Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[F:13])=[O:4]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
Chloroacetyl chloride (113 g, 1.0 mole) was added dropwise to a stirred mixture of 1,3-difluorobenzene (114 g, 1.0 mole) and anhydrous aluminum chloride (146.6 g, 1.1 mole) at room temperature (20° C.). The mixture was stirred for a further five hours at 50°-55° C. Methylene chloride (48.5 ml) was added slowly as the mixture was allowed to cool to room temperature. The methylene chloride layer was separated, washed with water (2×320 ml) and the solvent removed by distillation at reduced pressure leaving a pale yellow solid (180 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[N:4]([CH2:19][C@@H:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][O:22]C(=O)C)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].N#N>O1CCOCC1.O>[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[C:3](=[O:32])[N:4]([CH2:19][C@@H:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][OH:22])[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8]
Reactant: CC(=O)OC[C@@H](Cn1c(=O)c(Br)c(C)n(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: COc1cccc(B(O)O)c1F
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](CO)c3ccccc3)c2=O)c1F
Yield: 66.8 %

Procedure:
To compound 8a (4.05 g, 8 mmol) in dioxane/water (100/50 mL) was added 2-fluoro-3-methoxyphenylboronic acid (2.04 g, 12 mmol) and Na2CO3 (5.08 g, 48 mmol). The reaction mixture was deoxygenated with N2 for 10 min, tetrakis(triphenylphosine) palladium (0) (924 mg, 0.8 mmol) was added and the reaction mixture was heated at 100° C. overnight under the protection of N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated and purified by flash chromatography (silica, 50% EtOAc/hexanes) to give compound 8b (2.73 g, 66.9%). MS (CI) m/z 511.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)=[C:7]2[CH3:27].C([Si]([O:43][C:44]([O:46][CH3:47])=[CH2:45])(C)C)(C)(C)C.C([O-])(=O)C.[Li+]>O1CCCC1>[CH3:47][O:46][C:44](=[O:43])[CH2:45][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)[C:9]([CH:12]([CH3:13])[CH3:14])=[N:10]2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c12
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 96 h

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yl ester (0.075 g), tert-butyl-(1-methoxyvinyloxy)dimethylsilane (0.063 mL), lithium acetate (0.029 g) and tetrahydrofuran (2.0 mL) was purged with argon for 30 minutes, and then treated with tetrakis(triphenylphosphine)palladium (0) (0.017 g). The mixture was stirred at 70° C. for four days, cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (10:0 to 2:8 by volume) to give title compound as pale yellow oil (0.042 g).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:28]1[CH:27]=[C:26]([CH2:25][S:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=3[CH3:15])[CH2:17][CH2:18]2)(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3cccc(Cl)c3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution {4-[1-(3-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (52.4 mg, 0.104 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (49.8 mg, 2.08 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (2.1 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum. This crude product was further purified using preparative reverse-phase HPLC to give {4-[1-(3-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (9 mg, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (br. s, 1H), 7.95-8.12 (m, 1H), 7.90 (dd, J=9.03, 6.53 Hz, 1H), 7.65-7.74 (m, 2H), 7.55 (s, 1H), 7.46 (d, J=1.00 Hz, 2H), 7.36 (t, J=9.00 Hz, 1H), 4.54 (br. s., 2H), 4.13 (dd, J=5.52, 3.51 Hz, 1H), 3.78 (br. s., 4H), 3.48-3.65 (m, 1H), 2.91-3.22 (m, 3H), 2.42 (br. s., 5H), 1.69 (m, 2H). MS cald. for C25H26ClFNO4S [(M+H)+]: 490, obsd. 490.2.
Reaction SMILES: C([O:3][C:4]([C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[N:7][N:8]=[C:9](Cl)[CH3:10])=O)C.O.[NH2:18][NH2:19]>C(O)(C)C>[NH2:18][N:19]1[C:4](=[O:3])[C:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:7][N:8]=[C:9]1[CH3:10]
Reactant: CCOC(=O)C(=NN=C(C)Cl)c1cccs1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Cc1nnc(-c2cccs2)c(=O)n1N
Reaction time: 8 h

Procedure:
234 g (0.92 mol) of crude 1-ethoxycarbonyl-4-chloro-4-methyl-1-thien-2-yl-2,3-diazabutadiene were dissolved in 600 ml of isopropanol and 125 g (2.5 mol) of hydrazine hydrate were added at 60° C., whilst stirring. Stirring was continued for 8 hours at 60° C. The reaction solution was concentrated to one-third and water was added. The solid which had precipitated was then filtered off, thoroughly rinsed with water and dried. 125g (65.3% of theory) of 4-amino-3-methyl-6-thien-2-yl-1,2,4-triazin-5-one of melting point 210° C. were obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C(Cl)Cl.C1C=CC=CC=1>[Cl:19][CH2:15][C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: ClCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 10 h
Yield: 94.1 %

