Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[C:17](=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([F:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Fc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Br)c1F
Reaction time: 0.83 h

Procedure:
To a solution of 1-bromo-2-fluorobenzene (6.0 g, 34.3 mmol) in dry tetrahydrofuran (50 ml) under nitrogen, at −78° C. was added lithium diisopropylamide (2.5 M in hexane, 18.8 ml, 37.7 mmol). The mixture was stirred for 50 minutes and then poured onto crushed solid carbon dioxide. The reaction mixture was brought to ambient temperature and aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was washed with diethyl ether (2×100 ml), and then made acidic by addition of aqueous hydrochloric acid. The acidified aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated to dryness to give the title compound (4.24 g).
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCNCCN(Cc3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31), sodium hydride and benzyl bromide.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[CH:24]3)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1ccc2ncccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3ncccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and quinolin-6-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C22H23NO5 [M+H]+: 382.4.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:20]3[N:19]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:3]1.FC(F)(F)C(O)=O>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:20]3[N:19]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:3]1
Reactant: CC1CCCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCNCC2)C1

Procedure:
The title compound was prepared from (RS) 4-[3-[3-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole by standard trifluoroacetic acid deprotection as described supra.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([CH:16]=2)[C:13](O)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1>[C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:17]([F:18])([F:19])[F:20])=[C:12]([CH2:13][OH:14])[CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(Oc2ccccc2)ccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a stirred solution of crude 5-(phenyloxy)-2-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 36)(0.519 g, 1.84 mmol) in dry THF (40 ml) under nitrogen was added 1.0 M borane-tetrahydrofuran complex (6 ml, 6.0 mmol, Aldrich) dropwise. The solution was stirred for 30 min then heated at gentle reflux for 21 h. To the solution at ambient temperature was added methanol (10 ml) dropwise and then heated at reflux for 30 min. The solvent was removed in vacuo and then water added to the residue. The mixture was diluted with 2 M hydrochloric acid and the mixture was extracted with chloroform. The organic extract was concentrated in vacuo to give [5-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol as a colourless oil (0.494 g).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)(=[O:26])[CH3:25]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 140 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
100-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (150 mg, 0.42 mmol), tributyl(1-ethoxyvinyl)stannane (153 mg, 0.42 mmol) and Pd(PPh3)4 (49 mg, 0.04 mmol) in dioxane (3 mL) was heated to 140° C. for 2 h in a microwave reactor. The mixture was then concentrated in vacuo and the residue obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) afforded the compound obtained was taken up in THF (20 mL) and treated with a 2M aqueous solution of HCl (0.68 mL, 1.36 mmol). The solution was stirred at RT for 1 h and then concentrated in vacuo. The residue obtained was taken up in a saturated aq. solution of NaHCO3 and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (79 mg). UPLC-MS: MS 271.2 (M+H+); UPLC rt 0.59 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[CH:4]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C.C1(C)C=CC=CC=1>[OH:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11])=[O:15]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(O)cc1O)c1ccccc1F
Temperature: 60 °C

Procedure:
m-dimethoxybenzene (27.6 g) and o-fluorobenzoyl chloride (31.7 g) are dissolved in 200 ml of dichloroethane and AlCl3 (28.0 g) is added portionwise. After two hours an additional 56 g of AlCl3 is added and the reaction mixture warmed at 60° C. for 1.5 hours. It is then poured into H2O and extracted with ethylacetate. Drying and evaporation gives a crystalline compound. Trituration with toluene gives 2,4-dihydroxy-2'-fluorobenzophenone, mp 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:11]3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:11]3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.85 g, 1.19 mmol) prepared in example 146d in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (1.57 mL, 8.70 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated with ethyl acetate and hexane to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 440 mg, 70%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: COCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:3][CH:2]=1.[C:21]([C:29](O)=[O:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:28][C@H:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:29]([N:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=1)[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1)=[O:30]
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1
Reactant: O=C(O)C(=O)c1ccccc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@H](O)c2ccccc2)cc1
Yield: 32.8 %

