Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:34][O:33][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCN3CCOCC3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Propyl 3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (317 mg) and morpholine (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was pufified by thin layer chromatography using chloroform-methanol to give the title compound (106 mg, yield 87%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.[C:31]([OH:40])(=[O:39])[CH:32]([CH:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33]>CN1CCCC1=O.O>[C:36]([C@@H:34]([C@H:32]([C:31]([OH:40])=[O:39])[OH:33])[OH:35])([OH:38])=[O:37].[C:36]([C@@H:34]([C@H:32]([C:31]([OH:40])=[O:39])[OH:33])[OH:35])([OH:38])=[O:37].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
An alternative synthesis of the title compound. 2-(Chloromethyl)benzimidazole (11.95 g, 71.7 mmol) in 50 mL of N-methylpyrrolidone was treated with 1-(2-pyridyl)piperazine (12.88 g, 78.9 mmol) at 0° C. After one hour, the mixture was treated with triethylamine (7.98 g, 78.9 mmol) and allowed to warm to room temperature. After stirring for 22 hours, the mixture was treated with (L) tartaric acid (24.8 g, 165 mmol) in 50 mL of water. After addition was complete, the mixture was heated at 80° C. for one hour and then allowed to cool to room temperature. The mixture was filtered and the solids were washed with 100 mL of ethanol. The obtained solid was dried under reduced pressure to provide 38.1 g of the title compound as a solid. Elemental analysis calc'd for C25H31N5O12: C 50.59; H, 5.26; N, 11.80; O, 32.35. Found: C, 50.48; H, 5.27; N, 11.78; O, 32.41. DSC: sharp endotherm at 206° C.
Reaction SMILES: [Cl-].[NH4+].ClCCl.[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Cl[C:15]([CH3:23])([CH2:17][CH2:18][C:19](Cl)([CH3:21])[CH3:20])[CH3:16]>O>[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[C:10]2[C:15]([CH3:23])([CH3:16])[CH2:17][CH2:18][C:19]([CH3:21])([CH3:20])[C:11]=2[CH:12]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Temperature: 25 °C

Procedure:
13.40 g (100.0 mmol) of ammonium chloride and 100 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. A solution composed of 34.60 g (199.0 mmol) of 3-bromophenol, 89.00 g (486.0 mmol) of 2,5-dichloro-2,5-dimethylhexane and 300 ml of dichloromethane is added dropwise. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane, the extract is washed with water and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 80% heptane and 20% dichloromethane. After evaporating the solvents, 30.00 g (53%) of the expected compound are collected in the form of white crystals with a melting point of 93° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[CH2:18][C@@H:17]([OH:19])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[CH2:18][C:17](=[O:19])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2C[C@H](O)C[C@@H]12
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC(=O)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of 2-chloro-4-((3S,3aS,5R)-5-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (50 mg, 0.143 mmol) in DCM (5 mL) at 0° C. was added Dessmartin reagent (121 mg, 0.286 mmol) and reaction mixture was stirred at room temperature for 16 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate, water and extracted. Organic layer was washed with saturated NaHCO3 solution, water, and brine then dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 1% MeOH in DCM) provided the title compound (36 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH:37]1([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>[OH-].[Na+].C(#N)C>[CH:44]1([NH:43][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1.[C:27]1([S:33]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Yield: 73.2 %

Procedure:
Nε -benzyloxycarbonyl-L-lysine (8.41 g, 30 mmole) was dissolved in 1N aqueous sodium hydroxide (30 ml), and dioxane (10 ml) solution of benzene sulfonyl chloride (5 30 g, 30 mmole) was added dropwise to the solution while keeping the pH value thereof to between 10 and 11 with 1N aqueous sodium hydroxide while cooling with ice and stirring. The mixture was further stirred for 1.5 hours at room temperature and then insoluble matter was removed by filtration. The filtrate was washed with two 100 ml portions of diethyl ether. To the water layer, ethyl acetate (150 ml) was added and the solution was adjusted to pH 1.5 with 1N aqueous hydrochloric acid under vigorous stirring. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the oily residue thus obtained was dissolved in acetonitrile (200 ml), and then dicyclohexylamine (5.43 g, 30 mmole) was added thereto with stirring, and thereby Nα -benzenesulfonyl-Nε -benzyloxycarbonyl-L-lysine dicyclohexylamine salt (13.21 g, 73.2%) was obtained.
Reaction SMILES: [Mg].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH2:14]C)=[O:12].[OH-].[NH4+]>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Mg]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1Cc2ccccc2N1
Temperature: 0 °C

