Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8](C)[CH3:9].CO>ClC(Cl)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][NH:8][CH3:9]
Reactant: CN(C)CCOCc1cc(Br)ccc1F
Solvent: CO
Solvent: CC(Cl)Cl
Product: CNCCOCc1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 72 h

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-(2-fluoro-5-bromobenzyloxy)-(N,N-dimethyl)ethylamine (317 mg, 1.15 mmol) was dissolved in dichloroethane (3.5 ml). This solution was cooled to 0° C. and ACE•Cl (0.50 ml, 4.59 mmol) was added. The resulting mixture was warmed to ambient temperature, then heated to reflux and maintained at this temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. Methanol was added to the reaction mixture and the resulting mixture was stirred at ambient temperature for about three days. The mixture was then heated to reflux for thirty minutes. The solvents were removed in vacuo. The residue was taken up in methanol, heated to reflux for thirty minutes, and the solvents were then removed in vacuo. The title intermediate was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:18]=2)[CH:8]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and biphenyl-4-carbaldehyde using the method described in Example 1, Step A except the mine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 4H), 7.40 (m, 4H), 7.32 (m, 1H), 7.29-7.22 (m, 2H), 7.17 (m, 1H), 7.07 (d, 1H), 3.82 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.93 (t, 2H), 2.61 (t, 2H); MS 360 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Br:18][C:19]1[C:20]([CH3:29])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24]>>[Br:18][C:19]1[C:20]([CH3:29])=[N:21][N:22]([CH2:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[C:23]=1[CH3:24]
Reactant: Cc1nn(CC(=O)O)c(C)c1Br
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1nn(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c(C)c1Br
Yield: 32.4 %

Procedure:
Example 35 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (0.047 g) to give the title compound (0.032 g).
Reaction SMILES: II.[N+:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(O)C>[N+:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[CH:13]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: II
Solvent: CCO
Product: O=[N+]([O-])c1ccc2ccncc2c1
Reaction time: 66 h
Yield: 37 %

Procedure:
Under refluxing, a solution of iodine (4.0 g, 15.9 mmol) in ethanol (56 mL) was added dropwise to a stirred solution of 31-2 (2.0 g, 9.34 mmol) in ethanol (24 mL) during 5 h. Then the resulted mixture was stirred for a further 66 h. The solvent was removed and the residual was loaded onto a silica gel chromatography column (PE:EA=6:1) to give 31-3 as a brown dark solid (602 mg, yield 36%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:1]=[C:2]1[CH2:7][N:6]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C1)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc(Cl)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 544.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O:16][C:17](=O)[CH:18]([O:25][CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])C>C(O)(=O)C>[OH:24][C:19]1([C:20]([F:21])([F:22])[F:23])[CH:18]([O:25][CH3:26])[C:17](=[O:16])[NH:13][C:10]2[NH:11][N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[C:9]1=2
Reactant: CCOC(=O)C(OC)C(=O)C(F)(F)F
Reactant: Nc1cc(-c2cccc(F)c2)n[nH]1
Solvent: CC(=O)O
Product: COC1C(=O)Nc2[nH]nc(-c3ccccc3)c2C1(O)C(F)(F)F
Reaction time: 15 h
Yield: 45.2 %

Procedure:
5-Phenyl-2H-pyrazol-3-ylamine (i) (100 mg, 0.62 mmol) was dissolved in glacial acetic acid (1 mL), 4,4,4-Trifluoro-2-methoxy-3-oxo-butyric acid ethyl ester (95%, 0.17 mL, 0.92 mmol) was added at RT and stirring was continued for 15 h at 120° C. The mixture was evaporated to dryness and the isomeric mixture was directly purified by preparative HPLC (Agilent 1100 Series, Chromolith prep RP-18e, 100-25). A colorless solid (92 mg, 0.28 mmol, 46%) was obtained, characterized as compound (x).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][NH:23][CH2:22]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][N:23]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:7])=[CH:4][CH:3]=1)[CH2:22]2
Reactant: C1CC2CNCC(C1)C2
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CC3CCCC(C3)C2)cc1