Procedure:
In analogy to example 7, steps 1 and 2, p-tolyl-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (200 mg, 0.714 mmol) was coupled to benzoylformic acid (112 mg, 0.746 mmol) and reduced to give the title compound (97 mg, 32.2%) MS m/e: 415.1 [M+H]+ after separation on a chiral column.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc(O)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
p-Hydroxyxstyrene was converted to 1-(p-acetoxyphenyl)ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al (J. Org. Chem. 1958 23 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0-5 degrees Centigrade for 2 h. The mixture was then washed with ether, and the aqueous phase neutralised with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26]C(C)C)=[C:22]([CH:25]=3)[C:23]#[N:24])=[N:14][C:12]=2[N:13]=1.[OH:37]S(O)(=O)=O.[OH-].[Na+]>O>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([CH:25]=3)[C:23]([NH2:24])=[O:37])=[N:14][C:12]=2[N:13]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)Oc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc(O)c(C(N)=O)c3)nc2n1
Temperature: 90 °C

Procedure:
5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H2SO4 (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[OH:19])=[O:5])C.[F:24][C:25]([F:35])([F:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH2:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=3)[CH2:21][CH2:20]2)[CH:7]([OH:19])[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1O
Reactant: Nc1ccc(CC(F)(F)F)cc1
Product: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2O

Procedure:
The title compound was prepared in analogy to example 1 step C from a mixture of (3RS,4SR)-1-benzyl-3-hydroxy-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester and 4-(2,2,2-trifluoro-ethyl)-phenylamine). Light yellow solid. MS (ESI): 419.3 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1/[CH:23]=[CH:24]/[CH3:25])([C:11]([OH:13])=[O:12])[CH2:5]2.[CH3:27]CO>[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[CH2:23][CH:24]([CH3:27])[CH3:25])([C:11]([OH:13])=[O:12])[CH2:5]2
Reactant: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Reactant: CCO
Agent: [Pd]
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1CC(C)C
Temperature: 25 °C
Yield: 78 %

Procedure:
5-Fluoro-2-[3-methyl-2-((E)-propenyl)-benzoylamino]-indan-2-carboxylic acid (154) (270 mg, 0.76 mmol) is dissolved in absolute EtOH (15 mL) by heating. The resulting solution is cooled down to RT under argon and then is added the catalyst, Pd—C (5 wt. % Pd, 125 mg, 5.9% mmol). The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, 50° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (155) as white solid (210 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:8]1[CH3:22])=[O:6].[CH2:26]([C:30]1[CH:35]=[CH:34][C:33]([CH:36](Cl)[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)[CH:27]([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH2:43]([C:40]1[CH:41]=[CH:42][C:37]([CH:36]([NH:1][C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:8]2[CH3:22])=[O:6])[C:33]2[CH:34]=[CH:35][C:30]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Reactant: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc(N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc(NC(c2ccc(CC(C)C)cc2)c2ccc(CC(C)C)cc2)c1
Temperature: 20 °C
Reaction time: 14 h
Yield: 67.1 %