Procedure:
To a suspension of 9-anthracenemethanol (50 g, 0.24 mole) in methylene chloride (50 ml), a solution of thionyl chloride (32.3 g, 0.27 mole) in benzene (300 ml) was added, and reacted with stirring for 10 hours under reflux. The reaction mixture was poured into ice-water (500 ml). An organic layer separated was washed with H2O (100 ml×3), dried over anhydrous MgSO4 and evaporated to give 51.2 g of 9-chloromethylanthracene as residual crude orange yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 67.5 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered in to this solution at a pH of 10.5 subsequently, over the course of three hours, were 95.4 g (0.5 mol) of decanoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol) and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 65 to 70° C. and then adjusted to a pH of 1.5 to 3 using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.), and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 134.1 g (91.7% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)C1C=CC=CC=1>O>[C:22]1([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(COc2ccccc2)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: O
Solvent: ClCc1ccccc1
Product: c1ccc(CN(c2ccccc2)c2ccccc2)cc1

Procedure:
N-phenylbenzaldimine (1.81 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were heated at 75° C. in Na/DMF solution (2.0 g: 50 mL) for 30 minutes. The solution was then poured in 200 mL of water, the precipitate was filtered washed with water and dried. Recrystallization from methanol, 70 mL, gave white needles (73% isolated) mp 88°-90° C. (lit mp 86°-7° C.8, 88°-9° C.9). No depression in melting point occurred when this material was admixed with an authentic sample prepared from diphenylamine and benzyl chloride.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:38])[C@@H:6]([NH2:37])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:36])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:22][CH2:21]2)[CH2:12]1)=[O:10])[CH3:3].[CH3:39][O:40][CH2:41][CH2:42][C:43](O)=[O:44].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:2]([O:4][C:5](=[O:38])[C@@H:6]([NH:37][C:43](=[O:44])[CH2:42][CH2:41][O:40][CH3:39])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:36])[CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:24][CH2:25]2)[CH2:12]1)=[O:10])[CH3:3]
Reactant: COCCC(=O)O
Reactant: CCOC(=O)[C@@H](N)CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)NC(=O)CCOC
Temperature: 0 °C

Procedure:
To a mixture of N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (1 g), 3-methoxypropionic acid (0.17 ml) and 1-hydroxybenztriazole (0.24 g) in N,N-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.33 ml) under stirring at 0° C. After stirring at ambient temperature for overnight, the mixture was poured into water and extracted with ethyl acetate. The extract washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(3-methoxypropionyl)amino-β-alanine ethyl ester (0.59 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]C)=[O:32])[C:29]2([CH3:36])[CH3:35])=[C:4]([F:39])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47]>>[CH3:35][C:29]1([CH3:36])[C@H:28]([C:8]2[N:7]([CH2:6][C:5]3[CH:37]=[CH:38][C:2]([C:44]4[CH:43]=[CH:42][C:41]([F:40])=[C:46]([F:47])[CH:45]=4)=[CH:3][C:4]=3[F:39])[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=2)[C@@H:30]1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2F)C1(C)C
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)c(F)c3)cc2F)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic methyl cis-3-[1-(4-bromo-2-fluorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylcyclopropanecarboxylate and (3,4-difluorophenyl)boronic acid in Step A. MS (ESI): mass calcd. for C36H28F3N3O3, 607.21; m/z found, 608.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.83 (d, J=8.2, 1H), 7.76-7.72 (m, 1H), 7.68 (d, J=8.5, 1H), 7.58-7.54 (m, 1H), 7.35-7.20 (m, 7H), 7.14-7.11 (m, 1H), 6.93-6.88 (m, 1H), 5.46 (d, J=17, 1H), 5.43 (s, 2H), 5.41 (d, J=17, 1H), 2.34 (d, J=8.2, 1H), 2.13 (d, J=8.2, 1H), 1.31 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Mg].II.[C:17](O)(=[O:19])C>O1CCCC1.CN(C=O)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:17]=[O:19])[CH:11]=[CH:10]2
Reactant: CC(=O)O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: II
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
To a reactor equipped with a stirrer are charged 10 grams of 2-bromo-6-methoxynaphthalene prepared as in Example 7 hereof, 1.05 grams of magnesium and 35 mL of tetrahydrofuran (THF). The reaction is initiated by addition of a crystal of iodine. After one hour of heating at reflux with stirring, 10 mL of DMF mixed with 10 mL of THF is added and the mixture is again refluxed with stirring for 1.5 hours. The reaction mixture is hydrolyzed by addition of dilute acetic acid and a precipitate of crude 6-methoxy-2-naphthaldehyde is formed. The precipitate is recovered by filtration, washed with water, and purified by crystallization from methanol.
Reaction SMILES: [CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C@@H:54]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=1>C(Cl)Cl>[CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH:53][C@@H:54]([CH2:68][C:69]3[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=3)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=3)=[O:18])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)c1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(C)c1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[butyl(methyl)amino]isoquinoline-7-carboxylic acid (130 mg, 0.5 mmol) and N,N-diisopropylethylamine (525 μL, 3.0 mmol) in methylene chloride (6.25 mL) was added HBTU (190 mg, 0.5 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (174 mg, 0.42 mmol) was added in one portion and the reaction mixture was stirred at room temperature 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1–5% methanol in chloroform) gave 1-[butyl(methyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:24])[NH:5][C:6]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][CH3:23])=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C(O)C>[CH2:18]([N:17]([C:15]1[CH:14]=[CH:13][C:12]([O:20][CH2:21][CH2:22][CH3:23])=[C:11]([C:6]2[NH:5][C:4](=[O:24])[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH3:10])[N:7]=2)[CH:16]=1)[C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH3:19]
Reactant: CCN=C=O
Reactant: CCCOc1ccc(NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccc(N(CC)C(=O)NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Yield: 79.9 %

