Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]1[O:18][CH2:17]1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>C(O)C>[OH:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[CH2:17][CH:16]([OH:18])[CH2:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCCNCCO
Reactant: CCCCC(C)CCCCCCCCCCCOCC1CO1
Solvent: CCO
Product: CCCCC(C)CCCCCCCCCCCOCC(O)CN(CCO)CCO
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
In a 10 ml round bottomed flask, 12-methylhexadecylglycidylether (100 mg, 0.32 mmol), diethanolamine (35 mg, 0.33 mmol), and ethanol (1 ml) were placed. The content of the flask was stirred for 1 hour at 80° C. in a nitrogen atmosphere. The mixture was condensed under reduced pressure, and the resulting residue was purified by silica gel flush chromatography. As a result, 88 mg of the title compound was obtained as a pale yellow oil (yield: 66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccncc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-4-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 332(MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN1CCC(c2cccc(O)c2)CC1
Product: CCN1CCC(c2cccc(OS(C)(=O)=O)c2)CC1

Procedure:
Beginning with 3-(1-ethyl-piperidin-4-yl)-phenol and methanesulfonyl chloride. MS m/z (rel. intensity, 70 eV) 283 (M+, 6), 268 (bp), 189 (54), 131 (20), 79 (70);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21](O)=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[C:28]1([NH:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)C(C)C)C>>[C:28]1([N:34]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:21]([C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[N:20][C:11]([CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[O:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CCNc1ccccc1
Reactant: N#Cc1ccc(CCc2ncc3ccc(C(=O)O)cc3n2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.4 g (1.3 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred for 60 minutes at 50° C. Then the thionyl chloride was distilled off, the residue was dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl 3-(N-phenylamino)-propionate and 0.22 ml of (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 hours at ambient temperature. After evaporation of the solvent in vacuo the residue was chromatographed on silica gel and eluted with methylene chloride containing 1% methanol. Yield: 230 mg (37% of theory), Rf value: 0.64 (silica gel, methylene chloride/methanol=9:1)
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:14][C:13]([C:12]1[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccnc1Oc1ccc(F)cc1
Temperature: 0 °C
Yield: 64 %

Procedure:
A mixture of 20.0 g (89.6 mmol) of 2-(4-fluorophenoxy)-3-pyridinecarboxylic acid (for preparation, see: Villani, F. J. et al. J. Med. Chem., 1975, 18,3), 300 mL of methanol, and 5.5 mL of concentrated sulfuric acid was heated to reflux for 2 h. The cooled mixture was poured onto 500 mL of ice cold saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was filtered, washed with water, and dreid under vacuum to give 12.9 g (64% yield) of the title compound as a white solid, mp 97-99° C. Anal. Calcd for C13H10NO3F: C, 63.16; H, 4.08; N, 5.67. Found: C, 62.80; H, 4.08; N, 5.50.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](=O)[CH3:32]>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:31]([CH3:32])[CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: CC(=O)Cc1ccccc1F
Product: CCCC(NC(C)Cc1ccccc1F)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-(2-Fluoro-phenyl)-propan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.0, 19.4, 20.2, 21.2, 24.3, 26.6, 36.1, 36.5, 37.1, 37.3, 53.8, 54.3, 56.0, 59.0, 60.6, 61.2, 67.3, 104.7, 115.4, 115.6, 124.1, 124.2, 126.1, 128.2, 128.2, 131.1, 131.8, 131.9, 137.3, 162.7, 172.5; MS m/z 444.4 (M+1).
Reaction SMILES: [Cl:1][CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3].[CH:8]([N:11]=[C:12]=[O:13])(C)[CH3:9]>>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[Cl:1][CH2:9][CH2:8][N:11]=[C:12]=[O:13]
Reactant: CC(Cl)NC(=O)Cl
Reactant: CC(C)N=C=O
Product: C=CN=C=O
Product: O=C=NCCCl
Temperature: 70 °C
Yield: 2 %
Yield: 43 %

Procedure:
57 parts of 1-chloroethylcarbamyl chloride are introduced into 700 parts by volume of isopropyl isocyanate at 22° C., the solution is heated to 70° C. in the course of 1.5 hours, whilst passing a slight stream of nitrogen through it, and the reaction product is condensed in a cold trap at -70° C. 12 parts (43% of theory) of vinyl isocyanate, of boiling point 38.5° C./1,013 mbar, and 0.85 part (2% of theory) of chloroethyl isocyanate, of boiling point 92° C/1,013 mbar, are obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([Cl:42])[CH:34]=2)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([NH:32][C:30]([C:25]4[C:24]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[CH:34][C:35]=3[Cl:42])=[O:38])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a solution of 0.52 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.39 g of N,N-diisopropylethylamine in 25 ml of methylene chloride is added 1.1 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo 1.10 g of the desired product as a residue. M+ =516,518,520.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[F:5][C:6]([F:24])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO.CCOC(C)=O.[Pd]>[F:24][C:6]([F:5])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH:1]=[O:3])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=CNc1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Yield: 77.8 %

