc2)cc1)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a cooled (0) solution of benzyl (S)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (0.87 g, 5.76 mmol) in MeOH—AcOH (16 ml, 15:1, v/v) was added NaBH3CN (1.65 g, 26.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by sat. NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give benzyl (S)-4-[2-(2-nitrobenzylamino)-1-propoxy]benzoate (931 mg, 42%) as a yellow oil. 1H-NMR (CDCl3) δ1.21 (d, J=6.4 Hz, 3 H), 3.13-3.18 (m, 1 H), 3.88-3.97 (m, 2 H), 4.06-4.20 (m, 2 H), 5.34 (s, 2 H), 6.89-6.94 (m, 2 H), 7.29-7.65 (m, 8 H), 7.94-8.03 (m, 3 H); FAB-MAS, m/z 421 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1.[I-:24].[K+].II>C(O)C.CN.O>[CH3:1][C:2]1[C:3]([I:24])=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=1
Reactant: [I-]
Reactant: COCOc1ccc(Cc2c(C)cc(O)cc2C)cc1C(C)C
Agent: CN
Agent: II
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COCOc1ccc(Cc2c(C)cc(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (1.0 g, 3.18 mmol, G. Chiellini et al. Bioorg. Med. Chem. Lett. 2000, 10, 2607) in C2H5OH (30.0 mL) and 40% aqueous methylamine (6.20 mL) at 0° C. was added a solution of potassium iodide (2.5 g, 15.0 mmol) and iodine (0.98 g, 3.82 mmol) in H2O (6.20 mL). The reaction mixture was stirred at 0° C. for 1 h, quenched with water and extracted with ethyl acetate (2×30 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes to afford 3,5-dimethyl-2-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as white solid: 1H NMR (300 MHz, CD3OD): δ 6.93 (m, 2 H), 6.65 (m, 2 H), 5.18 (s, 2 H), 4.05 (s, 2 H), 3.48 (s, 3 H), 3.30 (m, 1 H), 2.41 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J=6.6 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:5); Rf=0.60.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][NH:7][C:6]2[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=[CH:12][C:5]=2[C:4](=[O:22])[NH:3]1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH:39][CH:40]3[CH2:42][CH2:41]3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][C:25]=1Br>>[NH2:23][C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([S:36]([NH:39][CH:40]3[CH2:42][CH2:41]3)(=[O:37])=[O:38])=[CH:34][CH:35]=2)=[CH:26][C:25]=1[C:10]1[CH:11]=[CH:12][C:5]2[C:4](=[O:22])[NH:3][C@@H:2]([CH3:1])[CH2:8][NH:7][C:6]=2[CH:9]=1
Reactant: C[C@H]1CNc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C(=O)N1
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Product: C[C@H]1CNc2cc(-c3cc(-c4ccc(S(=O)(=O)NC5CC5)cc4)cnc3N)ccc2C(=O)N1
Yield: 33 %

Procedure:
General method C was applied to (S)-3-methyl-8-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (303 mg, 0.7 mmol) and 4-(6-amino-5-bromopyridin-3-yl)-N-cyclopropylbenzenesulfonamide to give (S)-4-(6-amino-5-(3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)pyridin-3-yl)-N-cyclopropylbenzenesulfonamide as a yellow solid (180 mg, 33% yield) after purification by reverse phase preparatory HPLC. MS (EI) m/z=464.6 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[CH:15]([C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:31]3[CH2:32][CH2:33][N:28]([C:26]4[CH:27]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=[C:20]5[C:25]=4[N:24]=[CH:23][CH:22]=[CH:21]5)[CH2:29][CH2:30]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: CC(C)c1cc(N2CCNCC2)c2ncccc2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(C(C)C)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-isopropyl-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-isopropyl-8-piperazino quinoline (255 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 90 mg (20%); (M+H): 430; 1HNMR (400 MHz, CDCl3): δ 8.83˜8.12 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 8.08˜804 (dd,J1=1.8 Hz, J2=1.8 Hz, 1H), 7.75˜6.70 (m, 7H), 3.84 (s, 3H), 3.50˜2.86 (m, 12H), 2.90˜3.01 (m, 1H), 1.34˜1.33 (d, 7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH:2]=[CH2:3].I[CH2:22]I>CCOCC>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCOCCc1ccc(OCc2ccccc2)cc1
Reactant: ICI
Solvent: CCOCC
Product: c1ccc(COc2ccc(CCOCC3CC3)cc2)cc1

