Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
DMSO (5.2 mL, 72.6 mmol) in dichloromethane (14.5 mL) was added to a solution of oxalyl chloride (3.1 mL, 36.3 mmol) in dichloromethane (83 mL) at −70° C. under nitrogen. After stirring for 5 minutes, 2-(4-methoxyphenyl)ethanol (5.0 g, 33.0 mmol) dissolved in dichloromethane (33 mL) was added drop wise (20 min). Stirring was continued for an additional 20 min. and triethyl amine (9.7 mL, 69.3 mmol) was added, and the reaction mixture was stirred and warmed slowly to room temperature for 1 hour. The reaction mixture was diluted with water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide 2-(4-methoxyphenyl)acetaldehyde (553) (2.2 g, 44.4%) as an oil residue.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=1[C:44]1[O:45][C:46]([C:52]([F:55])([F:54])[F:53])=[C:47]([C:49](O)=[O:50])[N:48]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:49]([C:47]3[N:48]=[C:44]([C:38]4[C:37]([Cl:36])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:43])[O:45][C:46]=3[C:52]([F:55])([F:54])[F:53])=[O:50])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C(O)c1nc(-c2c(Cl)cccc2Cl)oc1C(F)(F)F
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester HCl salt (380 mg, 1.071 mmol), EDCI (513.3 mg, 2.678 mmol), 2-(2,6-dichlorophenyl)-5-trifluoromethyloxazole-4-carboxylic acid (366.61 mg, 1.125 mmol), HOBt (217.09 mg, 1.607 mmol) and ethyldiisopropylamine (485.63 mg, 3.749 mmol) were put into dichloromethane solvent (10 mL) and stirred at room temperature for 24 hours. After the reaction, aqueous NaHCO3 was added thereto, and extracted with dichloromethane. The organic layer was washed with brine, then the product was dried with anhydrous sodium sulfate, and solvent was removed. Column chromatography was conducted on the crude material to obtain trans-{4-[4-(3-{[2-(2,6-dichlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (609 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C@:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C@:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH:22][C:35]4[N:36]=[CH:37][C:32]5[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)[C:33]=5[N:34]=4)=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]2(C1)CN(c1ccc(N)nc1)C(=O)O2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@]5(CCCN(C(=O)OC(C)(C)C)C5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 43 %

Procedure:
Following general N—C coupling procedure 1, (S)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester as a white solid (0.115 g, 0.190 mmol in 43% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.37-1.51 (m, 13H) 1.51-1.69 (m, 3H) 1.69-1.84 (m, 2H) 1.85-2.15 (m, 11H) 2.47-2.68 (m, 2H) 3.10-3.19 (m, 6H) 3.19-3.33 (m, 2H) 3.43 (d, J=14.05 Hz, 1H) 3.58-3.71 (m, 2H) 3.71-3.80 (m, 2H) 3.85 (d, J=9.03 Hz, 2H) 4.12 (q, J=7.03 Hz, 1H) 4.44 (br. s., 1H) 4.80 (quin, J=8.78 Hz, 1H) 6.46 (s, 1H) 7.87-7.99 (m, 1H) 8.11 (dd, J=9.29, 2.76 Hz, 1H) 8.21 (br. s., 1H) 8.30 (br. s., 1H) 8.52 (d, J=9.03 Hz, 1H) 8.75 (s, 1H). MS m/z 605.5 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: N#Cc1cccc(CO)c1
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and (3-cyanophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H14N4O3, 335; Found, 335.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13]([O:21][C@@H:22]3[O:39][C@H:38]([CH2:40][O:41]C(=O)C)[C@@H:33]([O:34]C(=O)C)[C@H:28]([O:29]C(=O)C)[C@H:23]3[O:24]C(=O)C)=[N:14][NH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=1.C[O-].[Na+]>CO>[C@@H:22]1([O:21][C:13]2[C:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:9]=3)=[C:16]([C:17]([F:20])([F:19])[F:18])[NH:15][N:14]=2)[O:39][C@H:38]([CH2:40][OH:41])[C@@H:33]([OH:34])[C@H:28]([OH:29])[C@H:23]1[OH:24]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(CCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCCCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of 4-{[4-(3-hydroxypropyl)phenyl]methyl}-5-trifluoromethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.45 g) in methanol (7 mL) was added sodium methoxide (28% methanol solution, 0.068 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 3-(β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropyl)phenyl]methyl}-5-trifluoromethyl-1H-pyrazole (0.17 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:12]=1>CN(C=O)C>[CH2:35]([C:13]1[N:12]=[C:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[NH:16][C:15](=[O:17])[C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1nc(N)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc(NC(=O)Nc2ccccc2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
0.27 g of phenylisocyanate were added to a solution containing 0.3 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) -methyl]pyrimidin-4-one in ml of dry DMF at 0° C. After stirring at room temperature for 30 minutes the mixture was evaporated to dryness and the residue was crystallized from DMF; 0.22 g of a white solid was obtained (yield 56%, m.p. 217°-219° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16](Cl)(=[O:18])[CH3:17].FC(F)(F)C(O)=O>O>[C:16]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: OC(c1ccccc1)c1cccnc1Cl
Reactant: CC(=O)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(c1ccccc1)c1cccnc1Cl
Reaction time: 1 h

