Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]3[CH3:19])=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[C:36]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:14]([CH3:19])[CH2:15]2)=[O:37])=[CH:41][CH:42]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (41 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (60 mg, 88%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 7.23-7.01 (m, 4H), 5.40-5.15 (m, 1H), 4.85-4.60 (m, 1H), 4.46-4.30 (m, 1H), 4.20-4.00 (m, 1H), 3.82-3.60 (m, 1H), 3.40 (m, 1H), 3.00-2.70 (m, 2H), 2.28 (m, 1H), 1.70 (m, 1H), 1.40 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +514.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]([CH:14]=[CH2:15])=[CH2:13]>>[CH3:11][C:12]1[CH2:13][CH:8]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:10])[O:9][CH2:15][CH:14]=1
Reactant: C=CC(=C)C
Reactant: CC(C=O)c1ccccc1
Product: CC1=CCOC(C(C)c2ccccc2)C1
Yield: 13.3 %

Procedure:
4-Methyl-2-(1-phenylethyl)-3,6-dihydro-2H-pyran was prepared similarly according to EXAMPLE I using 2-phenylpropanal (500 g, 3.72 mol) and 2-methyl-1,3-butadiene (279 g, 4.1 mol). 4-Methyl-2-(1-phenylethyl)-3,6-dihydro-2H-pyran (100 g) was obtained with a boiling point of 115-116° C. at 3 mmHg.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24](Cl)[S:25][C:21]=2[CH:20]=1>C1COCC1.O>[Br:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[S:25][C:21]=2[CH:20]=1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (590 mg, 2.79 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 142 mg, 3.55 mmol) followed by 6-bromo-2-chlorobenzo[d]thiazole (631 mg, 2.54 mmol). The reaction mixture was stirred at 60° C. for 4 h. The mixture was cooled to rt, diluted with water (40 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol, 65% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:30][CH2:29][CH2:28][Br:27])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: BrCCCBr
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)[nH]c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc(-c3ccc[nH]3)n(CCCBr)c2-c2ccc(OC)cc2)cc1

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(2-pyrrolyl)-1-(3-bromopropyl)imidazole is prepared analogously to Example 22 by reacting 4,5-bis(4-methoxyphenyl)-2-(2-pyrrolyl)imidazole with 1,3-dibromopropane. Melting point 97° C.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:15])[N:6]=1)[NH2:4].C(N(CC)CC)C.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=O>C(O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[N:4][NH:3][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([CH3:15])[N:6]=2)[CH3:23])=[CH:27][CH:28]=1
Reactant: Cc1nc(NN)c2ccccc2n1
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C(C)=NNc2nc(C)nc3ccccc23)cc1
Yield: 40.8 %

Procedure:
To a solution of 4-hydrazino-2-methylquinazoline dihydrochloride (100 mg, 0.40 mmol) and triethylamine (0.14 mL, 0.81 mmol) in ethanol (3 mL) was added 61 mg (0.4 mmol) of 4-methoxyacetophenone. The resultant solution was refluxed overnight and the resultant reaction mixture was absorbed directly on Si gel. Purification by automated Si gel chromatography (gradient 100% hexanes to 100% ethyl acetate) on the Flashmaster II was performed yielding 50 mg (36%) of the titled compound as a bright yellow solid. HPLC Purity: 91%.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([C:12](=O)[CH3:13])[CH:11]=1)(=O)C.[CH3:21][C:22]([S@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH:12]([NH:27][S@@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])[CH3:13])[CH:9]=[N:8][C:7]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: CC(=O)OCc1cc(C(C)=O)cnc1OCC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(CO)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (0.11 g, colorless oil) from (5-acetyl-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl acetate (0.16 g, 0.55 mmol, Step-7) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 460 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](/[CH:9]=C/C(OC)=O)=[C:4]([Cl:15])[CH:3]=1.[O:16]=[O+][O-].CSC>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:16])=[C:4]([Cl:15])[CH:3]=1
Reactant: O=[O+][O-]
Reactant: COC(=O)/C=C/c1c(Cl)cc(Br)cc1Cl
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1c(Cl)cc(Br)cc1Cl

