Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]#[N:15])[C:7](=O)[C:6]12[O:21][CH2:20][CH2:19][CH2:18][O:17]1.N.C1COCC1>[Ni].CCO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][N:15]=[C:7]3[C:6]3([O:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 135 °C
Yield: 27.3 %

Procedure:
A mixture of 3-(5′-methoxy-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl)propanenitrile (1.00 g, 3.47 mmol) and wet Raney Nickel (1.00 g) in 2M EtOH.NH3 (45 mL) and THF (45 mL) was hydrogenated in a Parr Hydrogenation Bottle (250 mL) at 53 lb/in H2 for 20 hr. The mixture was filtered through Celite and the filtrate was poured into a steel pressure vessel and heated at 135° C. for 66 hr. The reaction was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with a step gradient CH2Cl2/CH3OH/NH4OH (98.5/1/0.5 to 97/2/1) to give the title compound as a tan solid (0.26 g, 27% ). NMR (300 Mz, DMSO-d6): consistent. MS: (API-ES+) 275[M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=1[CH3:38])[CH3:26].O>C(#N)C>[CH2:25]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:33][C:32]=1[CH3:38])[CH3:26]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.30 g, 1.8 mmol) and Cs2CO3 in 8 mL acetonitrile is added (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.25 g, 1.1 mmol). The solution is stirred for 6 hrs and poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organics are washed with water (10 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified using flash column chromatography (10%-20% ethyl acetate/hexanes) to afford 0.40 g (79%) of {2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid ethyl ester. To a stirred solution of this ester (0.21 g, 0.44 mmol) is added m-CPBA (50%) (0.31 g, 0.89 mmol) at 0° C. After 10 min. the solution is poured into water (50 mL) and extracted with methylene chloride (3×20 mL). The combine methylene chloride layers are washed with 1 N NaOH (25 mL), water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated in Vacuo. The crude sulphone is purified using flash column chromatography (10%-25% ethyl acetate hexanes) to give 0.15 g (68%) of {2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethanesulfonyl]-phenoxy}-acetic acid ethyl ester. Hydrolysis of this sulphone (0.15 g, 0.30 mmol) occurred under the usual conditions (3 eq. of a 1N solution of LiOH in 1 mL of a 3:2:1 solution of THF:MeOH:H2O) to provide the title compound 0.11 g (78%) after workup with aq. NH4Cl and ethyl acetate.
Reaction SMILES: C([O-])=O.[K+].[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[C:9]([C:17](=[O:19])[CH3:18])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1>[Ru].CO>[F:5][C:6]([F:20])([F:21])[C:7]1[CH:8]=[C:9]([C@@H:17]([OH:19])[CH3:18])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ru]
Agent: O=C[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A ruthenium complex Ru(OTf)[(S,S)-iso-BuSO2dpen] (p-cymene) (1.4 mg, 0.002 mmol), potassium formate (1.0 g, 12 mmol), and 3′,5′-bis(trifluoromethyl)acetophenone (2.56 g, 10 mmol, substrate/catalyst ratio=5000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. for 24 hours to give (S)-1-[3′,5′-bis(trifluoromethyl)phenyl]ethanol at 100% yield and 87.7% ee optical purity.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([Br:18])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2([CH3:17])[CH3:16])(=O)C.ClC1C=[C:22](C=CC=1)[C:23]([O:25]O)=[O:24].C(OCC)(=O)C>ClCCl.CCCCCC>[C:23]([O:25][C:4]1[CH:5]=[C:6]([Br:18])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]2([CH3:16])[CH3:17])(=[O:24])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A solution of 8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 15A, 10.3 g, 4.18 mmol) in anhydrous dichloromethane (30 mL) was treated with a 77% aqueous solution of 3-chloroperoxybenzoic acid (5.75 g, 33.44 mmol) and the resulting reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was then cooled in an ice bath and cautiously quenched with saturated sodium thiosulfate solution. The phases were separated and the organic phase was washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that on flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title compound as an oil (1.3 g, 92%).