Procedure:
A solution of 4-fluoro-N-quinolin-3-yl-benzamide (0.080 g, 0.299 mmol), 3-aza-bicyclo[3.3.1]nonane (0.200 g, 1.60 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in dimethyl sulfoxide (2 mL) was heated to 100° C. for 11 days. The DMSO solution was applied to a preparative reverse phase C18 column, and the product was eluted with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, to give the product as a trifluoroacetate salt, a yellow solid, 0.065 g (36%). MS: m/z 372 (MH+). 1H NMR (DMSO-d6): 1.40-1.50 (m, 1 H), 1.58-1.93 (m, 7 H), 2.05 (br s, 2 H), 3.04-3.08 (m, 2 H), 3.85 (d, 2 H), 7.00 (d, 2 H), 7.62-7.76 (m, 2 H), 7.96 (d, 2 H), 8.02 (d, 2 H), 8.95 (d, 1 H), 9.28 (d, 1 H) and 10.45 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19].[F:22][C:23]([F:40])([F:39])[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36]CO)[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH2:21][CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:40])([F:22])[F:39])[CH:25]=2)[CH2:35][CH2:34]1)=[O:19]
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COC(=O)c1sccc1Nc1ccnc2c(Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1sccc1Nc1ccnc2c(Cl)cccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
A mixture of 6.37 g of the product of Step A, 6.17 g of 4-[3-trifluoromethylphenyl]-1-piperazine-ethanol and 50 ml of anhydrous toluene was refluxed for an hour while passing the condensed toluene through a column filled with siliporite and after cooling to 60° C, 150 mg of sodium hydride were added thereto. The mixture was refluxed with stirring for 16 hours and the toluene was distilled. The product was extracted with methylene chloride, washed with water and dried to obtain 11.6 g of 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl 3-(8-chloro-4-quinolylamino)-2-thiophene-carboxylate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[S:27][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]3[CH:8]=[CH:7][S:27][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Product: c1cn(-c2nc(NCCc3ccc4c(c3)OCO4)c3ccsc3n2)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[F:22])[CH:4]=1)#[CH:2].Cl[Sn]Cl.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.CCO.C1(C)C=CC=CC=1>[C:1]([C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[S:37])=[CH:15][C:14]=2[F:22])[CH:4]=1)#[CH:2]
Reactant: C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: Cl[Sn]Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: C#Cc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a solution of the alkyne 410 (200 mg, 0.64 mmol) in MeOH (10 ml) was added SnCl2×2H2O (574 mg, 4 eq, 2.54 mmol) and the reaction mixture was heated to reflux for 3 hours. It was then cooled to RT, concentrated and crude amine 411 was used directly in the next step with no additional purification (182 mg, 100%). To a solution of 411 (182 mg, 0.64 mmol) in EtOH (2 ml) and toluene (6 ml) was added 2-phenylacetyl isothiocyanate (227 mg, 2 eq, 1.28 mmol) and the reaction mixture was stirred at RT for 2 hrs, concentrated under reduced pressure and the residue was purified by column chromatography (1:3 EtOAc:hexane) to afford 406 as a white solid (25 mg, 9% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 11.82 (s, 1H), 8.58 (d, J=5.48 Hz, 1H), 8.01 (m, 1H), 7.88 (s, 1H), 7.50 (m, 2H), 7.25 (m, 5H), 6.73 (d, J=5.48 Hz, 1H), 5.01 (s, 1H), 3.81 (s, 2H). LCMS: 462.2 (M+H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38]([CH2:43][CH2:44][OH:45])[CH:39]=[CH:40][C:41]=1[F:42].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:45][CH2:44][CH2:43][C:38]3[CH:39]=[CH:40][C:41]([F:42])=[C:36]([F:35])[CH:37]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1ccc(F)c(F)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(F)c(F)c2)cc1
Reaction time: 18 h
Yield: 6.8 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(3,4-difluorophenyl)ethanol (33.7 mg, 0.213 mmol) and Ph3P-resin (33.5 mg, 0.128 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(3,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (1.7 mg, 2.93 μmol, 6.86% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.48-7.39 (m, 1H), 7.39-7.32 (m, 1H), 7.24-7.14 (m, 2H), 7.07-6.99 (m, 3H), 5.86 (s, 1H), 4.34-4.18 (m, 2H), 3.24 (br. s., 1H), 3.07 (t, J=6.4 Hz, 2H), 2.85-2.76 (m, 1H), 2.44 (s, 3H), 2.18 (d, J=10.3 Hz, 1H), 2.05 (s, 3H), 1.98-1.90 (m, 1H), 1.49 (br. s., 1H), 1.36-1.23 (m, 1H), 1.18 (d, J=13.2 Hz, 1H), 1.13 (s, 9H), 1.02 (d, J=13.2 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=581.5.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5](=[O:21])[C:6](N(C)C)([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)[CH3:7]>CO.[C].[Pd]>[F:1][C:2]([F:22])([F:23])[CH2:3][O:4][C:5](=[O:21])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CC(C)Cc1ccc(C(C)(C(=O)OCC(F)(F)F)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)OCC(F)(F)F)cc1
Reaction time: 5 h
Yield: 79 %