Procedure:
A mixture of 4.39 g 2-chloro-α-phenyl-3-pyridinemetanol (see Ex. 20), 3.14 g acetyl chloride and 8 ml trifluoroacetic acid is stirred for 1 hr. at room temperature. The reaction liquid is added dropwise to water, and the solid formed is filtered, washed, dried and crystallised from cyclohexane. Yield: 4.46 g title product, m.p. 100°-2° C.; Cl 13.82 (13.55).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18]2>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH:20]3[CH2:23][CH:17]2[CH2:22][CH2:21]3)=[CH:4][CH:3]=1
Reactant: C1CC2CC1CN2
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CC3CCC2C3)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A stirred solution of 4-bromobenzyl bromide (66 mg, 0.26 mmol), triethylamine (0.22 mL, 1.56 mmol) and 2-azabicyclo[2.2.1]heptane (71 mg, 0.52 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was cooled to ambient temperature, the solid removed by filtration and the filtrate concentrated under reduced pressure to afford the title compound (70 mg, quantitiative yield) that was used in the next step without further purification. LCMS (Method B): RT=2.04 min, M+H+=266/268.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10](=[O:24])[N:11]([O:16]CC1C=CC=CC=1)[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]>[Pd].C(O)C>[OH:16][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:24])[O:9][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)CN(O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Ammonium formate (7.9 g, 125 mmol) and 10% palladium on carbon (2 g) were added to a solution of tert-butyl-N-benzyloxy-N-(2-methylpropyl)carbamate (Compound 54 Part B, 6.27 g, 22.4 mmol) in ethanol (100 mL). The reaction mixture was stirred at ambient temperature for 5 hours then concentrated under vacuum at 50° C. The residue was taken up in methylene chloride, washed with water, dried with magnesium sulfate and then concentrated to provide 4.2 g of tert-butyl N-hydroxy-N-(2-methylpropyl)carbamate as a yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([O:25][C:26]1[CH:53]=[CH:52][C:51](Br)=[CH:50][C:27]=1[C:28]([NH:30][C:31]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[CH2:18]([O:25][C:26]1[CH:53]=[CH:52][C:51]([N:8]2[CH2:9][CH2:10][CH:5]([N:4]([CH3:11])[CH3:3])[CH2:6][CH2:7]2)=[CH:50][C:27]=1[C:28]([NH:30][C:31]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C1CCN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
4-(Dimethylamino)piperidine dihydrochloride (0.11 g), cesium carbonate (0.44 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and cesium carbonate (0.13 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 7 hours. The reaction mixture was cooled to room temperature, and tripotassium phosphate (0.29 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(4-(dimethylamino)piperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [C:1]1(C)C(S(O)(=O)=O)=CC=CC=1.[C:12]12([CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:13]2=[O:14].FC(F)(F)C(O)=O.CS(O)(=O)=O.S(=O)(=O)(O)O.[CH2:44]([Cl:46])[Cl:45]>COCCOC.C1COCC1.C(Cl)(Cl)Cl>[C:12]12([CH2:22][S:23]([OH:26])(=[O:24])=[O:25])[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:13]2=[O:14].[Cl:45][CH:44]([Cl:46])[CH3:1]
Reactant: ClCCl
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: CC(Cl)Cl

Procedure:
Compound 2 is first treated as described above in Method B, Step 1, to obtain an intermediate phenol dihydropyridine which is then treated with about 0.1-0.3 meq (preferably 0.1 meq) of an acid (toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid; preferably, camphorsulfonic acid) in a solvent such as CH2Cl2, CHCl3, dichloroethane, THF, DME, or mixtures thereof (preferably methylene chloride) at about 25° to 50° C. for about 2-24 hours to obtain compound 1a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([O:14][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COC1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 83.2 %