Procedure:
4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 mL), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:32])[CH2:24][C:25]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:26])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>CN(C=O)C>[CH3:33][S:34]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:32])[CH2:24][C:25](=[O:26])[N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:36])=[O:35]
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCOS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
For the preparation of the starting material Compound I-90, please refer to Example 107. A 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of 2-[(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (100 mg, 0.22 mmol, 1.00 equiv) in 5 mL of distilled DMF. MsCl (38 mg, 0.33 mmol, 1.50 equiv) and triethylamine (66.7 mg, 0.66 mmol, 3.00 equiv) were added at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched with water, extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with DCM/MeOH (20:1 to 10:1) to give 2-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (107 mg) as a white solid. MS (ES): m/z 537 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[NH:9][C:10](=[O:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)=O>C(O)(=O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]1[N:7]=[C:8]2[NH:9][C:10](=[O:17])[CH2:11][CH:12]=[C:13]2[N:14]=1
Reactant: COc1cc(SC)ccc1C(=O)Nc1[nH]c(=O)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(SC)ccc1C1=NC2=CCC(=O)NC2=N1

Procedure:
An amount of 6.2 gm of 2-[(2-methoxy-4-methylmercapto-benzoyl)-amino]-3-nitro-1H-pyridin-6-one is dissolved in 370 ml of glacial acetic acid and hydrogenated with hydrogen in the presence of 6 gm of 10% palladium charcoal at ambient temperature under 5 bars of pressure (duration of reaction: two hours). The catalyst is filtered off, and the filtrate is refluxed for about 1.5 hours with stirring. Then, about 250 ml of the solvent is evaporated off, and the remaining solution is poured onto ice water and neutralized with ammonia. The precipitate obtained is recrystallized from methanol. Another fraction can be obtained by evaporating the mother liquors of crystallization and triturating the residue with ether:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[O:26][CH3:25])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: COc1ccccc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccccc1OC

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-methoxyphenyl)carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-methoxybenzoic acid using the general procedure described in example 3. HR MS: Obs. mass. 501.0984. Calcd. mass. 501.0984 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:18])[CH3:2].[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH2:6][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:22]1[CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CCOC(CCNc1c(N)cnc2ccccc12)OCC
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3ccccc3c2n1CCC(OCC)OCC
Yield: 91.3 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize N4-(3,3-diethoxypropyl)quinoline-3,4-diamine (20.7 g, 71.5 mmol) by reaction with trimethyl orthobutyrate (13.2 g, 89.4 mmol) to provide 1-(3,3-diethoxypropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (22.3 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:10]=[C:9]2[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])([CH3:27])[CH3:26])=[CH:4][CH:3]=1.[CH3:35][S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]([C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:42]=[CH:41][CH:40]=[C:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:44]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:10]=1)([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Temperature: 82.5 °C
Reaction time: 0.08 h
Yield: 44.8 %

Procedure:
To a solution of tert-butyl 2-(1-(4-bromophenyl)-2-(2-(2-chlorophenyl)propan-2-yl)-1H-imidazol-4-yl)pyrrolidine-1-carboxylate (20 mg, 0.036 mmol) in THF (3 mL) was added 3-(methylsulfonyl)phenylboronic acid (14.7 mg, 0.073 mmol). The resulting solution was stirred at 80-85° C. for 5 min and then tetrakistriphenylphosphine palladium (0) (5-10 mg) was added followed by the addition of 60 μL of 1.0 M sodium carbonate. The reaction was maintained at 80-85° C. for 30 min. LC/MS analysis indicated the reaction was complete. The reaction mixture was cooled and filtered over celite, concentrated. The crude product was purified by prep HPLC to give 1,1-dimethylethyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate (10 mg, 50%). 1H NMR (CD3OD): δ 1.4 (m, 9H), 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.2 (s, 3H), 3.4 (m, 1H), 3.6 (m, 1H) 4.6 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, 6H), 7.7 (m, 3H), 7.95 (m, 2H), 8.2 (m, 1H); LC/MS M+H 620 (observed).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23]OS(C2C=CC=CC=2C)(=O)=O)[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[Na+].[I-:36]>>[C:1]([NH:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][I:36])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccccc2C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Reactant: [I-]
Agent: [Na+]
Product: C=CCO[C@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Yield: 88 %

