Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C.C1(C)C=CC=CC=1.[O-]CC.[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:11]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCOc1ccc(-c2ccc(C=O)cc2)c(F)c1F
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(OCC)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
4-Ethoxy-4′-formyl-2,3-difluoro-1,1′-biphenyl (s49) (30.0 g), ethyl diethylphosphonoacetate (30.8 g) and toluene (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Sodium ethoxide in ethanol solution (20%; 46.7 g) was added at the same temperature, and the stirring was continued for another 2 hours. After the reaction mixture had been returned to 25° C., the stirring was continued for another 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in 2-propanol (150 ml), to which Pd/C (1.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder to give ethyl 3-(4′-ethoxy-2′,3′-difluoro-(1,1′-biphenyl)-4-yl)propionate (s50) (28.9 g). The yield based on the compound (s49) was 75.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14]([O:18][C:19]([CH2:21][O:22][NH2:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C[O-].[Na+]>CO>[C:14]([O:18][C:19]([CH2:21][O:22][N:23]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.), O-t-butoxycarbonylmethylhydroxylamine (1.62 g.) and methanol (20 ml.) was adjusted to pH 5 to 6 by adding an 1 N methanol solution of sodium methoxide and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in an 1 N aqueous solution of sodium hydroxide to adjust to pH 7.0. The aqueous solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid under ice-cooling and extracted with ether. The extract was washed with water and dried over magnesium sulfate. The solution was concentrated to dryness under reduced pressure to give crystals of 2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 116° to 118° C. (dec.).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].Cl[CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[CH2:22]([N:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:13])[CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: C=C(C)n1c(=O)n(CC2CN(Cc3ccccc3)CCO2)c2ccccc21
Yield: 72.9 %

Procedure:
The condensation of 0.1 mol of 1-isopropenyl-2,3-dihydro-benzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine in accordance with the procedure (a) of Example 1 gives, after evaporation of the solvent under reduced pressure, 30 g of an oil which solidifies slowly. Recrystallization from a 250/25 mixture of isopropyl ether and isopropanol gives 26.5 g of 4-benzyl-2-(1-isopropenyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine, m.p. 117° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[C:5]=1O)(=[O:3])[CH3:2].C([O-])=O.[NH4+:27].O>C(O)C>[C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[C:5]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(=O)C1=C(O)C(=O)N(c2ccc(C)cc2)C1C1CCCCC1
Agent: O=C[O-]
Solvent: O
Solvent: CCO
Product: CC(=O)C1=C(N)C(=O)N(c2ccc(C)cc2)C1C1CCCCC1

Procedure:
A reaction mixture of 4-acetyl-5-cyclohexyl-3-hydroxy-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-one (139 mg, 0.44 mmol) and ammonium formate (342 mg, 4.44 mmol) in ethanol (0.2M, 2.2 ml) is heated at reflux for 16 hours. The solvent is removed in vacuo to give a white residue. Water is added to the residue to dissolve some of the white solid leaving a sandy-coloured precipitate. This mixture is then filtered, washed with a small amount of diethyl ether and dried under high vacuum at room temperature to give a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[N:27]3[N:28]=[CH:29][CH:30]=[C:26]3[N:25]=[CH:24][CH:23]=1)[CH3:20])=[CH:7]2.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:31][N:32]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([C@@H:19]([NH:21][C:22]2[N:27]4[N:28]=[CH:29][CH:30]=[C:26]4[N:25]=[CH:24][CH:23]=2)[CH3:20])=[CH:7]3)[CH:34]=[N:33]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Nc1ccnc2ccnn12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@H](Nc1ccnc2ccnn12)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of (S)-8-chloro-2-phenyl-3-(1-(pyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)isoquinolin-1(2H)-one II-2 (66 mg, 0.158 mmol, 1.0 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.316 mmol, 2.0 eq), PdCl2(dppf) (13 mg, 0.016 mmol, 0.1 eq) and Na2CO3 (84 mg, 0.79 mmol, 5.0 eq) was suspended in a mixture of N,N-dimethylacetamide (5 mL) and water (2 mL). The resulting mixture was degassed and back-filled with argon three times and stirred at 80° C. under argon overnight. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenyl-3-(1-(pyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)isoquinolin-1(2H)-one II-5 (43 mg, 60% yield). ESI-MS m/z: 462.2 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)C.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:12]([C:6]1[CH:7]=[C:8]([O:11][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][C:5]=1[NH2:4])([O-:14])=[O:13]