Procedure:
Magnesium turnings (3.60 g) are added to a mixture of ethyl indole-2-carboxylate (I, Aldrich Chemical, 13.963 g) in methanol (200 ml). After evolution of gas has started, the mixture is placed in an ice bath and the temperature kept below 45°. After 4.5 hours all of the magnesium is used up and the temperature is 7°. At this time the mixture is added to ice cold hydrochloric acid (3N, 120 ml). The acidic mixture is then made alkaline (pH 10) with ammonium hydroxide (3N). The mixture is then extracted with methylene chloride (3 x). The combined organic layers are dried over magnesium sulfate and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([Cl:27])=[N:21][C:22]([C:23]([O:25]C)=[O:24])=[C:11]2[CH2:10][N:9]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([Cl:27])=[N:21][C:22]([C:23]([OH:25])=[O:24])=[C:11]2[CH2:10][N:9]=1
Reactant: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A solution of 2 g (0.005 mole) of 6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester 0.7 g (0.012 mole) of potassium hydroxide, 60 ml of methanol and 2 ml of water was refluxed under argon for 2.5 hrs. The solution was evaporated in vacuo at 50°-60°. An aqueous solution of the residue was acidified with acetic acid to give a gelatinous, white precipitate. The precipitate was collected by filtration, washed with water and air dried on the funnel overnight to give off-white solid. Recrystallization from a solution of ethanol and methylene chloride gave white plates with mp 250°-253° (dec).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[OH:19])(=[O:8])=[O:7].[H][H]>[Pd]>[CH3:23][O:22][CH2:21][CH2:20][N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=1[OH:19])(=[O:7])=[O:8]
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 87.5 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N,N-di-(2-methoxyethyl)-6chloro-2-hydroxy-3-nitrobenzenesulfonamide (100 mg, 0.27mmol) was reduced with hydrogen and 10% Pd/C (50 mg) to form the desired product (80 mg, 87%). 1H NMR (MeOD-d4): δ 6.85 (m, 2H), 3.58 (t, 4H), 3.47 (t, 4H), 3.21 (s, 6H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[O:8][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.CO.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>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[O:6][C:5]([C:7]3[O:8][C:9]([C:12]4[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(-c2ccc(-c3ccc(Br)o3)o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccc(-c4ccc(C#N)cc4)o3)o2)cc1
Temperature: 80 °C
Yield: 52 %

Procedure:
Method (i): Referring now to Scheme 4, to a stirred solution of 4 (1.256 g, 4 mmol), and tetrakis(triphenylphosphine)palladium (230 mg) in toluene (8 mL) under a nitrogen atmosphere was added 4 mL of a 2 M aqueous solution of Na2CO3 followed by 4-cyanophenyl boronic acid (658 mg, 4.8 mmol) in 4 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 24 h, then cooled, and the precipitate was filtered. The precipitate was partitioned between methylene chloride (250 mL) and 2 M aqueous Na2CO3 (20 mL) containing 2.4 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 15 in 52% yield; mp 298-299° C. (DMF). 1H NMR (DMSO-d6); δ 7.09 (d, J=3.6 Hz, 2H), 7.39 (d, J=3.6 Hz, 2H), 7.89 (d, J=8.1 Hz, 4H), 7.97 (d, J=8.1 Hz, 4H). 13C NMR; δ 151.1, 145.8, 133.3, 132.7, 123.8, 118.6, 111.4, 109.45, 109.40. MS (m/z, rel.int.); 336 (M+, 100), 307 (5), 279 (5), 206 (15), 168 (15). High resolution calcd for C22H12N2O2 ms 336.08988. Observed 336.08978. Calcd for C22H12N2O2-0.75H2O: C, 75.52; H, 3.86; N, 8.00. Found. C, 75.12; H, 3.48; N, 7.74
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1=C(N(C)c2ccc(F)cc2)OCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.5 %

Procedure:
A solution of ethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, potassium carbonate (0.063 g, 0.45 mmol) and methyliodide (0.026 mL, 0.42 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water then extracted with ethyl acetate for 3 times. The organic layer was dried over sodium sulfate and concentrated to afford ethyl 2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.13 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:3][CH2:4][O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]CCCCCC[Si](C)(C)O[Si](C)(C)C.CC(CCC=C(C)C)CCOC(=O)CCCCCCCCC=C.[CH3:55][SiH:56]([CH3:62])[O:57][Si:58]([CH3:61])([CH3:60])[CH3:59]>>[CH3:1][CH:2]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[CH2:3][CH2:4][O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][Si:56]([CH3:62])([CH3:55])[O:57][Si:58]([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)=CCCC(C)CCOC(=O)CCCCCCCCCC[Si](C)(C)O[Si](C)(C)C
Reactant: C[SiH](C)O[Si](C)(C)C
Agent: C=CCCCCCCCCC(=O)OCCC(C)CCC=C(C)C
Product: CC(C)=CCCC(C)CCOC(=O)CCCC[Si](C)(C)O[Si](C)(C)C

Procedure:
According to the same procedure, 11-(1,1,3,3,3-pentamethyl-disiloxanyl)-undecanoic acid 3,7-dimethyl-oct-6-enyl ester was prepared from undec-10-enoic acid 3,7-dimethyl-oct-6-enyl ester and pentamethyldisiloxane.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:19])([CH3:18])[CH2:10][N:11]1[CH:15]=[C:14](I)[N:13]=[C:12]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26]>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:19])([CH3:18])[CH2:10][N:11]1[CH:15]=[C:14]([Sn:25]([CH3:27])([CH3:26])[CH3:24])[N:13]=[C:12]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(I)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: C[Sn](C)(C)Cl
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1nc([Sn](C)(C)C)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 26.8 %