Reaction SMILES: NC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(NCCC=O)(OC(C)(C)C)=O.[C:51]([O:55][C:56](=[O:85])[NH:57][CH2:58][CH2:59][CH2:60][NH:61][CH:62]([C:66]1[N:75]([CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:74](=[O:83])[C:73]2[C:68](=[CH:69][C:70]([Cl:84])=[CH:71][CH:72]=2)[N:67]=1)[CH:63]([CH3:65])[CH3:64])([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl>[C:51]([O:55][C:56](=[O:85])[NH:57][CH2:58][CH2:59][CH2:60][NH:61][C@@H:62]([C:66]1[N:75]([CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:74](=[O:83])[C:73]2[C:68](=[CH:69][C:70]([Cl:84])=[CH:71][CH:72]=2)[N:67]=1)[CH:63]([CH3:65])[CH3:64])([CH3:53])([CH3:54])[CH3:52]
Reactant: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NCCC=O
Agent: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@@H](NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet and cold bath was charged with 10.0 g of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3 H-quinazolin-4-one (a compound of Formula 301 prepared, e.g., as described in Example 1.6 or 3.1), 50 mL of DCM and 6.20 g (1.2 eq) of sodium triacetoxyborohydride and cooled to 10° C., followed by the portionwise addition of N-Boc-3-aminopropanal 7.1 g (1.4 eq). Upon indication of completion by TLC, the reaction was quenched with 2.0 mL of methanol and stirred for an additional 30 minutes, during which a slight exotherm was observed. The mixture was washed with 1N hydrochloric acid (until the aqueous layer was clear and acidic)(also exothermic) and then washed with 2N sodium hydroxide (until basic), followed by drying over sodium sulfate, and filtration. The resulting off-white foam solid was filtered and solvents partially stripped under vacuum to give 16.0 g (110% yield) of the title compound of Formula 302, {3-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:29](Cl)(=[O:38])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:29](=[O:38])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)CCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and hydrocinnamoyl chloride.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[C:27](Cl)(=[O:29])[CH3:28].Cl>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C=CC=CC=1>[C:27]([C:23]1[CH:24]=[CH:25][C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)=[CH:21][C:22]=1[F:26])(=[O:29])[CH3:28]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3)CC2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
Successively, anhydrous aluminum chloride (30.8 g, 0.23 mol) was dissolved in nitrobenzene (150 ml), followed by adding to the solution, the total quantity of the above compound 3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (38.7 g) at room temperature, dissolving the mixture together with stirring, adding acetyl chloride (27.3 g, 0.348 mol) over 15 minutes, reacting the mixture on heating at a reaction temperature of 35°-40° C. for 2 hours, adding the reaction solution after completion of the reaction to a mixture of 6N hydrochloric acid (50 ml) with ice water (500 g) to subject them to decomposition reaction, adding toluene (500 ml) to extract the resulting oily layer, washing the extract solution with an aqueous solution of sodium hydrogen carbonate, further washing it with water until the washing water became neutral, distilling off toluene and nitrobenzene and recrystallizing the residue from ethyl acetate to obtain 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (VII) wherein R1 =C3H7 and R"=CH3) (23.8 g). This product exhibited liquid crystal phases and had a crystal-nematic phase transition point (C-N point) of 90.5° C. and a nematic phase-isotropic liquid phase transition point (N-I point) of 204.7° C. (iii) Successively, the compound 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]fluorobenzene (23.8 g) was added to diethylene glycol (100 ml), followed by agitating the mixture, adding hydrazine hydrate (17.9 g) and potassium hydroxide (20.1 g), gradually raising the temperature with stirring to react the mixture at 180° C. for 3 hours, allowing the resulting material to cool down to room temperature, adding water (500 ml), extracting the deposited crystals with toluene (100 ml), washing the extract solution with water, drying it over anhydrous sodium sulfate, distilling off toluene and recrystallizing from ethyl acetate to obtain 2-ethyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (15.2 g).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27]C(C)(C)C)=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)C(=O)O)C1=O
Reaction time: 3 h

