Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28]O)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28][NH:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 70 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (737 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (745 mg, 70%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[O-].[Na+].Br[C@H:11]([CH2:15][CH3:16])[C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1.CO>[CH3:16][CH2:15][C@H:11]([N:1]1[C:2](=[O:6])[CH2:3][CH2:4][CH2:5]1)[C:12]([NH2:14])=[O:13]
Reactant: O=C1CCCN1
Reactant: CC[C@@H](Br)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine-2-one (85 mg, 1 mmol) in 6 ml of toluene is added sodium methoxide (0. 19 ml of a 30% solution in MeOH, 1 mmol, 1 equiv.). The mixture is heated to 40° C. and concentrated to dryness under reduced pressure. The solid residue is taken up in 3 ml of tetrahydrofuran, cooled to 0° C. and (R)-2-bromobutyramide (IId) (optical purity >98%) (166 mg, 1 mmol, 1 equiv.) is added. The mixture is stirred for 1 h at 0° C. and further 16 h at room temperature. The mixture is then concentrated to dryness under reduce pressure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH3:15])=[C:17]([CH3:25])[C:18]=1[CH3:24]
Reactant: COc1ccc(C(C)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)N2CCNCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice chilled solution containing 4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.4 g 1.38 mmol) and 10 ml dichloromethane, was added trifluoroacetic acid (2 ml) dropwise. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by flash chromatography on silica gel eluted, with 10% MeOH(NH3)/dichloromethane. 1-[1-(4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine was obtained as a yellow oil (0.16 g 47%). Analysis H1 NMR (400 MHz, CDCl3): 7.23 (1H, d), 6.69 (1H, d), 3.8 (3H, s), 3.55 (1H, q), 3.484 (2H, s), 2.838 (4H, m), 2.47 (2H, m), 2.38 (2H, m), 2.271 (3H, s), 2.167 (3H, s), 1.26 (3H, d). MS (LC-MS): Calculated for C15H24N2O 248.36, found 249.25 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13]C(=O)C)[CH2:10][C@H:9]1[CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:17][NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OC(C)(C)C)C1
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](S)C[C@H]1CN
Yield: 83.2 %

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (8.58 g) in a mixture of dichloromethane (26 ml) and methanol (129 ml), hydrazine hydrate (4.11 ml) is added. The mixture is heated to reflux for 2 hours and 45 minutes and filtered. The filtrate is concentrated in vacuo. The residue is dissolved in dichloromethane, washed with water, dried over sodium sulfate, and concentrated in vacuo to give crude (2S,4S)-1-t-butoxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (4.1 g). Yellow syrup.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: CN(C)CCO
Solvent: ClCCl
Product: COc1ccc(C2(OCCN(C)C)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 125 mL dichloromethane was added 3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 6.06 g (11.96 mmol), giving a suspension. N,N-dimethyl-ethanolamine 4 g (44.9 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After an hour at room temperature, additional N,N-dimethylethanolamine 2 g (22.45 mmol) was added, followed by stirring for 48 hours at room temperature. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 4 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a crude foam, 2.86 g. The crude material was purified by chromatography on 200 g silica gel eluted with 5% methanol in chloroform. The appropriate fractions were evaporated to a glassy solid, 2.0 g. The product was identified by 1H NMR, MS [M--H]+ =578 Da.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH:42][C:13](=[O:15])[C:12]5[CH:11]=[CH:10][C:9]([CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:17][CH:16]=5)=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Oc4ccc5c(c4)CCC(c4ccc(F)cc4)O5)nc3)cc2)CC1
Reaction time: 3 h

