Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: COc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (112 mg, 1.19 mmol) was added in one charge to a stirred solution of 5-bromo-2-({[4-(methyloxy)phenyl]methyl}oxy)benzoic acid (may be prepared as described in Description 18; 200 mg, 0.59 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg, 0.71 mmol) and 1-Hydroxybenzotriazole (96 mg, 0.71 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 200 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[Cl:29]C1C=C2C(=CC=1)NC(=O)C2>>[Cl:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:28])/[C:19]/2=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)cc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (Example A57), except substituting 5-chlorooxindole (14 mg, 0.08 mmol), the title compound was prepared as an orange solid (13.5 mg, 42%). 1H NMR (400 MHz, d6-DMSO) δ 13.63 (br s, 1H), 10.78 (br. s, 1H), 8.56 (d, J=4.0 Hz, 2H), 8.40 (d, J=10.0 Hz, 1H), 7.91 (s, 1H), 7.89 (d, J=13.2 Hz, 2H), 7.72 (d, J=3.5 Hz, 2H), 7.57 (d, J=12.0 Hz, 1H), 7.52 (d, J=12.0 Hz, 2H), 7.30 (d, J=10.0 Hz, 1H), 6.90 (d, J=11.5 Hz, 1H); MS ESI 399.2 [M+H]+, calcd for [C23H15ClN4O+H]+ 399.09.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=NO)c1ccccc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
329 mg (1.0 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 149 mg (1.1 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 235 mg (55% of theory)
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C@@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41](O)=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CS(N)(=O)=O>CN(C)C=O>[CH2:10]([C@@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([NH:9][S:6]([CH:3]4[CH2:5][CH2:4]4)(=[O:8])=[O:7])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (301 mg, 7.5 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (930 mg, 7.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 0.77 mmol) and 1,1′-carbonyldiimidazole (310 mg, 1.9 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. 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% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (86 mg, 20%) as a white solid: LC/MS m/e calcd for C31H33N3O5S (M+H)+: 560.65, observed: 560.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
2-(4-Bromophenyl)acetic acid (20 g, 93 mmol), tert-butyl carbazate (14.7 g, 111 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.4 g, 112 mmol) and 1-hydroxybenzotriazole monohydrate (17.1 g, 112 mmol) were dissolved in dichloromethane (400 ml), and N,N-diisopropylethylamine (80 ml) was added. After stirring at room temperature for 16 hrs, the reaction mixture was washed with 1M hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (dichloromethane:methanol=99:1→90:10) to give tert-butyl 2-[(4-bromophenyl)acetyl]hydrazinecarboxylate (27 g, yield 88%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:13]1C=CN=C1)=O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
Using the method of Example 6, a solution of 2.81 g of phenylacetic acid in 200 ml of methylene chloride is treated at 0° C. with 3.35 g of carbonyldiimidazole. The mixture is stirred for 40 minutes. Then 2.86 g (0.0159 mole) of the (±)-amine from Example 1, Part C, above is added. The mixture is stirred for 24 hr and partitioned with saturated aqueous sodium bicarbonate. The organic phase is dried and concentrated to yield the titled (±)-benzeneacetamide product free base which is dissolved in a minimum volume of methanol and treated with one equivalent of maleic acid which has been dissolved in a minimum volume of methanol, and the mixture is diluted with diethyl ether to give the titled maleate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=[CH:24][C:23]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1cccnc1Nc1ccc(Cl)c(Cl)c1
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)c2cccnc2Nc2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 1-(2-(3,4-dichlorophenylamino)pyridin-3-yl)ethanone (100 mg, 0.355 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (68.67 mg, 0.355 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7g) (137 mg, 84% yield).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:21]([O:20][C:18](=[O:19])[NH:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)NC1CCNCC1
Reaction time: 2 h

Procedure:
To a solution of 1.8 g 4-butoxycarbonylamino-piperidine-1-carboxylic acid benzyl ester in 60 ml EtOH were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 2 h. The reaction mixture was filtrated over a plug of Celite and washed with EtOH to give the product as colorless oil after evaporation of the solvent.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1.Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1.CN(C)C=O.[H-].[Na+]>O>[C:31]([C:30]1[C:25]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:23])=[C:14]([O:21][CH3:22])[CH:15]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)#[N:32]
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxyphenyl]methanol (5.00 g), 2-chloro-3-cyanopyridine (2.65 g) and N,N-dimethylformamide (150 mL) was added sodium hydride (60%, oil, 0.70 g) at room temperature and the mixture was stirred for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give crystals (6.60 g, yield 99%) of 3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[C:12]#[N:13].C[O-].[Na+].CN(C)[CH:20]=[O:21]>CO>[C:12]([C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH3:14])=[N:3][C:2]=1[O:21][CH3:20])#[N:13]
Reactant: Cc1nc(Cl)c(C#N)c2c1CCCC2
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)c2c(c1C#N)CCCC2

