Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.N12CCCN=C1CCCCC2.Cl.[C:52](Cl)(=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[N:55][CH:54]=1.Cl>O1CCCC1.CN(C)C=O>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:52](=[O:59])[C:53]4[CH:58]=[CH:57][CH:56]=[N:55][CH:54]=4)[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2)c1cccnc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 37.2 %

Procedure:
To the solution of the product of Example 345 (0.015 g, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.022 mL, 0.160 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.020 mL, 0.129 mmol). The mixture was cooled to 0° C. and nicotinoylchloride hydrochloride (0.007 g, 0.035 mmol) was added. The mixture was stirred for 2.5 hours and then warmed to 23° C. and stirred for 2.5 hours. Additional 1,8 diazabicyclo[5.4.0]undec-7-ene (0.010 mL, 0.068 mmol) and nicotinoylchloride hydrochloride (0.006 g, 0.032 mmol) were added and the mixture was stirred at 23° C. for 15 hours. Added additional nicotinoyl chloride hydrochloride (0.006 g, 0.032 mmol) and stirred at 23° C. for 6 hours. A few drops of N,N-dimethylformamide were added to increase solubility. Added additional nicotinoyl chloride hydrochloride (0.006 g, 0.032 mmol) and stirred at 23° C. for 72 hours. Hydrochloric acid (4 M in dioxane) (0.095 mL, 0.370 mmol) was added and the reaction mixture was concentrated under reduced pressure. The resulting solid was then washed with diethyl ether and water. The solid was dissolved in 1% triethylamine/dichloromethane and purified by preparative thin layer chromatography eluting with 5%(5% triethylamine/methanol)/dichloromethane. The silica gel was washed with 10% (5% triethylamine/methanol)/dichloromethane to give the triethylamine salt of the title compound (0.0068 g, 31%). 1HNMR(500 MHz, DMSO-d6) δ 1.17 (t, J=7.32 Hz, 9 H) 3.09 (q, J=7.32 Hz, 6 H) 4.60 (d, J=4.88 Hz, 2 H) 5.44 (bs, 2 H) 7.00 (bs, 1 H) 7.12 (m, 1 H) 7.26 (m, 5 H) 7.46 (m, 1H) 7.53 (dd, J=7.63, 4.58 Hz, 1 H) 8.12 (d, J=7.32 Hz, 1 H) 8.26 (m, J=7.93 Hz, 1 H) 8.72 (d, J=3.66 Hz, 1 H) 8.86 (bs, 1 H) 9.09 (s, 1 H) 9.16 (bs, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([NH:24][C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.C(O)(=O)C.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([NH:24][C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc(C=CC=CC(=O)Nc2ccccc2C(=O)O)cc(OC)c1O
Yield: 541.7 %

Procedure:
To a solution of 56 mg (0.12 mmol) of the amide compound prepared above in 1 ml of dioxane was added 4 ml of 80% acetic acid. The mixture was heated under reflux for 2 hours. Water was added to the reaction solution, and crystals then formed were isolated by filtration and recrystallized from methanol. There was obtained 24 mg (0.65 mmol) of N-{5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4-pentadienoyl}anthranilic acid. Spectrophotometric data of the product support the structure shown below. ##STR69##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10].[CH2:14]([O:16][CH:17]([O:21][CH2:22][CH3:23])[CH2:18][CH2:19]Cl)[CH3:15].[H-].[Na+].[NH2-].[Na+]>C1(C)C=CC=CC=1.COCCOC.CN(C)C=O.C1(C)C(C)=CC=CC=1.C1C=CC=CC=1>[CH2:14]([O:16][CH:17]([O:21][CH2:22][CH3:23])[CH2:18][CH2:19][C:8]([CH:11]([CH3:13])[CH3:12])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:9]#[N:10])[CH3:15]
Reactant: CCOC(CCCl)OCC
Reactant: Cc1ccccc1C(C#N)C(C)C
Agent: [H-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: c1ccccc1
Product: CCOC(CCC(C#N)(c1ccccc1C)C(C)C)OCC