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 2.0 g. of 4-acetamido-3-nitrophenol, 2.2 g. of β-bromophenetole, 3 g. of potassium carbonate, and 20 ml. of dimethylformanide is heated under nitrogen for 16 hours at 110° C. The mixture is cooled and poured into ice water. The precipitated solid is collected, washed with water, and dried to give 2-nitro-4-(2-phenoxyethoxy)-aniline.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:14]([N:27]1[C:35]2[C:30](=[CH:31][C:32](Br)=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:37]([OH:39])=[O:38])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:27]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:28]([C:37]([OH:39])=[O:38])=[CH:29]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2ccc3c(c2)cc(C(=O)O)n3C(c2ccccc2)c2ccccc2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 109 except that 3-acetamidobenzeneboronic acid and 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid were used.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH2:18]([O:20][C:21](=[O:30])[C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[C:23](O)=[O:24])[CH3:19].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:18]([O:20][C:21](=[O:30])[C:22]([OH:29])([C:23](=[O:24])[NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)[CH2:26][CH2:27][CH3:28])[CH3:19]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: CCCC(O)(C(=O)O)C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(O)(C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21)C(=O)OCC
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A solution of 500 mg (2 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 466 mg (2 mmol) (RS)-2-hydroxy-2-propyl-malonic acid monoethyl ester in 40 ml tetrahydrofuran were cooled to 0° C. and 331 mg (2 mmol) 1-hydroxy-benzotriazole hydrate, 830 μl (5 mmol) diisopropylethylamine and 470 mg (2 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50) yielded 630 mg (71%) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid ethyl ester as a colorless foam, MS (m/e): 397.3 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[C:3]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:3]2[C:2]([S:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(-c2ncccc2S)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1cccnc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A mixture of 4-(3-mercaptopyridin-2-yl)benzonitrile (0.18 g, 0.85 mmol), ethyl 2-bromo-2-methylpropanoate (0.195 g, 1 mmol), and K2CO3 (0.138 g, 1.0 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and purified by chromatography to yield ethyl 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.137 g, 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O1CCOCC1>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1/[N:12]=[CH:15]/[N:16]([CH3:18])[CH3:17])#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: C1COCCO1
Product: CN(C)/C=N/c1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 5-nitroanthranilonitrile (1.00 g, 6.13 mmol) in dioxane (25 mL) was added dimethylformamide dimethylacetal (0.88 g, 7.36 mmol). The reaction mixture was stirred at 100° C. for 2 h and then cooled to room temperature and refrigerated. The precipitate was filtered out, washed with cold ether several times, and then dried in vacuo to give 1.30 g (97%) of (E)-N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([O:30][C@@H:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11][C@@H:10]3[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:28][CH:29]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(-c2ccccc2)cc1
Yield: 33.4 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 22 mmol), 4-phenylphenol (3.73 g, 22 mmol) and pyridinium p-toluenesulfonate (108 mg) in chloroform (150 ml) was heated at reflux for 2 h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (2.95 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1COCC1.C([Li])CCC.[Cl-:20].[Cl-].[CH3:22][Zr:23]([CH3:45])(=[SiH2:44])([CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[CH3:43])[CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O-:9].[Cl-:20].[CH3:45][Zr:23]([CH3:22])(=[SiH2:44])([CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[CH3:43])[CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33]
Reactant: Cc1ccc(O)c(C)c1
Agent: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc([O-])c(C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.0 g (8.2 mmol) of 2,4-dimethylphenol in 20 ml of toluene/2 ml of THF was admixed at room temperature with 3.0 ml (8.2 mmol) of a 20% strength solution of butyllithium in toluene. The mixture was stirred for another 1 hour at 60° C. At room temperature, 1.9 g (4.0 mmol) of dimethylsilanediylbis(2-methylindenyl)zirconium dichloride were added as a solid. The suspension was stirred for 8 hours at 60° C. and subsequently filtered hot through Celite. After evaporation of the solvent to leave a volume of about 7 ml, the yellow solid which precipitated at −30° C. was filtered off and dried under reduced pressure. This gave 0.65 g (29%) of dimethylsilanediylbis(2-methylindenyl)zirconium monochloride mono(2,4-di-methylphenoxide) (5).