Procedure:
To a mixture of 0.80 g of 2-dimethylamino-2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester in 20 ml of methanol was added 0.22 g of palladium-carbon(10%). Hydrogenation was carried out at 50°-60° C. for 5 hours. After the reaction was complete, the catalyst was removed by filtration and the filtrate produced was freed of solvent by distillation to give an oily product. This product was distilled in vacuo to give 0.55 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester as a colorless oil. Mass spectrum: parent ion 288 m/e.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:16]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:30]=[CH:31][C:26]([S:23]([N:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11]3([C:9]([OH:10])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:24])=[O:25])=[CH:27][CH:28]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Yield: 100.3 %

Procedure:
A solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)amino]-cyclopentane-1-carboxylic acid benzyl ester (12.1 grams, 22.4 mmole) in methanol (270 mL) was treated with 10% palladium on activated carbon and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 3.5 hours. After filtration through nylon (pore size 0.45 μm) to remove the catalyst, the solvent was evaporated to afford 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)amino]cyclopentane-1-carboxylic acid as a white foam (10.1 grams, 100%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 4.0 g, 8.0 mmol), 3-(dimethylamino)phenylboronic acid (3.3 g, 20 mmol), bis(triphenylphosphine)palladium(II) dichloride (567 mg, 0.8 mmol) in 1,4-dioxane (40 mL) and an aqueous sodium carbonate solution (2N, 21 mL) was heated in a microwave reactor to 100° C. for 3 h under nitrogen. At this time, the reaction was cooled to 25° C., diluted with ethyl acetate (50 mL) and then washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (60 g, petroleum ether/ethyl acetate 15:1) afforded N,N-dimethyl-3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)but-1-enyl)benzenamine (3.0 g, 83%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (dd, 1H, J1=4.5 Hz, J2=3.6 Hz), 7.85 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.65 (d, 2H, J=7.8 Hz), 7.38-7.36 (m, 1H), 7.31-7.14 (m, 4H), 7.06 (t, 1H, J=8.1 Hz), 6.65-6.48 (m, 3H), 6.14 (d, 1H, J=10.2 Hz), 2.77 (s, 6H), 2.72-2.64 (m, 1H), 1.14 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](O)([CH3:20])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([O:26][CH3:27])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH3:20])=[CH:16][CH2:17]3)=[CH:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CC=C2C
Temperature: 80 °C

Procedure:
To a solution of methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-hydroxy-3-methylindane-5-carboxylate (22.6 mg, 0.061 mmol) in toluene (1 mL) at room temperature was added TsOH (5.8 mg, 0.030 mmol). The reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was diluted with EtOAc. The organic layer was washed consecutively with sat. aq. NaHCO3 (1×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo to give methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-methyl-1H-indene-5-carboxylate. LCMS calc.=377.2; found=376.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H); 7.41 (s, 1H); 7.14 (d, J=8.7 Hz, 1H); 6.63 (d, J=12.1 Hz, 1H); 6.30 (t, J=1.5 Hz, 1H); 3.72 (s, 3H); 3.72 (s, 3H); 3.42 (d, J=1.5 Hz, 2H); 3.29-3.21 (m, 1H); 2.25 (s, 3H); 1.31 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:5]=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([F:40])[CH:28]=2)[CH:20]=1.CO.[OH-].[Na+].Cl.[C:46]1([S:52]([OH:55])(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)C.O1CCCC1>[C:46]1([S:52]([OH:55])(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[CH3:18][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([F:40])[CH:28]=2)[CH:20]=1
Reactant: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCCCN4CCCC4=O)cc3C)c2)cc1F
Agent: Cl
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of ethyl 3-{4-[({2′,6′-dimethyl-4′-[3-(2-oxopyrrolidin-1-yl)propoxy]biphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (1.13 g, 2.07 mmol), methanol (5 mL) and tetrahydrofuran (10 mL) was added 1 M aqueous sodium hydroxide solution (4.14 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid, and diluted with ethyl acetate, and the organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) to give a colorless oil. The obtained oil was diluted with ethyl acetate, and benzenesulfonic acid was added. The precipitated crystals were collected by filtration, washed, and dried to give the title compound (0.78 g, yield 56%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[CH:14]=2)=[C:8]([CH3:29])[CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[C:32]([O:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:29])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH:25]=[O:26])=[CH:27][CH:28]=3)[CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)(=[O:34])[CH3:33]
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)CCOc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-{[4′-(3-hydroxy-3-methylbutoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}benzaldehyde, acetic anhydride, pyridine, DMAP and chloroform was stirred at room temperature for 2 days to obtain 3-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)-1,1-dimethylpropyl acetate.