Procedure:
The alkylation of 2-(2-methylphenyl)-3-methylbutyronitrile of Formula II: ##STR3## with 3,3-diethoxypropylchloride is carried out conveniently in an inert organic solvent in the presence of an alkaline condensing agent. Suitable inert organic solvents are aromatic hydrocarbons, e.g. benzene, toluene or commercial xylene, tertiary amides, e.g. dimethylformamide, or higher-boiling aliphatic ethers, e.g. ethyleneglycol dimethylether. Preferable alkaline condensing agent is sodium hydride or sodium amide. The reaction is advantageously effected by dropping a toluenic sodium amide suspension to a boiling solution of the above reactants in anhydrous toluene and refluxing the mixture for a period of 4 to 10 hours. The so formed acetal, 5,5-diethoxy-2-isopropyl-2-(2-methylphenyl) valeronitrile of Formula III: ##STR4## is isolated on cooling the mixture by short agitation with water, separation of the toluenic phase and evaporation of the solvent. The obtained crude product is purified by distillation under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:3]=1[C:4](OCC)=[O:5].Cl.[CH:24](N)=[NH:25]>C(N)=O>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][C:11]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:1]=[CH:24][NH:25][C:4]2=[O:5]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Reactant: N=CN
Agent: Cl
Solvent: NC=O
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Temperature: 130 °C
Yield: 55.9 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate (7.15 g, 22.8 mmol) and formamidine hydrochloride (2.012 g, 25 mmol) in formamide (20 mL) was heated at 130° C. for 12 hours, to afford 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one as a solid (3.75 g, 56%). 1H NMR (300 MHz, CDCl3) δ 10.89 (br, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.16 (s, 1H), 4.29 (t, 4H), 3.86 (t, 4H), 3.48 (s, 6H); LC-MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[C:11](O)=[O:12]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:11][OH:12]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of LiAlH4 (2.2 g) in THF (100 mL) at 0° C. under nitrogen was added 3-chloro-4-fluorobenzoic acid (Aldrich; 10 g). After stirring for 1 hour at 0° C. the mixture was stirred for 1 hour at 25° C. followed by the addition of a further 1.0 g of LiAlH4. Stirring was continued for a further 12 hours at 25° C. after which time the mixture was cooled to 0° C. and quenched with H2O. The mixture was then acidified with 1N HCl (aq) and extracted with EtOAc. After washing with NaHCO3 (aq) and drying (MgSO4), the organic solution was evaporated to give the title compound as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9]/[C:10](=[CH:14]\C1C=CC=C(OC)C=1)/[C:11](O)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])([CH3:26])([CH3:25])[CH3:24]>>[Si:1]([O:8][CH2:9][C:10](=[CH2:14])[C:11]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:28]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cccc(/C=C(\CO[Si](C)(C)C(C)(C)C)C(=O)O)c1
Reactant: CC(C)(C)c1cccc(N)c1
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)Nc1cccc(C(C)(C)C)c1

Procedure:
The title compound was prepared as described in Example 10, Step 3, using (E)-2-((tert-butyldimethylsilyloxy)methyl)-3-(3-methoxyphenyl)acrylic acid and 3-tert-butyl aniline. LCMS, FA: Rt=2.51 min, [MH+ 348.0].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O[C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([NH2:17])[CH3:16].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].[Ta].O>[NH2:17][CH:15]([CH2:14][CH2:13][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][CH:5]=1)([CH3:19])[CH3:18])[CH3:16]
Reactant: CC(N)CCCC(C)(C)O
Reactant: Nc1ccccc1
Agent: [Ta]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CC(N)CCCC(C)(C)c1ccc(N)cc1
Temperature: 185 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of 102 parts of anhydrous zinc chloride in 153 parts of 36% w/w aqueous hydrochloric acid and 200 parts of water are added 140 parts of aniline and 136 parts of 6-hydroxy-6-methyl-2-heptylamine hydrochloride (heptaminol hydrochloride). The whole is charged to a 1 liter tantalum-lined autoclave and stirred at 185° C. for 24 hours. The reaction mixture, after being discharged from the autoclave, is added to a hot solution of 750 parts sodium hydroxide in 1500 parts of water and stirred until cool. The organic phase is extracted with diethylether, washed with water, evaporated and distilled under reduced pressure. After recovering 58 parts of aniline there are obtained 135 parts of 2-amino-6-(4-amino-phenyl)-6-methyl-heptane boiling point 138°-40° C./65 Pa (82% yield based on heptaminol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:18][CH3:19])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[C:11]([Cl:16])[C:10]=3[N:17]=2)=[N:4][O:5][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH:28]1[S:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1.[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:18][CH3:19])[C:9]3[C:14]([O:15][CH2:27][CH:28]4[S:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:29]4)=[CH:13][N:12]=[C:11]([Cl:16])[C:10]=3[N:17]=2)=[N:4][O:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCSC(CBr)C1
Reactant: CCn1c(-c2nonc2N)nc2c(Cl)ncc(O)c21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2c(Cl)ncc(OCC3CN(C(=O)OC(C)(C)C)CCS3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
To a solution of the compound of intermediate VII (2.36 g, 8.40 mmol) in DMF (160 mL) was added anhydrous cesium carbonate (8.32 g, 25.0 mmol) and 1,1-dimethylethyl 2-(bromomethyl)-4-thiomorpholinecarboxylate (enantiomer E1) (2.50 g, 8.40 mmol). After stirring at ambient temperature for 4 h, sat NH4Cl was added and the reaction was extracted with EtOAc. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue subjected to flash chromatography (MeOH/CH2Cl2, silica gel) to give the 2.3 g of the desired compound contaminated with 1,1-dimethylethyl 7-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]oxy}tetrahydro-1,4-thiazepine-4-(5H)-carboxylate. This was used without further purification in the next step. MS (ES+) m/z 496 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:9]3[C:14]([C:15]=2[C:16](=[O:20])[C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1.[BH4-].[Na+]>CCO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)[C:9]3[C:14]([C:15]=2[CH:16]([OH:20])[C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(C(=O)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C)c1-c1c(C(O)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Reaction time: 1.5 h