Procedure:
A solution of allyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-6-O-tolylsulfonyl-α-D-mannopyranoside, prepared as described above, (3.68 g, 7.37 mmol) and NaI (2.21 g, 14.7 mmol) was gently refluxed for 10 hours, and cooled. The mixture was concentrated, and the residue was chromatographed on silica gel, with toluene-EtOAc (1:2), to give allyl 2-acetamido-3,4-di-O-acetyl-2,6-dideoxy-6-iodo-α-D-mannopyranoside (2.96 g, 88 percent);
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[OH:8].[C:9]([O:13][C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][C:17]1([C:20]([O:8][CH:3]2[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]2[CH3:1])=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1CCC(C)C1O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCC(C)C1OC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of 2,5-dimethylcyclopentanol (0.55 g), compound 1 (0.97 g), and 4-(dimethylamino)pyridine (0.06 g.) in methylene chloride (100 ml) was added dicyclohexylcarbodiimide (1.09 g.), and the resulting mixture was stirred overnight. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated. Ethyl acetate was then added to the residue, and the mixture was filtered again. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and the solvent was evaporated to a colorless oil (1.18 g. 83%). The product was purified by column chromatography on silica gel, 4:1 hexane:ethyl acetate, eluent.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:15].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]2[CH:12]([O:13][CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:15])[CH2:29][CH2:28]1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: COC1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1c2ccccc2C(=O)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 10 h
Yield: 21.4 %

Procedure:
The procedure is as in Example 25, starting with (RS)-2-(2-bromoethyl)-3-methoxyisoindolinone (2.4 g), 4-[(5-fluoro-3-indolyl)methyl]piperidine (2.1 g) and sodium bicarbonate (0.74 g) in a mixture of dimethylformamide (50 cc) and tetrahydrofuran (40 cc). The mixture is heated to boiling for 10 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with ethyl acetate as eluent, and recrystallization a first time in acetonitrile (40 cc) and then in methyl ethyl ketone (35 cc), (RS)-2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-3-methoxyisoindolinone (0.8 g), m.p. 175° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].O>CN(C)C=O>[F:42][C:40]([F:43])([F:41])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:10][CH:9]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)cn1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Reaction time: 0.08 h

Procedure:
6-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-ol (141 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto is added 60% sodium hydride (10 mg) under ice-cooling and the mixture is stirred for 5 minutes and thereto is added ethyl 4-bromobutyrate (48 μl), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (154.1 mg). MS (m/z): 757 [M+H]+
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24](O)=O)[CH2:19][C:20](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:20]1[CH2:19][N:18]([CH2:23][C:24]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CN(CCCc1ccccc1)CC(=O)O
Reactant: Nc1ccccc1N
Solvent: OCCO
Product: c1ccc(CCCN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1

Procedure:
2c was synthesised by an analogous procedure to that described for 2a using o-phenylenediamine (4.32 g, 40 mmol) and N-(3-phenyl)propyliminodiacetic acid (5 g, 20 mmol) in ethyleneglycol (10 ml) at 190° C. Yield 6.9 g (84%). 1H NMR (400.13 MHz, CD3OD, r.t.), δ 1.74 (quintet, 2H, CH2), 2.45 (m, 4H, CH2), 3.95 (s, 4H, NCH2), 6.88 (d, 2H, ArH), 6.94-6.95 (dd, 3H, ArH), 7.21 (m, 4H, ArH), 7.56 (m, 4H, ArH), 12.33 (broad s, 1.5H, NH). 13C NMR (100.6 MHz, MeOH-d4, r.t.), δ 29.49 (CH2), 34.04 (CH2), 53.95 (2 x NCH2) 55.13 (NCH2), 115.47 (broad, ArC), 123.59 (ArC), 126.58 (ArC), 129.09 (ArC), 129.24 (ArC), 142.95 (ArCq), 154.22 (ArCq from imidazole ring). Anal. Calc. for C25H25N5 (in %) C, 75.54; H, 6.85; N, 17.62. Found C, 75.88; H, 6.55; N, 17.65. +CI MS: (m/z): 396 ([MH+]), 280 ([M-CH2Ph]+).