Procedure:
4-(4-Methylpiperazin-1-ylmethyl)benzoic acid (ca 0.19 g), 6-[2-(4-fluoro-phenyl)-chroman-6-yloxy]pyridin-3-ylamine (0.18 g) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.12 g) were added into dichloromethane (12 ml). The mixture was stirred at room temperature and after 4 hours more 4-(4-methylpiperazin-1-ylmethyl)-benzoic acid (ca 0.11 g) and 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide hydrochloride (0.0.46 g) were added. Stirring was continued for additional 3 hours. Water and dichloromethane were added and organic and water phases were separated. Water phase was extracted with dichloromethane. The product was purified by column chromatography using dichloromethane-methanol (9:1) as an eluent to give N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}-4-(4-methylpiperazin-1-ylmethyl)benzamide. 1H NMR (300 MHz, d6-DMSO) δ: 1.90-2.08 (m, 1H), 2.11-2.21 (m, 1H), 2.18 (s, 3H), 2.38 (bs, 8H), 2.68-2.79 (m, 1H), 2.91-3.05 (m, 1H), 3.54 (s, 2H), 5.13 (dd, 1H, J 2.0, 10.1 Hz), 6.86 (d, 2H, J 1.2 Hz), 6.90 (s, 1H), 6.98 (d, 1H, J 8.8 Hz), 7.19-7.27 (m, 2H), 7.43-7.54 (m, 4H), 7.92 (d, 2H, J 8.2 Hz), 8.18 (dd, 1H, J 2.7, 8.9 Hz), 8.48 (d, 1H, J 2.7 Hz), 10.31 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO

Procedure:
A solution of trans-2-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetra-hydrofuran (440 mg) in ethyl acetate (6 mL) was hydrogenated over 10% palladium on charcoal (120 mg) at 45 psi for 1 h. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give the title compound Rf 0.1 (hexane-ethyl acetate; 1:1, v/v); NMR (CDCl3) δ 1.07 (t, CH2CH2CH3), 3.60 (q, SO2CH2), 3.95 (q, SO2CH2CH2), 3.84 (s, OCH3), 3.88 (s, 2 OCH3), 4.11 (t, CH2CH2CH3), 5.13-5.25 (m, H-2 & H-5), 6.61 (s, 2 H, C5ArH), 7.32 & 7.49 (2 d, J=2.0 Hz, C2ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[N:12]=[CH:11]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc3c(cnn3-c3ccc(C#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 4-fluorobenzonitrile (0.11 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 4-[5-(4-Methoxy-phenoxy)-indazol-1-yl]-benzonitrile (110 miligrams) MS: 342.4 [M+H]+ and 4-[5-(4-Methoxy-phenoxy)-indazol-2-yl-]-benzonitrile (75 miligrams) MS: 342.4 [M+H]+ as colorless syrups.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[Br:35][CH2:36][C:37](Br)=[O:38].O>O1CCCC1>[C:18]([C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([N:2]([CH3:1])[C:37](=[O:38])[CH2:36][Br:35])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Br)CBr
Reactant: CNc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CBr)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Three grams of [7-[3-(methylamino)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl methanone was dissolved in 150 ml of tetrahydrofuran. The solution was stirred as 2 ml of diisopropylethylamine, and then 2.3 g of bromoacetyl bromide were added. A precipitate formed immediately. The mixture was stirred at room temperature for 18 hours. A 150 ml portion of water was then added, the mixture heated until solution occurred, and then cooled at -10° C. A precipitate of the desired compound was obtained. It was collected, washed with water, and dried at 60° C. in vacuo giving 1.7 g, mp 175°-177° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:28][CH2:29][O:30][CH3:31])=[CH:6][C:7]([O:24][CH2:25][O:26][CH3:27])=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43]Cl.[Cl-].[Na+]>CN(C)C=O>[CH:1]([C:4]1[C:5]([O:28][CH2:29][O:30][CH3:31])=[CH:6][C:7]([O:24][CH2:25][O:26][CH3:27])=[C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:12]([S:15][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(OC)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SCCCN(C)C)n1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 121.6 %

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-(4-methoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F53-04: 3.5 g, 7.9 mmol), potassium carbonate (2.6 g, 18.9 mmol) and dimethylformamide (150 mL) were placed in a 500 mL eggplant shaped flask, and then 3-dimethylaminopropyl chloride hydrochloride (1.49 g, 9.4 mmol) was added, and the mixture was stirred at 100° C. for 2 hours. A similar operation was carried out using the same amount of materials, and after the reaction was completed, the mixture was cooled, mixed with saturated sodium chloride solution (700 mL) and extracted twice with ethyl acetate. The organic layers were combined, washed 4 times with saturated sodium chloride solution (500 mL), dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (F68-01: 5.1 g, 61%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:33])([F:1])[CH2:3][CH2:4]2)=[O:9])=[CH:37][CH:36]=1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To the solution of 0.15 (0.37 mmol) (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20) in 5 ml dichloromethane. 0.13 g (0.74 mmol) copper(II) acetate, 0.17 g (1.1 mmol) 4-chlorophenylboronic acid and 0.12 ml (0.12 mg, 1.5 mmol) pyridine were added and the suspension was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give the compound as a light yellow solid (88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([Cl:19])[CH:16]=[C:15](Cl)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH:22]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:14]=[C:15]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[CH:22]3)[CH:16]=[C:17]([Cl:19])[N:18]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(Nc1nc(Cl)cc(Cl)n1)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc2[nH]cnc2c1
Product: CC(Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4,6-dichloropyrimidine and benzimidazole according to the procedure described in EXAMPLE 306, Step B.
Reaction SMILES: [C@@H:1]1([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([OH:13])[C:11]=3[N:10]=[CH:9]2)[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]1>C(O)C.O.[Pd]>[C@@H:1]1([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([OH:13])[C:11]=3[N:10]=[CH:9]2)[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Yield: 79.4 %