Procedure:
Tetrabutylammonium bromide (1.06 g, 3.3 mmol) is added to a solution of 1-(4-bromophenyl)piperidin-4-ol (2.56 g, 10 mmol) in toluene (30 mL). The reaction mixture was cooled to 0° C. and aq. 35% sodium hydroxide (30 mL) was added followed by a drop-wise addition of tert-butyl bromoacetate (2.92 g, 15 mmol). The mixture was then allowed to reach room temperature and was stirred for 17 hours at this temperature. The layers were separated and the organic layer was washed twice with water (4 mL), dried over sodium sulfate, concentrated under vacuum and co-evaporated with petroleum ether. Purification of the crude material by flash column chromatography on silica gel (0-20% ethyl acetate in petroleum ether) yielded the desired pure material 3.08 g as pale yellow solid. MS (m/z): 372 (M+2)+
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NC1CCCCCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
Dissolve 4-bromo-benzoyl chloride (2.0 g, 9.1 mmol) in DCM (20 mL). Cool the solution to 0° C. and add triethylamine (2.54 mL, 18.2 mmol) followed by cycloheptylamine (1.24 g, 10.9 mmol). Warm the mixture to room temperature over 1 h. Wash the mixture with saturated NaHCO3 (15 mL). Collect the organic layer, and extract the aqueous layer with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (120 g) eluting with hexane/EtOAc (1:1) to obtain the title compound as a solid (2.5 g, 93%). MS (APCI+) m/z: 296 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][C:12](OC(C)=O)=[O:13]>>[C:12]([C:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=2[S:6][CH:7]=1)(=[O:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2sccc2c1
Product: CC(=O)c1csc2ccc(C)cc12
Reaction time: 8 h
Yield: 50 %

Procedure:
1 g of 5-methylbenzo(b)thiophene (6.75×10−3 moles) was stirred at 55° C. with 0.8 ml of Ac2O (8.10×10−3 moles). 0.83 ml of BF3 Et2O were added and stirring was continued for 8 hours.11 The solvent was removed in the rotary evaporator and the residue was extracted with AcOEt and H2O. It was decanted and washed with NaHCO3 and H2O. It was dried with Na2SO4, the solvent was removed and the product was purified in successive columns of AcOEt/hexane (1:1) and toluene respectively. A product was obtained which was a mixture of the substitution isomers in positions 2- and 3- of the benzo(b)thiophene ring in a proportion of approximately 20/80 (determined by the ratios of the areas of the NMR signals), which was passed to the following reaction. Yield: 50%.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6].Cl.[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.O>[CH2:8]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6])=[O:30])=[CH:32][CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: OCC=CCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC=CCO)cc1
Reaction time: 4 h

Procedure:
To a mixture of 8.8 g. of 1,4-dihydroxy-2-butene and 2.84 g. of 4-dimethylaminopyridine is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. The heat evolution is moderated with ice and stirring is continued for 4 hours. Chloroform and water are added and the chloroform extract chromatographed to remove any diacylated by-product. Evaporation to crystallization yields the 4-hydroxy-2-buten-1-yl 4-(n-hexadecylamino)benzoate as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]([OH:21])=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].N1C2C(=CC=CC=2)C=[CH:23]1>>[CH2:1]([C:3]1([CH2:18][C:19]([OH:21])=[O:20])[C:8]2[N:9]([CH3:23])[C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Product: CCc1cccc2c3c(n(C)c12)C(CC)(CC(=O)O)OCC3

Procedure:
Following the procedure of example 49.A. except using (1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the indole component afforded the title compound as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=4)[C:23]=3[CH3:24])=[O:18])=[CH:12][C:11]=2[CH3:35])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>O1CCOCC1.C(O)C.[C].[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][N:26]=4)[C:23]=3[CH3:24])=[O:18])=[CH:12][C:11]=2[CH3:35])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)N1CCC(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 54.2 %

Procedure:
N-{6-[1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl]-5-methylpyridin-3-yl}-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (180 mg) described in Example K39 was dissolved in 1,4-dioxane (2 ml) and ethanol (2 ml), 10% palladium-carbon (containing ca. 50% water; 90 mg) was added, and stirred at room temperature under hydrogen atmosphere for 8.5 hours, then ethanol (1 ml) was added and stirred at 40° C. for two days. The reaction solution was filtered through Celite, washed with chloroform and ethanol and the solvent was evaporated in vacuo. The precipitated solid was washed with ethyl acetate and ethanol to give the titled compound (98 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:35])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C)C(=N)N(C)C.Cl>ClCCl>[CH3:35][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]2[C:9]=1[CH:10]=[C:11]([CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=3)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:15])[F:16])[NH:1]2
Reactant: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cc2[nH]c(CC(O)(CC3(C)CCOc4ccc(S(C)(=O)=O)cc43)C(F)(F)F)cc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 7.9 %

Procedure:
To a chilled (0° C.) solution of 130 mg (0.25 mmol) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile in 5 mL of dichloromethane was added 105 μL (0.74 mmol) of trifluoroacetic anhydride. After 15 minutes, the reaction was concentrated in vacuo and the residue was diluted with diethyl ether and concentrated in vacuo, three times. The resulting oil was dissolved in 1 mL of DMSO and then 0.09 mL (0.74 mmol) of tetramethylguanidine was added and the mixture was warmed at 140° C. in a microwave oven. After 10 minutes, the mixture was cooled, poured onto crushed ice with 1N aqueous HCl and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparatory TLC (silica gel, 1:1 ethyl acetate-hexanes) to afford first 35 mg (27%) of the title compound as a single diastereomer (M−1=505) and second 10 mg (8%) of the title compound as the opposite diastereomer (M−1=505).