Procedure:
A mixture of 4-[1-(3-aminobenzoyl)-2-methylindol-3-yl]butyric acid (587 mg), bis(4-isobutylphenyl)methyl chloride (905 mg) and diisopropylethylamine (754 mg) in dichloromethane (20 ml) was stirred at 20° C. for 14 hours. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on a silica gel column (50 ml) eluting with a mixture of chloroform and methanol (50:1) to give 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-2-methylindol-3-yl]butyric acid (720 mg).
Reaction SMILES: [CH3:1][C@:2]12[C@@:18]3(C[O:19]3)[CH2:17][CH2:16][C@@H:15]1[CH2:14][C@H:13]1[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]([OH:21])[CH2:8]3)[CH2:3]2.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl.O>ClCCl>[CH3:31][O:32][CH2:33][O:21][C@H:9]1[CH2:8][C@H:7]2[C@@H:12]([C@@H:13]3[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@@:2]2([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]2[CH2:14]3)[CH2:11][CH2:10]1
Reactant: COCCl
Reactant: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@@]4(C)C(=O)CC[C@@H]4C[C@@H]32)C1
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of compound 46 (200 mg, 0.72 mmol) in dry dichloromethane (10 mL) was added N,N-diisopropylethylamine (260 mg, 2.0 mmol) and chloromethyl methyl ether (241 mg, 3.0 mmol) at room temperature. After 16 h, water (30 mL) was added and the product extracted into dichloromethane (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to give compound 47 (230 mg, 100%) as a white solid: [α]D25 −40.0 (c 0.20, CHCl3); 1H NMR (CDCl3) δ 4.60 (s, 2H), 3.83-3.82 (m, 1H), 3.31 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3) δ 220.9, 94.5, 71.2, 55.0, 48.3, 47.7, 46.9, 45.6, 39.3, 38.1, 37.9, 36.6, 35.6, 33.9, 30.2, 28.3, 24.0, 2.39, 13.5; IR νmax 1740 cm−1.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([O:22][Si:2]([CH3:1])([CH3:8])[CH3:9])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C)(C)C(O)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(O[Si](C)(C)C)c1cccc(Br)c1
Reaction time: 8 h
Yield: 64 %

Procedure:
N-trimethylsilylimidazole (9.5 mL, 64.86 mol) was added to a solution of the crude 1-(3-bromo-phenyl)-2,2-dimethyl-propan-1-ol in tetrahydrofuran (100 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into distilled water, followed by extraction with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=20:1) to give the title compound as a colorless oil (11.0 g, 64% in two steps).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C@@H:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C@@H:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc(N)cc2C1=O
Reaction time: 26 h
Yield: 88.8 %

Procedure:
A suspension of diethyl(S)-2-(4-nitrophthalimido)glutarate (35.6 g, 94.1 mmol) and 10% palladium on carbon (0.5 g) (Aldrich) in ethanol (200 ml) was shaken under a hydrogen atmosphere (40-50 psi) for 26 hours. The solution was filtered through celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (250 g) eluting with diethyl ether:hexane (4:1) to give diethyl(S)-2-(4-aminophthalimido)glutarate as a viscous yellow oil (29.1 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.12 (t, J=7 Hz, 3H, ester CH3), 2.17-2.39 (m, 4H, glu CH2CH2), 3.87-3.98 (m, 2H, ester CH2), 4.05-4.18 (m, 2H, ester CH2), 4.75-4.82 (m, 1H, glu CH), 6.57 (br s, 2H, NH2), 6.82 (dd, J=8,2 Hz, 1H, Ar), 6.93 (d, J=2 Hz, 1H, Ar), 7.51 (d, J=8 Hz, 1H, Ar). Mass spectrum (CI—CH4) 349 (M+1, 40.8%), 303 (60.1%), 275 (100%). Anal. Calculated for C17H20N2O6: C, 58.62; H, 5.79; N, 8.04. Found: C, 58.62; H, 5.80; N, 8.00.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>>[OH:10][C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Ic1ccncc1
Reactant: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Product: CC(O)(c1ccncc1)c1ccc(-c2ccc(C#N)nc2)cn1
Yield: 18.4 %

Procedure:
Using 4-iodo pyridine (0.22 g, 1.076 mmol), and 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile (0.12 g, 0.54 mmol) and procedure described for example 7 and step 4, crude product was obtained. The crude product was purified by preparative TLC (5% methanol in ethyl acetate) to obtain 6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile as off-white solid (30 mg, 18% yield) in 98% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.94 (s, 1H), 8.46 (d, 2H), 8.38 (dd, 1H), 8.23 (dd, 1H), 8.14 (d, 1H), 7.82 (d, 1H), 7.49 (d, 2H), 6.27 (s, 1H), 1.9 (s, 3H); LC-MS m/z calculated for [M+H]+ 303.12. found 303.1.