Procedure:
A solution of the olefin 8 (0.38 g, 1.6 mmol) in a mixture of ethanol-water (4:1) (70 ml) was hydrogenated in the presence of 10% Pd/C (0.07 g) at 50 psi for 6 h. The mixture was filtered through celite, the filtrate was concentrated, and cooled. The solid obtained was filtered and dried to yield 0.3 g (78%) of 11: mp softens at 184°-186° C., but does not melt up to 300° C.; 1H NMR (DMSO-d6) δ 1.72-2.48 (4H, m, 2' and 3'-H), 3.21-3.67 (2H, m, 5'-H), 4.17-4.38 (1H, m, 4'-H), 4.72 (1 H br s, OH, exchangeable), 6.20 (1H, dd, J=3.81 Hz, 4.1 Hz, 1'-H), 7.90 (1H, s, 8-H), 8.15 (1H, s, 2-H), 12.20 (1 H, br s, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:23][C:24]1([CH3:30])[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COC(=O)N1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OCC2(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 0.8 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), 4,4-dimethyl-oxazolidin-2-one (575 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol), and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(4,4-dimethyl-2-oxo-oxazolidine-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3 mg, 0.4%) as a light yellow oil: LC/MS m/e calcd for C23H26N2O4 (M+H)+: 395.47, observed: 395.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][N:27]=[CH:28]2>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][N:27]=[CH:28]3)[CH:7]=1
Reactant: Nc1cccc2cnccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2cnccc12)C(F)(F)F

Procedure:
Analogously to Example 20, 500 mg (1.6 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 500 mg (1.9 mmol) of 5-aminoisoquinoline in 16 ml of acetic acid are reacted to form 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(isoquinolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol and subsequently reduced with 509 mg (2.4 mmol) of sodium triacetoxy borohydride. After chromatography on silica gel with hexane-ethyl acetate (0-60%), 221 mg of product is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(NC(C)C)(C)C.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>ClCCl>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1cccs1
Reactant: COCCOCCl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCCOCOCCc1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
15.0 g of 2-thiopheneethanol was dissolved in 350 mL of dichloromethane, and 30.2 g of diisopropylamine was added thereto. The resulting mixture was cooled to 0° C. and 17.5 g of 2-methoxyethoxymethyl chloride was added thereto. The resulting mixture was stirred for 2 hours and heated to reflux for 2 hours. The reaction product solution was cooled and concentrated by evaporation under reduced pressure. To the residue, 200 mL of water and 250 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 700 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.5 g (yield of 85%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.Br[CH2:32][CH2:33][O:34][CH2:35][CH2:36]Br>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: BrCCOCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.0 g, 3.30 mmol) obtained in Example 5 was dissolved in tetrahydrofuran (70 ml). At −78° C., a hexane solution (1.57M, 5.3 ml, 8.3 mmol) of n-butyl lithium was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 10 minutes and then stirred for another 30 minutes under ice cooling. At −78° C., 2-bromoethyl ether (0.55 ml, 3.9 mmol) was added dropwise to the reaction mixture. After completion of the dropwise addition, the temperature of the reaction mixture was elevated to room temperature over 14 hours. Water (2.0 ml) was added to the reaction mixture. The residue obtained by concentrating the resulting mixture under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to yield a white solid. The resulting white solid was washed with diisopropyl ether/methylene chloride, whereby the title compound (317 mg, 26%) was obtained as a white powder.