Procedure:
3-Chloro-4-cyano-1-methyl-5,6,7,8-tetrahydroisoquinoline (10.0 g) was refluxed with sodium methoxide (1.1 equiv) in a mixture of methanol (150 ml) and anhydrous dimethylformamide (20 ml) for 24 hr. The bulk of the solvent was evaporated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ether. The dried (mgSO4) organic fraction was evaporated and the residue was purified by column chromatography over silica gel with dichloromethane elution to give 4-cyano-3-methoxy-1-methyl-5,6,7,8-tetrahydroisoquinoline as white crystals, mp 116° C. Pmr spectrum (CDCl3 ; δ in ppm): 1.81 (4H,m); 2.39 (3H,s); 2.50-2.94 (4H,m); 3.98 (3H,s).
Reaction SMILES: [CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]C)=[O:5].[ClH:20]>O1CCOCC1>[ClH:20].[CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CN(C)Cc1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CC(=O)O)Cc1ccc(NS(C)(=O)=O)cc1
Yield: 100 %

Procedure:
A solution of methyl 2-(methyl(4-(methylsulfonamido)benzyl)amino)acetate (0.977 g, 3.41 mmol) and HCl 6N (14.22 ml, 85 mmol) in dioxane (100 ml) was heated at 70° C. overnight. The solvent was removed and crude 2-(methyl(4-(methylsulfonamido)-benzyl)amino)acetic acid hydrochloride was obtained (1.054 g, 3.41 mmol, 100% yield, MS/ESI+ 273.1 [MH]+) and used in the next step without further purification.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:14]1([CH2:24][CH2:25]O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:24][CH2:25][O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: OCCc1cccc2ccccc12
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1cccc2ccccc12

Procedure:
Reaction of caffeic acid and 2-(1-naphthyl)ethanol as outlined in method A except that the reaction time was increased to 6 days, provided product 67H-148-A as a snow-white solid in 21% overall yield: mp 165°-168° C.; 1H NMR (DMSO-d6) δ:8.21 (d, 1H, J=8.1 Hz), 7.97-7.94 (m, 1H), 7.84 (t, 1H, J=5 Hz), 7.64-7.39 (m, 5H), 7.03 (d, 1H, J=1.8 Hz), 6.99 (dd, 1H, J=1.8 Hz & 8.1 Hz), 6.23 (d, 1H, J=15.9 Hz), 4.44 (t, 2H, J=7.0 Hz), 3.45 (t, 2H, J=7.0 Hz); FABMS (NBA, -VE) m/z 333 (M--H). Anal. (C21H18O4.1/4H2O) C, H.
Reaction SMILES: C(O[C:4](=O)[C@@H:5](OC)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OCC(O)=O)=[CH:9][CH:8]=1)C.[CH2:21]([O:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C@@H:36]([C:38](=[O:55])[NH:39][CH2:40][CH2:41]C2C=CC(OC3C=CC=CC=3)=CC=2)C)=[CH:31][CH:30]=1)[C:25]([OH:27])=[O:26])C>>[C:7]1([CH:6]([C:5]2[CH:4]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:41][CH2:40][NH:39][C:38]([CH2:36][O:35][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:24]([O:23][CH3:21])[C:25]([OH:27])=[O:26])=[CH:34][CH:33]=2)=[O:55])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCC(c2ccccc2)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3,3-eiphenyl-propylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C27H29NO5 [M+H]+: 448.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-])=[O:10])=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)[O-])cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(CO)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a cooled (−78° C.) solution of 4-isopropoxy-3-(trifluoromethyl)benzoate (13.1 mmol) in DCM (85 mL) under nitrogen was added 2.0 M solution of LAH (19.0 mmol) by a syringe. The reaction was allowed to return to room temperature and stirred for 16 h. The reaction was cooled to 0° C. and quenched with water (0.95 mL) and 10% NaOH (aq) (1.90 mL). The mixture was filtered through Celite®. The filtrate was concentrated under vacuum to give the title compound as an oil (11.27 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.06 Hz, 6H), 4.46 (d, J=5.81 Hz, 2H), 4.75 (septet, J=6.02 Hz, 1H), 5.20 (t, J=5.75 Hz, 1H), 7.23 (d, J=8.46 Hz, 1H), 7.47-7.56 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.C(OC1C=CC(C=CC(Cl)=O)=CC=1)C.O.O.O.O.O.O.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.Br>O1CCCC1.C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:12])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Reactant: C1CNCCN1
Agent: Br
Agent: CCOc1ccc(C=CC(=O)Cl)cc1
Solvent: O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(C=CC(=O)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
From 11.52 g. of 4-ethoxycinnamic acid and 10.71 g. of thionylchloride was prepared 4-ethoxycinnamoyl chloride, a solution of which in tetrahydrofuran was added gradually to a solution of 23.4 g. of piperazine hexahydrate, 20.67 g. of 47% hydrobromic acid and 90 ml. of ethanol. The resulting mixture was stirred overnight at room temperature and cooled with ice, the forming crystals being filtered off. The filtrate was condensed and treated just as in Reference example 1 to obtain 11.23 g. of the desired product (72% yield). The product was treated with concentrated hydrochloric acid to give the corresponding hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].[C:30]([N:38]=[C:39]=[S:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([NH:38][C:30](=[O:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[S:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2nc3cc(NC(=S)NC(=O)c4ccccc4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (377 mg, 0.950 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Anhydrous tetrahydrofuran (10 mL) added followed by dropwise addition of benzoyl isothiocyanate (178 mg, 1.093 mmol) and mixture stirred under Ar at ambient temperature for 3 hours then allowed to stand overnight at room temperature. 3-(Dimethylamino)propyl functionalized silica gel (205 mg, 0.286 mmol) added and mixture stirred for 1 hour, filtered and concentrated to yield crude. The product was purified using silica gel column chromatography eluting with 2.5% 2M NH3 in methanol/97.5% dichloromethane to afford a pale yellow oil. Trituration with diethyl ether/hexanes yielded an off white solid 20 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]-imidazol-5-ylcarbamothioyl)benzamide. Yield: 160 mg (31.7%) 1H NMR (DMSO) δ: 0.80 (t, 6H, J=7.0), 1.30 (t, 3H, J=7.0), 2.34-2.50 (2×m, 6H), 3.98 (q, 2H, J=7.0), 4.16 (t, 2H, J=6.3), 4.27 (s, 2H), 6.87 (d, 2H, J=8.4), 7.18 (d, 2H, J=8.5), 7.34 (d, 1H, J=8.4), 7.44-7.59 (2×m, 3H), 7.62-7.69 (m, 1H), 7.94-8.03 (2×m, 3H), 11.48 (br s, 1H), 12.60 (br s, 1H). MS (ESI): 530 (MH+, 100%)
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:24])=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>FC(C1C=CC=CC=1)(F)F>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH3:24])=[C:16]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:17]=2)[CH:14]=1
Reactant: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)c(C)n3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)C2CC2)nc2ccc(O)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.1 %