Procedure:
The compound (0.33 g, 1 mmol) of example 195 was dissolved in ethanol (10 ml), and added with ethyl isocyanate (0.8 g, 1.1 mmol). After refluxed for 1 h, the reaction mixture was concentrated to dryness. The resultant solid was recrystallized from ethyl acetate-petroleum ether to obtain the title compound (0.32 g, yield: 80%). 1H NMR (DMSO-d6) δ: 11.81 (1H, br), 7.58 (1H, d), 7.30 (1H, dd), 7.19 (1H, d), 5.65 (1H, t), 4.07 (2H, t), 3.55 (2H, q), 3.00 (2H, m), 2.56 (2H, q), 2.46 (2H, q), 1.77 (2H, m), 1.18 (3H, t), 1.04 (3H, t), 0.99 (3H, t), 0.98 (3H, t), 0.95 (3H, t).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=O)[CH2:7][C:6]=2[CH:25]=1.Cl.O(C(C)C(N1CCN(CC2C=CC=CC=2)CC1)=O)C1C=CC=CC=1>>[O:9]([CH:8]([CH3:7])[CH2:10][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:25][CH:6]=1
Reactant: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: CC(Oc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CC(CN1CCN(Cc2ccccc2)CC1)Oc1ccccc1
Yield: 40 %

Procedure:
By carrying out the preparation as in Example 1, but replacing 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl) carbonyl]-4-benzylpiperazine with the 1-(2-phenoxypropionyl)-4-benzylpiperazine hydrochloride obtained in Example 7, the title product is obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[CH2:18][CH3:19])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:24]([NH2:25])=[C:23]([O:29][CH3:30])[CH:22]=1>C(OCC)(=O)C>[Br:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:24]([NH:25][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]4[CH2:18][CH3:19])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: CCC1CCCCN1c1cccc2nc(Cl)n(C)c12
Reactant: COc1cc(Br)cc(C)c1N
Solvent: CCOC(C)=O
Product: CCC1CCCCN1c1cccc2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Temperature: 110 °C
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-7-(2-ethyl-1-piperidinyl)-1-methyl-1H-benzimidazole (100 mg, 0.36 mmol) and 4-bromo-2-methoxy-6-methylaniline (390 mg, 1.8 mmol) was heated at 110° C. for 12 h. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate in water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with a 15% acetone/hexanes mixture to afford 49.3 mg (30%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][CH2:30][O:31][C:32]([C@@H:34](O)[CH3:35])=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:24]([C@H:21]1[CH2:20][CH2:19][C@H:18]([CH2:17][CH2:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][C@H:34]([CH3:35])[C:32]([O:31][CH2:30][CH3:29])=[O:33])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:23][CH2:22]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(-c3ccc(O)cc3)cc2)CC1
Reactant: CCOC(=O)[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(-c3ccc(O[C@H](C)C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A solution of 4 g of 4-hydroxy-4'-[4-(trans-4-pentylcyclohexyl)-1-butyl]biphenyl, 1.3 g of ethyl L(-)-lactate, 2.9 g of triphenylphosphine and 100 ml of tetrahydrofuran was treated with 1.9 g of diethyl azodicarboxylate. The reaction mixture was stirred at room temperature overnight, then concentrated and suspended with 100 ml of hot hexane. The precipitate which thereby resulted was removed by filtration and the filtrate was concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) and recrystallization from ethanol gave 2.9 g of pure ethyl 2(R)-[4'-[4-(trans-4-pentylcyclohexyl)-1-butyl]-4-biphenylyloxy]propionate with m.p. (C-SB) 71° C. and cl.p. (SB -I) 76° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: COc1cscn1
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cscn1
Temperature: 130 °C
Yield: 55.1 %

Procedure:
A mixture of 4.0 g (34.7 mmol) of 4-methoxythiazole (9), 12.8 g (68.7 mmol) of dodecanol, 0.7 g (3.7 mmol) of p-toluenesulfonic acid monohydrate, and 75 mL of toluene was heated at 130° C. for 24 hours. The mixture was cooled to room temperature and purified by flash chromatography (silica gel, 5.5×30 cm, methylene chloride). The resulting oily solid was recrystallized from 20 mL of cold pentane to give 5.15 g (55% yield) of 4-dodecyloxythiazole (10) as a colorless solid. 1H NMR (500 MHz) δ 8.58 (d, 1H, J=2.3 Hz), 6.13 (d, 1H, J=2.3 Hz), 4.13 (t, 2H, J=6.6 Hz), 1.83 (m, 2H), 1.49-1.28 (m, 18H), 0.90 (t, 3H, J=7.0).