Procedure:
Ammonium formate (1.38 g, 22 mmol) and 10% Pd/C (230 mg, 0.2 mmol) are added to a solution of 1-(2,2,2-trifluoroethyl)-4-(4-nitrophenyl)piperidine (1.26 g, 4.4 mmol) in EtOH (10 mL) and EtOAc (10 mL). The suspension is heated at reflux for 24 hours, adding further portions of ammonium formate (2 g) after 4 h and 8 h. The mixture is filtered through celite and evaporated to afford an orange solid. This is partitioned between DCM (40 mL) and water (20 mL) and the layers separated. The aqueous phase is extracted with DCM (2×20 mL) and the combined organic layers are dried over MgSO4 and evaporated under reduced pressure to afford N-{4-[l-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}formamide as a pale orange solid (980 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[NH:7]1)=[O:5])[CH3:2].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[N:7]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCC(C(=O)O)N1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
To an aqueous solution of trans-2,5-pyrrolidine dicarboxylic acid monoethyl ester (4.8 g, 0.25 m) at 5° C. was simultaneously added benzyl chloroformate (4.8 ml, 0.032 m) and a solution of sodium carbonate (5.4 g, 0.05 m) in water (20 ml). The mixture was stirred at 5° C. for 45 minutes and then extracted with ether. The aqueous mixture was acidified to pH 3 with dilute hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to yield the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(CO)ccc1NS(=O)(=O)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 4-phenylsulfonylamino-3-methoxybenzyl alcohol (522 mg; prepared in Reference Example 43.) in methylene chloride (1 5 ml), manganese dioxide (3 g) was added in a stream of argon. The solution was stirred for 1 hour at room temperature. After the termination of reaction, the reaction mixture was filtered. The filtrate was concentrated to give the title compound (404 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:29]([CH3:30])=[CH:28][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:40]1COCC1.CO>>[CH3:40][C@:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([C:11]1[C:29]([CH3:30])=[CH:28][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:7]([OH:9])=[O:8]
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]cc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(-c3cnc4[nH]cc(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@](C)(OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate: (8 mg, 0.015 mmol) in THF/CH3OH (0.5 mL/0.5 mL) was added 2N NaOH (75 μL, 0.15 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C28H26ClN3O3S: 520.14 (M+H+); Found: 520.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.86 (d, J=1 Hz, 1H), 8.57 (d, J=1 Hz, 1H), 7.84 (s, 1H), 7.71-7.26 (m, 5H), 5.26 (s, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([Cl:26])[C:5](=[O:25])[CH2:6][C:7]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(O)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=1.CCCC[Sn](Cl)(O[Sn](Cl)(CCCC)CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:26][C:4]1[C:3](=[O:2])[O:27][C:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:6][C:5]=1[OH:25]
Reactant: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC)c(Cl)c1)C1CCCC1
Agent: CCCC[Sn](Cl)(CCCC)O[Sn](Cl)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Yield: 72.8 %

Procedure:
A solution of 2-Chloro-7-(3-chloro-4-methoxy-phenyl)-5-cyclopentyl-5-hydroxy-3-oxo-heptanoic acid methyl ester (2.33 g, 5.6 mmol, from Step 1 below), and bis(dibutylchlorotin)oxide (1.38 g, 2.5 mmol), dissolved in toluene (18 mL) were heated at reflux for 30 mins. The resulting mixture was concentrated and purified by silica gel chromatography to give the title compound (1.57 g, 75% yield, two Steps). 1H NMR (CDCl3): δ 1.36-1.79 (br m, 8H), 2.02 (m, 2H), 2.41 (m, 1H), 2.65 (m, 3H), 2.89 (d, 1H, J=17.7 Hz), 3.88 (s, 3H), 6.47 (br s, 1H), 6.85 (d, 1H, J=8.4 Hz), 7.01 (dd, 1H, J=8.4, 2.1 Hz), 7.16 (d, 1H, J=2.1 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[I-].[Li+]>N1C=CC=CC=1>[Cl:24][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH:25]([CH3:26])[CH3:27])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(C(C)C)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1cccc(-c2c(C(=O)O)c(C(C)C)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-isopropyl-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid methyl ester (50 mg, 0.13 mmol) and lithium iodide in pyridine. Off-white solid (18 mg, 37%). LC-MS: 366 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH2:31])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]#[N:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.75 h