Procedure:
To a mixture of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-2-methyl-1H-imidazole (1.5 g, 3.8 mmol) in DCM (15 mL) was added ethylmagnesium bromide (1.9 mL, 3 mol/L, 5.7 mmol) at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride (6.5 ml, 1 mol/L, 6.5 mmol) was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM, The organic was washed with water twice, dried over anhydrous Na2SO4, concentrated to give 0.44 g of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole. Yield=63%. 1H NMR (CDCl3, 400 MHz): δ 7.04 (s, 1H, ArH), 3.74 (s, 2H), 2.43 (s, 3H), 1.24-1.20 (m, 6H), 0.88 (s, 9H), 0.29 (s, 6H), 0.03 (s, 8H). LC-MS: m/z=375 [M+H+]
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]([CH:21]1[CH2:26][CH2:25][CH:24](C2CCC(=O)CC2)[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].Cl>C1COCC1>[CH2:17]([CH:21]1[CH2:26][CH2:25][CH:24]([C:12]2[C:11]([C:10]3([OH:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC1CCC(c2cccc(OCc3ccccc3)c2C2(O)CCCCC2)CC1
Reaction time: 12 h

Procedure:
To the Grignard reagent which was prepared from 2.31 g (95.1 mmol) of dried magnesium and 25.0 g (95.0 mmol) of 4-benzyloxy-bromobenzene in 300 ml of THF, was added dropwise 100 ml of solution of 21.0 g (88.8 mmol) of 4-(4-n-butylcyclohexyl)-cyclohexanone in THF at room temperature, and the mixture was stirred at the same temperature for 12 hours. The reaction solution was added to 500 ml of 0.5N hydrochloric acid, the product thus formed was extracted with ether, the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: toluene), the solvent was distilled off, and the residue was recrystallized from toluene to give 11.8 g (28.1 mmol) of 4-(4-(4-n-butyl-cyclohexyl(-1-hydroxycyclohexyl)-1-benzyloxybenzene. Yield of this compound based on 4-(4-n-butylcyclohexyl)cyclohexanone was 31.6%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C[Al](C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38](OC)=[O:39])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:39])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: COCCN
Agent: C[Al](C)C
Product: COCCNC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 66.2 %

Procedure:
Following the general procedure outlined in Example 193, 2-methoxy-ethylamine (0.17 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (200 mg, 0.44 mmol) were reacted to give the desired product 145 mg (66%). LC-MS: 498.2 (MH+, m/z), 1.90 (Rt, min).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)([O-])=O.[C:12](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][NH:37]2)=[CH:33][CH:32]=1>ClCCl>[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][NH:36][N:37]2[C:5]3[CH:6]=[CH:7][CH:10]=[CH:11][C:4]=3[N:1]=[CH:12]2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc2cn[nH]c2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc(CNn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To the solution of 0.145 g (0.98 mmol) of 4-nitrobenzaldehyde in 3 ml of dichloromethane was added 0.31 g (1.47 mmol) of sodium triacetoxyborohydride, 0.6 ml (0.98 mmol) of acetic acid and 0.13 g (0.98 mmol) of 6-aminoindazole. After stirring the mixture overnight at room temperature, the solvent was evaporated. The resulting residue was dissolved in 10 ml of ethanol, 20 mg of 10% palladium on carbon was added and stirred under hydrogen atmosphere overnight. The catalyst was filtered off through celite. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 0.2 g (86%) of the title compound. 1H-NMR (CDCl3) δ: 4.12 (2H,br), 6.50–6.70 (5H, m), 7.52 (1H, d), 7.86–7.94 (2H, m), 8.18 (1H, br), 8.29 (1H, br).
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
3.1 g (6.7 mmol) of ethyl 2-{3′-[(tert-butoxycarbonylmethylamino)-methyl]biphenyl-4-yloxy}benzoate are placed in 50 ml of dichloromethane and 2.6 ml of trifluoroacetic acid. After stirring at room temperature for 8 hours, the reaction medium is concentrated, placed in water, brought to pH 8 with aqueous 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 2.3 g of ethyl 2-(3′-methylaminomethylbiphenyl-4-yloxy)benzoate are obtained in the form of an orange-colored oil, in a yield of 95%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].N[C:19]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1C.O.[CH3:34][N:35](C)C=O>>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:35][CH2:34][C:19]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:17])[CH3:16]
Reactant: CC1CCCCC1(N)Nc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
340 mg (1.34 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide (obtained in Example 3/c) are added to 270 mg (1.32 mmol) of (1-amino-methylcyclohexyl)phenylamine (obtained in Example 2/b) in 10 ml of dimethylformamide. The reaction medium is stirred at 100° C. under microwave irradiation for 30 min. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water and then dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20, v/v). 396 mg of N-(2,6-diisopropylphenyl)-2-[(1-phenylaminocyclohexylmethyl)-amino]acetamide are obtained in the form of a white solid. M.p. 104-6° C., yield=71%.