Procedure:
To a solution of 320 mg (0.64 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 1, Step G) in DCM (3184 μL) was added trifluoroacetic acid (2453 μL, 31.8 mmol) at 0° C. After being stirred at 25 C. for 3 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure 3-times to provide the title compound as a pale yellow foam which was used in the subsequent reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]5[S:21][CH:22]=[CH:23][N:24]=5)=[O:18])[C:10]=4[N:9]=3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(N4CCOCC4)nc3)nc12
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 57.1 %

Procedure:
A mixture containing 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (7; 20 mg, 0.056 mmol) and morpholine (48; 49 mg, 0.56 mmol) in DMSO (1.5 mL) was stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solids were collected by filtration and dried. The solids were redissolved in EtOAc and enough petroleum ether was added to precipitate the product out again. The solids were collected by filtration, washed with MeOH and dried to afford 2-(6-morpholinopyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 247) as a pale yellow solid (13 mg, 57%). MS (ESI) calcd for C20H18N6O2S: 406.12; found: 407 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:25](=[O:26])[C@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:28]([CH3:30])[CH3:29])[CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC1(C)CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-(4-chlorophenyl)-2,2-dimethylpiperazine (0.76 g, 3.38 mmol) in DMF (10 mL), was added (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.735 g, 3.38 mmol), BOP (1.496 g, 3.38 mmol) and DIPEA (0.588 mL, 3.38 mmol). The mixture was stirred at rt for 2 h, quenched with aq. NaHCO3, extracted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by a flash column chromatography using 30% EtOAc in hexanes as an eluent. The product containing fractions were concentrated and dried to give (R)-tert-butyl 1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (1.36 g, 3.21 mmol, 95% yield) as a yellow oil. To (R)-tert-butyl 1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was added 4N HCL in dioxane and the resulting mixture stirred at room temperature until the starting material had been consumed. The volatile solvents were removed and the product dried to give (R)-2-Amino-1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methylbutan-1-one hydrochloride as a white solid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:13][Si](C)(C)C)[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20]>ClCCl.FC(F)(F)C(O)=O>[C:7]1([C@H:5]([N:4]2[CH2:3][CH:20]=[C:19]([C:18]([O:22][CH3:23])=[O:21])[CH2:13]2)[CH3:6])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCN(C[Si](C)(C)C)[C@H](C)c1ccccc1
Reactant: C#CC(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=CCN([C@H](C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a stirred solution of (1R)-N-(methoxymethyl)-1-phenyl-N-[(trimethylsilyl)-methyl]ethanamine (55.83 mL, 205.62 mmol) and methyl prop-2-ynoate (22.5 mL, 252.9 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added trifluoroacetic acid (800 μL, 10.45 mmol). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (26.5 g, 56%) as a yellow oil. δH (500 MHz, CDCl3) 7.41-7.29 (m, 4H), 7.28-7.21 (m, 1H), 6.77-6.70 (m, 1H), 3.72 (s, 3H), 3.71-3.65 (m, 1H), 3.65-3.42 (m, 4H), 1.40 (d, J 6.6 Hz, 3H). Method F HPLC-MS: MH+ m/z 232, RT 1.62 minutes.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22](=[O:34])[NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][N:25]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[C:24]1([NH:23][C:22]([C:19]2[CH:20]=[CH:21][C:15]3[N:14]=[C:13]([C:9]4[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=4[CH3:12])[NH:17][C:16]=3[CH:18]=2)=[O:34])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4nccc5ccccc45)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3nccc4ccccc34)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{4-[6-(isoquinolin-1-ylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester (85 mg) in MeOH (2 mL) was added 0.5 mL of 1.0 N NaOH and the mixture was stirred at ambient temperature for 18 h. To this solution was added 0.5 mL of 1.0 N HCl then the solvent was removed under reduced pressure. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was triturated with MeCN to give 3-{4-[6-(isoquinolin-1-ylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid as a tan solid. MS (ESI) m/z 465.1 (M+H), retention time=1.01 min, Method 10.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[NH2:4].[CH3:17][C:18](=O)[CH2:19][CH2:20][C:21](=O)[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:22][C:21]1[N:4]([NH:3][C:5]2[N:6]=[N:7][C:8]([N:11]3[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)=[CH:9][CH:10]=2)[C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NNc1ccc(N2CCSCC2)nn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CCSCC2)nn1
Yield: 50 %

Procedure:
3-Hydrazino-6-(4-thiomorpholinyl)-pyridazine di-hydrochloride and 2,5-hexanedione are reacted in acetic acid in the presence of sodium acetate according to the procedure of example 2. The product is recovered by evaporating the acetic acid and slurring the residue in aqueous sodium bicarbonate. The solid obtained after filtration is purified by chromatography through silicagel using a chloroform-methanol mixture 97.5:2.5 mixture as the eluent. Yield 50%. M.p. 203° C. (from ethyl acetate). Elemental analysis, I.R. and N.M.R. data are in agreement with the assigned structure.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:34][CH3:35])([CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]([CH2:30][CH2:31][CH3:32])[C:18](=[O:29])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>CCO>[CH3:35][O:34][C:5]([CH3:33])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]([CH2:30][CH2:31][CH3:32])[C:18](=[O:29])[N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH:20]=2)=[CH:11][CH:12]=1)[C:4]([OH:36])=[O:3]
Reactant: CCCn1c(CCOc2ccc(CC(C)(OC)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(CCOc2ccc(CC(C)(OC)C(=O)O)cc2)cn(Cc2ccc(C)cc2)c1=O
Yield: 103.7 %

Procedure:
The 2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (0.015 g, 0.031 mmol) was combined with aqueous 5 N NaOH (0.1 mL) in EtOH (3 mL) and heated to reflux under N2 for 1 h. The reaction was cooled and the solvent removed in vacuo to give a residue that was acidified with aqueous 1 N HCl (3 mL). The mixture was extracted with Et2O and water, the organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.015 g (100%) 2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid. MS (ES+) m/z calcd for C26H32N2O5 [M+1] 453, found 453. 1H NMR.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH2:10][CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>ClCCl>[Si:22]([O:12][CH2:11][CH2:10][NH:9][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(NCCO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(NCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a stirred solution of 2-(1-phenylethylamino)ethanol (33) (2.71 g, 16.4 mmol, Eq: 1.00) in dichloromethane (60 ml) were added diisopropylethylamine (2.97 g, 4.01 ml, 23.0 mmol, Eq: 1.4) followed by tert-butyldimethylsilyl chloride (2.72 g, 18.0 mmol, Eq: 1.1) at room temperature under nitrogen atmosphere. The resulting solution was stirred for 16 hrs and then it was poured into water (200 ml). The organic layer was separated, washed with brine, and dried with MgSO4, concentrated, and chromatographed (silica gel, gradient 0 to 10% ethyl acetate-hexane) to obtain 2-(tert-butyldimethylsilyloxy)-N-(1-phenylethyl)ethanamine (34) (oil, 3.75 g, 13.4 mmol, 81.8% yield).