Procedure:
To an ice-cooled solution of 1.15 g (2.49 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetamide (Example 82, Step A) in THF (21 mL) was added 1.73 mL (12.4 mmol) of triethylamine and 865 μL (6.22 mmol) of TFA. The resulting tan solution was stirred at 0° C. for 2.75 h, then was warmed to room temperature and stirred for an additional 2 h. The reaction was recooled to 0° C., quenched with 1 N citric acid, and then extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The combined organic layers were washed with saturated aqueous sodium chloride (1×), then were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (5 to 35% EtOAc/hexanes, gradient elution) provided the title compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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:27]([C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2cc(C#N)ccc2C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 8-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 31) (0.397 g, 0.999 mmol), zinc cyanide (0.176 g, 1.499 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.100 mmol) in DMF (4 ml) was stirred and heated at 80° C. for 2 hours then cooled and diluted with EtOAc/water (40 ml of each) and the organic washed with 3×20 ml of water, dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:4 EtOAc/iso-hexane to give the title compound (198 mgs) as a gum which crystallised slowly. MS (ES) C15H18N2O3 requires 274; found 175 [M+H−100]+.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=1>ClCCl.O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:32])=[CH:28][CH:27]=1
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc(-c2ccccn2)s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccn2)s1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a cooled solution (0° C.) of 0.23 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 523 μl of N,N-diisopropylethylamine in 5 ml of dichloromethane is added 0.436 g of 5-(2-pyridinyl)thiophene-2-carbonyl chloride. The mixture is stirred at room temperature for 16 hours under argon and diluted with 40 ml of CH2Cl2 and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1N NaHCO3, brine and dried (Na2 SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from ethyl acetate plus a small amount of hexane to give 0.485 g of tan crystals, m.p. 150°-154° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:48])([CH3:47])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]([C:31]#[N:32])[N:30]=3)=[O:25])=[C:19]([C:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl.CCO>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH2:7][C:8]([CH3:48])([CH3:47])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[NH:30][C:29]([C:31]#[N:32])=[CH:28][N:27]=3)=[O:25])=[C:19]([C:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N1CCC(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of {2-[4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (40 mg, 0.050 mmol) in 2 mL of DCM and 20 μL of EtOH was added 1.5 mL of TFA. The solution was stirred for 3 h at 25° C., diluted with 2 mL of EtOH and concentrated in vacuo. Trituration of the residue with ether afforded 8.4 mg (29%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.10 (d, 1H, J=8.4 Hz), 8.00 (s, 1H), 7.16 (d, 1H, J=8.4 Hz), 7.07 (s, 1H), 5.79 (s, 1H), 4.55-4.48 (m, 1H), 3.30 (s, 6H), 2.89-2.87 (m, 2H), 2.40-2.25 (m, 4H), 1.96-1.93 (m, 2H), 1.86-1.83 (m, 6H), 1.64-1.61 (m, 2H). Mass Spectrum (ESI, m/z): Calcd. for C26H33N6O2, 461.2 (M+H), found 461.3.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([N:11]([CH2:14][CH3:15])CC)C.[C:16](Cl)(=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:1]([NH:8][C:16](=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:11][CH2:14][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:22])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: CCCCCCCN
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCCCCCCNC(=O)c1ccc(C(=O)NCCCCCCC)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 4.6 g heptylamine, 4.04 g triethylamine and 30 ml methylene dichloride, was added with stirring 4.06 g terephthaloyl chloride under ice cooling. Stirring was continued at room temperature for two hours, and the solid which separated out was collected by filtration, washed with methylene dichloride and water in that order, and dried, giving 6.5 g of N,N'-diheptylterephthalamide.
Reaction SMILES: [CH:1]([O-])([O-])[O:2]C.O.[C:7]1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]=[C:19]([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C[O-].[Na+]>CO>[CH3:7][O:18][C:19]([O:2][CH3:1])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC([O-])[O-]
Reactant: CCC(=O)CSCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(CSCC(=O)OC)(OC)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Methyl orthoformate (10.8 ml) and p-toluenesulfonic acid monohydrate. (catalytic amount) are added to a solution of methyl 2-(2-oxobutylthio)acetate (5.80 g, Reference compound No. 36-1) in methanol (60 ml), and the mixture is refluxed for two hours. The reaction mixture is cooled to 0° C., sodium methoxide (1.98 g) is added to the mixture, and the whole is stirred for 20 minutes. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the resulting residue, and the whole is washed with saturated brine. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled away under reduced pressure to give the titled reference compound (6.85 g).