Procedure:
9 mg 2-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetamide (Example 34) was mixed with 1 ml EtOH, 1.8 mg of NaBH4 was added and the mixture was stirred for 1.5 h. The mixture was evaporated, water was added, followed by extraction with EtOAc. The crude product was purified by reversed phase flash chromatography (acetonitrile/water) to provide 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-hydroxyacetamide (E36). ES/MS m/z: 376.3 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.78 (m, 1H), 7.13-6.93 (m, 5H), 6.79 (m, 2H), 2.23, 2.21 (two s, 3H) and 1.93, 1.90 (two s, 3H).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][C:2]1=[O:21].[BH4-].[Na+]>CO>[CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH:2]1[OH:21]
Reactant: CCCC(=O)Nc1c2c(nc3ccccc13)CCC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)Nc1c2c(nc3ccccc13)CCC(O)C2
Reaction time: 12 h
Yield: 76.5 %

Procedure:
In 20 ml of methanol was dissolved 1 g of the compound of Example 52, and 0.14 g of sodium borohydride was added to the solution and reaction was carried out at room temperature for 12 hours. After removal of the solvent under reduced pressure, 30 ml of chloroform and 30 ml of water were added to the residue and the mixture was stirred. The chloroform layer was separated, dried over sodium sulfate and then condensed and crystallized from chloroform-ethyl acetate to give 0.77 g of the title compound. Melting point: 260° to 265° C. (decomposed).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:17])=[C:6]2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].C(O)C>O.[Fe]>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:17])=[C:6]2[C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc2c(F)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2c(F)c(-c3ccc(N)cc3)n(CC3CC3)c2c1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
A mixture of 1-cyclopropylmethyl-6-ethoxy-3-fluoro-2-(4-nitro-phenyl)-1H-indole (161 mg, 0.45 mmol), iron powder (170 mg), NH4Cl (170 mg, 3.2 mmol), ethanol (4 mL) and H2O (1.5 mL) were heated at 80° C. for 90 minutes. The reaction mixture was diluted with H2O and was extracted with CH2Cl2. The organic layer was dried and concentrated to provide 4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenylamine (122 mg, 83%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([CH2:21][CH2:22][S:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(CCSc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C(CCSc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
21.2 g of 2-(2-phenylthioethyl)malonic acid dibenzyl ester are dissolved in 70 ml of dioxan. The solution is heated to 70°, and, whilst stirring, 50.5 ml of 1 N sodium hydroxide solution are added. Stirring is continued for 20 minutes at 70°, the mixture is cooled and the dioxan is distilled off at 40° under reduced pressure. The aqueous solution is covered with a layer of 100 ml of ether and acidified at 0° with 35 ml of 2 N hydrochloric acid. The ether phase is separated off and the aqueous phase extracted twice with 100 ml of ether each time. The combined ether phases are extracted with 100 ml of 0.5 N potassium bicarbonate solution and then three times with 50 ml of 2 N sodium carbonate solution each time. The combined sodium carbonate solutions are acidified at 0° with 2 N hydrochloric acid. The oil that precipitates is dissolved by extracting three times with 60 ml of chloroform each time. The combined chloroform solutions are dried over magnesium sulphate and concentrated by evaporation under reduced pressure. The residue is dried for 15 hours at room temperature at 0.1 torr. 2-(2-Phenylthioethyl)malonic acid monobenzyl ester is obtained as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=[CH:3]1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[CH3:12][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][CH:5]=[C:6]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)c1cccc(=O)n1C
Yield: 28.5 %