Procedure:
To a solution of N-{6-[(4-methoxybenzyl)oxy]-3-methylimidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (700 mg, 1.99 mmol) and anisole (1.73 mL, 15.9 mmol) in trifluoromethylbenzene (7 mL) was added trifluoroacetic acid (1.4 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (65 mg, 14%) as a slightly-yellow solid.
Reaction SMILES: C([Li])CCC.[Li].C(Br)CCC.[CH3:12][O:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.CN(C)CCN(C)C.[F:28][C:29]([F:45])([F:44])[C:30]1[CH:43]=[CH:42][C:33]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1.C(=O)=O>O.O1CCCC1.C(OCC)C>[CH3:12][O:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:45])([F:44])[F:28])=[CH:43][CH:42]=1)[OH:35]
Reactant: O=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]
Solvent: CCCCBr
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A butyllithium solution, prepared from 1.02 g. (0.145 g. at.) of lithium and 7.9 g. (0.058 mol) of butyl bromide in 70 ml. of anhydrous diethyl ether, was added drop-wise at -60° C. to -65° C. under a nitrogen atmosphere to a solution of 4.9 g. (0.044 mol) of 1-(methoxymethyl)imidazole and 3.1 g. (0.044 mol) of N,N,N',N'-tetramethylethylenediamine in 125 ml. of anhydrous tetrahydrofuran. The reaction mixture was kept standing for 2 hours at -60° to -65° C. and then 11 g. (0.044 mol) of 4-(trifluoromethyl)benzophenone, dissolved in 75 ml. of anhydrous tetrahydrofuran, were added drop-wise. The temperature was maintained at -65° C. for one hour and then the reaction mixture was allowed to attain room temperature overnight. 10 ml. of water and solid carbon dioxide were added and the solvent was distilled off. The residue was dissolved in dilute hydrochloric acid, the solution was washed with diethyl ether and made alkaline with potassium carbonate. The solid substance formed was filtered off and dissolved in chloroform. The solution was washed with water, dried over sodium sulphate and concentrated by evaporation of the solvent. The residue was crystallised from isopropyl alcohol. 1-(Methoxymethyl)-α-phenyl-α-(p-trifluoromethyl-phenyl)imidazole-2-methanol was obtained. Melting point 158°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](Cl)=[O:12].[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:12])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)c1c[nH]c2ccc(F)cc12
Reactant: CCCCN1CCC(CN)CC1
Product: CCCCN1CCC(CNC(=O)c2c[nH]c3ccc(F)cc23)CC1
Yield: 64 %

Procedure:
5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methylamine (Description 1a) as in the method of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 5-fluoroindole-3-carboxamide as an off-white solid (64%).