Procedure:
To a suspension of Zn/Cu couple (3.24 g) and dry ether (20 ml) was added to the compound of formula (7), (2 g, 0.0075 mol) in ether (10 ml) followed by the addition of diiodomethane (4.2 ml, 0.052 mol). The reaction mixture was refluxed under nitrogen atmosphere for 72 h (monitored by TLC) and filtered. The filtrate was washed with water, dried, concentrated and the residue purified by column chromatography on silica gel, eluting with light petroleum ether:ethyl acetate(2:50) to afford pure product of formula (8), as an oil 1.8 g (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCO.C1COCC1>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: ClCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 85 °C
Yield: 77.7 %

Procedure:
A mixture of 4-chlorothiobenzamide (0.5 g, 2.9 mmol) and 1,3-dichloroacetone (0.4 g, 3.18 mmol) in EtOH-THF (20 mL-10 mL) was heated to 85° C. for 10 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO3 solution. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 3-5% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g, yield 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91-7.88 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (s, 1H), 4.75 (s, 2H). MS (ESI) m/z: Calculated for C10H7Cl2NS: 242.97. found: 244.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([OH:15])[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:8]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(C)c(Cc2ccc(C=O)c(O)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (743 mg, 2.14 mmol) was dissolved in acetone (50 ml) and, after addition of anhydrous sodium carbonate (593 mg, 4.30 mmol) and benzyl bromide (477 mg, 2.79 mmol), the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered and the residue obtained by concentration of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (864 mg, 1.98 mmol, 93%).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[OH:6][CH:7]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)=[O:9].CN1CCOCC1>ClCCl>[Br:1][CH2:2][C:3]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)[C:7]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)=[O:6])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1ccc(C(=O)C(OC(=O)CBr)c2ccc(CC)cc2)cc1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of bromoacetyl chloride (2.00 mL, 24.2 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 6.5 g, 24.2 mmol) and N-methylmorpholine (NMM; 2.7 mL, 24.2 mmol) in anhydrous dichloromethane (180 mL). The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 2 hours before additional 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (0.5 mL) and NMM (0.6 mL) were added to aid in completeion. After 1 hour, the mixture was washed with saturated sodium bicarbonate solution, 1N HCl and brine. Following drying and solvent evaporation, the residue was purified by flash chromatography on silica gel (gradient elution with 10% ethyl acetate in hexanes followed by 25% ethyl acetate in hexanes) and furnished 6.10 g (65%) of bromoacetoxy-1,2-di(4-ethylphenyl)ethanone as a pal-yellow oil which was used in subsequent reactions without further purification.
Reaction SMILES: C1(CC[N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)CCCCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:29][CH2:30]Cl>O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:29][CH2:30][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36]
Reactant: COc1cc(CCCl)cc(OC)c1OC
Reactant: O=C(NC1CCN(CCC2CCCCC2)CC1)c1ccccc1
Solvent: O
Product: COc1cc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc(OC)c1OC

Procedure:
Prepared in exactly the same way as for the compound of Example 1 except that 3,4,5-trimethoxyphenethyl chloride was used in place of cyclohexylethyl bromide. The title compound was obtained as a monohydrate (1.2 g.), m.p. 193°-4° C. (Found: C, 66.7; H, 7.6; N, 6.9. C20H30N2O4. H2O requires C, 66.4; H, 7.5; N, 6.7%).
Reaction SMILES: C([NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19])=[O:8])(=O)C(C)C.[OH-:20].[K+]>>[Cl:18][C:14]1[CH:15]=[CH:16][C:17]([NH:9][C:7]([NH2:6])=[O:8])=[C:12]([CH2:11][C:10]([OH:19])=[O:20])[CH:13]=1
Reactant: [OH-]
Reactant: CC(C)C(=O)NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: [K+]
Product: NC(=O)Nc1ccc(Cl)cc1CC(=O)O

Procedure:
The title compound was prepared in 43% yield by hydrolysis of N-isobutyryl-5-chloro-2-oxindole-1-carboxamide with 1N potassium hydroxide, substantially according to the procedure of Preparation 1. After hydrolysis was complete and the reaction mixture was acidified, the product precipitated. It was recovered by filtration and recrystallized from ethanol to give the title compound as colorless crystals, m.p. 187.5° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC1CN(c2cccc(F)c2)C(=O)O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
A solution of mesylate 109 (2.89 g, 10.0 mmol) in anhydrous DMF (20 mL) was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (60 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The white precipitate was collected by filtration, washed with water (2×40 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione 110 (3.12 g, 91.8% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H13FN2O4, LCMS (EI) m/e 341 (M++H).