Procedure:
In Example 22, 0.4006 g (2.611 mmol) of methyl 6-oxo-1,6-dihydropyridine-2-carboxylate and 0.4006 g (2.899 mmol) of potassium carbonate were combined in a 25 mL RBF. 1 mL of DMSO followed by 4 mL (64.25 mmol) of methyl iodide was added and the reaction refluxed for 4 hours. The solvent was removed under reduced pressure and the resulting oil was extracted with hot hexanes (8×25 mL), the extracts were combined and solvent removed to yield a yellow oil. Recrystallization from hexanes yielded the product as white/yellow crystals (0.1245 g, 28.52%). Melting Point: 56-57° C. IR: (Nujol) 3437.61, 1731.13, 1652.94, 1590.77, 1457.45, 1443.48, 1379.43, 1265.53, 1218.08, 1156.78, 1086.06, 900.89, 825.45, 817.06, 765.03, 755.48, 722.85 cm−1. 1H NMR: (500 MHz, CDCl3) 3.67 (s, 3H), 3.91 (s, 3H), 6.71 (dd, J=1.2, 9.1 Hz, 1H), 6.74 (dd, J=1.2, 6.8 Hz, 1H), 7.29 (dd, J=6.7, 9.1 Hz, 1H). 13C NMR: (126 MHz, CDCl3) 33.40, 52.90, 110.42, 124.46, 137.21, 138.21, 162.45, 162.70.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](N(OC)C)=[O:9])=[CH:3][CH:2]=1.[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(-c2ccccc2)cc1)c1ccccc1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
Under N2, to a mixture of 2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide (500 mg, 1.96 mmol) in anhydrous THF was added phenylmagnesium bromide (5 mL, 5 mmol) at −78° C., and the mixture was stirred for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to give Intermediate 5 (430 mg, yield 80.7%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([C:29]([O:31]CC4C=CC=CC=4)=[O:30])([CH3:28])[CH3:27])[CH:20]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>[Pd].CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([C:29]([OH:31])=[O:30])([CH3:27])[CH3:28])[CH:20]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(OC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(OC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Reaction time: 3 h

Procedure:
10% Palladium on carbon (180 mg, 10 wt %) was added to a solution of 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-phenyl ester (1.76 g, 3.41 mmol) in methanol (15 mL) and the resulting mixture hydrogenated at atmospheric pressure for 3 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 1.26 g (87%) of: 3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-phenyl ester as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:24])=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=S)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[C:3]2[O:24][C:9]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=S)Nc2cccc(Br)c2O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3cccc(Br)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 0.798 mg (1.93 mmol) 1-(3-bromo-2-hydroxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-thiourea in 8 ml THF, 0.197 g (4.8 mmol) NaOH (in 5 ml water) and 0.419 g (2.12 mmol) toluene-4-sulfonyl chloride are added. The reaction mixture is stirred at room temperature for 1.5 h. Then the reaction mixture is concentrated in vacuo. To the residue EtOAc and sat. NaCl-solution are added and the layers are separate. The water layer is extracted 3× with EtOAc. The combined organic layers are washed with water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is stirred in diethyl ether, filtered and dried to afford the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C=O)C>[C:10]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[C:12]([CH2:13][C:1]#[N:2])[CH:11]=1
Reactant: [C-]#N
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
NaCN (1.1 g, 22.26 mmol) was added to a solution of 3-phenylbenzyl bromide (5.0 g, 20.23 mmol) in dry DMF (100 mL). The resulting reaction mixture was stirred at room temperature for 3 h and then quenched with water. The organic product was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% EtOAc in petroleum ether) to afford 2-([1,1′-biphenyl]-3-yl)acetonitrile (3.8 g, yield 97%). 1H NMR (300 MHz, CDCl3) δ 7.61-7.56 (m, 4H), 7.50-7.45 (m, 3H), 7.42-7.36 (m, 1H), 7.34-7.31 (m, 1H), 3.83 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][N:10]([CH3:16])[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(O)CO>CC(O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][CH2:15][CH:11]([N:10]([CH3:16])[CH3:9])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: CN(C)C1CCNC1
Agent: [Cu]I
Solvent: OCCO
Solvent: CC(C)O
Product: CN(C)C1CCN(c2cccc(Br)c2)C1
Temperature: 80 °C

Procedure:
1-Bromo-3-iodobenzene (1 eq, 3.53 mmol, 1 g), copper(I) iodide (0.05 eq, 0.177 mmol 0.034 g) and potassium phosphate tribasic carbonate (2 eq, 7.07 mmol, 1.51 g) are dissolved in 2-propanol (15 ml) under an inert atmosphere of nitrogen. Then, N,N-dimethylpyrrolidin-3-amine (2 eq, 7.07 mmol, 0.807 g) and ethylene glycol (2 eq, 7.07 mmol, 0.394 ml) are added and the reaction mixture heated at 80° C., overnight.