Reaction SMILES: [CH3:1][N:2](C)[C:3](=[O:44])[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.ClCC(NC)=O>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:4][C:3]([NH:2][CH3:1])=[O:44])[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CNC(=O)CCl
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)NC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-chloro-N-methylacetamide as the alkylating reagent in Step 1. The product was isolated as a white solid (41 mg, 80%). LCMS: m/e 601.45 (M+H)+, 2.31 min (method 11). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d, J=4.58 Hz, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 4.24 (d, J=15.56 Hz, 1H), 3.92 (d, J=15.26 Hz, 1H), 2.88 (s, 3H), 3.08-2.74 (m, 1H), 2.31-1.30 (m, 22H), 1.78 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1.CCOCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH2:15][CH:14]2[C:16](=[CH2:1])[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: CN1CC2CCCC(C1)C2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C1C2CCCC1CN(C)C2
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
To a solution of 6.9 g of methyltriphenyl phosphonium bromide in toluene (30 ml) was added 2.2 g of potassium tert-butoxide at 0° C. and the resulting mixture was stirred for 30 minutes. Next, 3.0 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-one was added thereto and the mixture was reacted for 1 hour. After adding ether, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering and concentrating, the residue was purified by silica gel column chromatography (eluted with ether/n-hexane) to thereby give 3.1 g of the title compound as a yellow oily substance.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[NH:16][C:15](=O)[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1.C(OCC)C.O>CN(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:3][C:15]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=[C:7]([CH3:6])[N:16]=1
Reactant: Cc1nc2c(c(=O)[nH]1)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(Cl)c2c(n1)CCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
To a mixture of 4.5 mL of phosphorus oxychloride and 20 drops of dimethylaniline in 50 mL of toluene was added 4.2 g of 5,6,7,8-tetrahydro-2-methyl-4-quinazolone. The resulting mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was poured into a ice cold aqueous potassium carbonate. After stirring for 5 minutes the mixture was added to diethyl ether/water. The organic layer was recovered washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield a yellow oil. This oil was purified on silica to yield the desired compound as a light yellow solid (4.45 g, 95%): 1H NMR (DMSO-d6, 300 MHz) δ 2.78 (m, 2H), 2.64 (m, 2H), 2.50 (s, 3H), 1.78 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:17][C:11]=2[N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](Br)[CH2:39][CH3:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([N:13]2[C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:17][C:11]=3[N:10]=[C:9]2[CH2:8][C:2]([CH3:1])([CH3:30])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:39][CH3:40])=[CH:34][CH:33]=1
Reactant: CCC(Br)c1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1C(CC)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
A suspension of ethyl 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)propanoate) (300 mg, 0.74 mmol), 1-bromo-4-(1-bromopropyl)benzene (413 mg, 1.49 mmol) and cesium carbonate (727 mg, 2.23 mmol) in DMF (3.7 mL) was heated to 100° C. for 3 days. The mixture was cooled and partitioned between water and EtOAc. The organic layer was dried and concentrated to a residue. Purification using FCC afforded the title compound. MS (ESI): mass calcd. for C33H34BrN3O3, 599.18; m/z found, 600.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.5, 1H), 8.05 (d, J=8.5, 1H), 7.83 (d, J=8.2, 1H), 7.74 (ddd, J=8.4, 6.9, 1.4, 1H), 7.62-7.53 (m, 3H), 7.28-7.25 (m, 2H), 6.97-6.92 (m, 3H), 6.62 (d, J=2.3, 1H), 5.38 (dd, J=10.0, 5.9, 1H), 5.34-5.22 (m, 2H), 4.05 (qd, J=7.1, 0.8, 2H), 3.08 (q, J=15.6, 2H), 2.42-2.23 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.15 (t, J=7.1, 3H), 0.72 (t, J=7.3, 3H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH:5]=[N:4][N:3]=[N:2]1.Cl.O1CCOC[CH2:12]1>CO>[N:1]1([CH2:6][C:7]([O:9][CH3:12])=[O:8])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1cnnn1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)Cn1cnnn1

Procedure:
A mixture of tetrazol-1-yl acetic acid (5 g, 39 mmol) and 4M hydrochloric acid in dioxan (100 μL) in methanol (50 mL) was heated under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure to provide the title compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[CH3:36])[CH:26]=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)C.Cl>CCO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([C@@H:8]([C:9]4[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=4)[CH2:7][C:6]([OH:37])=[O:5])=[CH:20][CH:19]=3)[CH:24]=2)=[C:30]([CH3:36])[CH:31]=1
Reactant: CCOC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(Cl)cc3C)c2)cc1)c1nccn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1-c1cccc(COc2ccc([C@H](CC(=O)O)c3nccn3C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10% NaOH (aq) (1 mL) was added to a solution of (S)-ethyl 3-(4-[3-(4-chloro-2-methylphenyl)benzyloxy]phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.10) (49 mg, 0.1 mmol) in EtOH (2 mL). The reaction mixture was stirred at room temperature for 4 hours. 1N HCl was added to neutralize the mixture to pH 6-7. The mixture was extracted with EtOAc (2×20 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was flash chromatographed (silica gel, 0-10% MeOH in DCM) to afford (S)-3-[4-(4′-chloro-2′-methyl-biphenyl-3-ylmethoxy)-phenyl]-3-(1-methyl-1H-imidazol-2-yl)-propionic acid (9) as a colorless oil. MS ESI (neg.) m/e: 459 (M−H). 1H NMR (500 MHz) (DMSO) δ 7.87 (broad s, 1H); 6.63-7.46 (m, 13H); 5.06 (s, 2H); 4.49 (dd, J=8.4, 3.2 Hz, 1H); 3.39 (s, 3H); 3.29 (dd, J=15.0, 8.5 Hz, 1H); 3.10 (dd, J=15.2, 3.0 Hz, 1H); 2.23 (s, 3H).