Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[N:34]=[C:35]=[O:36].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:35]([NH:34][C:28]3[C:29]([Cl:33])=[CH:30][CH:31]=[CH:32][C:27]=3[Cl:26])=[O:36])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1c(Cl)cccc1Cl)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.01 g; 3.04 mmol) in THF (25 mL) was added dropwise n-BuLi (1.2 mL; 2.5 mol/l in hexanes; 3.04 mmol), at −78° C. After 1 hour at −78° C., a solution of 2,6-dichlorophenyl isocyanate (0.63 g; 3.34 mmol) in THF (5 mL) was added dropwise. The mixture was allowed to warm to RT and then 5% aqueous NaHCO3 was added. Subsequently, the mixture was extracted with Et2O. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O:hexanes 1:1) to afford 4-(4-benzyl-morpholin-2-yl)-N-(2,6-dichloro-phenyl)-benzamide (0.68 g).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:26]1([CH:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH:10]3[CH:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][NH:8][CH2:9]3)[CH2:25][CH2:24]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Yield: 98.8 %

Procedure:
A mixture of 232 mg (0.6 mmol) of 1-phenylmethyl-3-(SR)-((4-phenyl) piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 9, Step B), 894 mg (14.1 mmol) of ammonium formate and 116 mg of 20% Pd(OH)2 on carbon in 10 mL of MeOH was heated at reflux for 1 h. The reaction mixture was cooled and filtered througha pad of Celite. The reaction flask and filtered solids were rinsed with 50 mL of EtOAc and the filtrate was concentrated in vacuo. The residue was partitioned between 50 mL of EtOAc and 30 mL of sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4. The aqueous layer was extracted with 50 mL of EtOAc; the extract was dried and the organic layers were combined and concentrated in vacuo to afford 190 mg (95%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.63-1.80 (m, 4H), 1.93-2.05 (m, 2H), 2.39-2.53 (m, 5H), 2.83 (d, J=10.7, 1H), 2.93-3.02 (m, 2H), 3.08 (t, J=9.6, 1H), 3-47-3.53 (m, 1H ), 5.19 (br s, 1H ), 7.19-7.38 (1OH). Mass Spectrum (NH3 -CI): 321 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(OCC)(=O)C.C(O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:13]2[O:12][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc3ccccc3o2)nc1
Reaction time: 4 h
Yield: 17.7 %

Procedure:
In a 100 ml-three-necked flask, 2.80 g (15.4 mM) of 2-chloro-5-trifluoromethylpyridine, 2.50 g (15.4 mM) of 2-benzofuranylboronic acid, 14 ml of toluene, 7 ml of ethanol and 14 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.55 g (0.48 mM) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring for 4 hours was performed under nitrogen stream. After the reaction, the reaction mixture was cooled on an ice bath and stirred at room temperature after addition of ethyl acetate and saturated saline water. The organic layer was washed with water and dried with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a residue. The residue was purified by alumina column chromatography (eluent: toluene) and recrystallized from methanol to obtain 0.72 g of 2-(5-trifluoromethylpyridine-2-yl)benzofuran (Yield: 17.7%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[N:19]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)(=[O:28])=[O:29])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:37]=[CH:38][C:39]([NH:40][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:41][CH:42]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccncc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccncc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Phenyl chloroformate (0.177 mL, 1.41 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-pyridin-4-ylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (0.640 g, 1.41 mmol) and sodium bicarbonate (0.178 g, 2.12 mmol) in dioxane (175 mL) at RT under air. The resulting slurry was stirred at RT for 2 hours. Two more portions of phenyl chloroformate (2×0.005 mL) were added and the reaction allowed to stir at RT. Water was then added to the reaction and the solids were filtered and dried in a vacuum oven at 55° C. overnight to give the desired material as a tan solid (0.758 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-].Cl>CN(C=O)C.CC(=O)OCC.C1COCC1.CO>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:10](=[O:12])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:13]([F:16])([F:15])[F:14])[CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(OC)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
Prepared using General Procedures 6 and 9: To a stirred solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.14 mmol), methyl 4-amino-2-methoxybenzoate (387 mg, 2.14 mmol) and TEA (744 μL, 5.34 mmol) in DMF (5 mL) was added HATU (852 mg, 2.24 mmol). After 1 h the reaction mixture was diluted with EA (100 mL) and washed with brine (2×100 mL). The organic layer was pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford a white solid. The solid was diluted with THF (15 mL) and MeOH (10 mL) and then 1 N LiOH (427 μl, 4.27 mmol) was added and the solution stirred at room temperature. After 18 h the reaction mixture was acidified by the addition of 1 N HCl (50 mL) and the organics removed under vacuum. The residue was extracted with EA (100 mL) and the organics were washed with brine (200 mL) and dried over magnesium sulfate. The solvent was concentrated to afford 404 mg (49%) 2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-23 as a white powder. LCMS-ESI (m/z) calculated for C18H16F3NO5: 237 found 236 [M−H]−, tR=1.90 min (Method 10).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:48])[NH:18][C:19]2([CH2:37][C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)=[O:39])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:20]2=[O:36])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)O.O.C(OCC)(=O)C>C(O)C>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[CH2:28][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=2)=[O:48])([CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[O:39])[C:20]1=[O:36])[CH3:32]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c2ccccc21)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(CO)cc2)c2ccccc21)OCC
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
3-(N′-(4-t-butyldimethylsilyloxymethylphenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl) indolin-2-one (308 mg) was dissolved in ethanol (15 mL), concentrated sulfuric acid (10 mg) was added, and the mixture was stirred at 15-30° C. for one hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was dried with anhydrous sodium hydrogensulfate and the solvent was distilled off. The reaction mixture was purified by silica gel column chromatography to obtain 225 mg of the title compound (yield: 88%).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:17]1[CH2:16][CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)=[CH:28][CH:27]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(OC3CCNCC3)cc2)CCOCC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[4-(4-cyanotetrahydro-2H-pyran-4-yl)phenoxy]-1-piperidinecarboxylate (720 mg) was dissolved in dichloromethane (50 ml) at 0° C. TFA (10 ml) was added and the mixture stirred whilst warming to room temperature over 2 hours. The reaction mixture was then concentrated in vacuo, and partitioned between dichloromethane (80 ml) and 0.5M NaOH (50 ml). The dichlorormethane solution was dried over Na2SO4 and evaporated to give 4-[4-(4-piperidinyloxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile as a colorless oil which crystallized on standing (500 mg, 94%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([C@@H:45]2[CH2:47][C@H:46]2[C:48](Cl)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:48]([C@@H:46]3[CH2:47][C@H:45]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)[C@@H]1C[C@H]1c1ccccc1)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the mixture cooled to 0° C. Added to this was (1R,2R)-2-phenylcyclopropanecarbonyl chloride (10 μl, 0.07 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% CF3CO2H, Sunfire 19×100 mm, C18, 5 μm). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate isolated by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-((1R,2R)-2-phenylcyclopropanecarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (5.5 mg, 39% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 6.61-7.66 (9H, m), 4.70-4.87 (1H, m), 4.09-4.63 (2H, m), 3.40-4.02 (3H, m), 2.24-2.49 (1H, m), 2.06-2.23 (1H, m), 1.80-1.96 (1H, m), 1.45-1.76 (1H, m), 1.20-1.45 (10H, m), 1.11-1.19 (3H, m), 0.86-1.03 (8H, m). 19F NMR (500 MHz, CD3OD) δ ppm −115.29, −115.86. LCMS (M+H) calcd for C12H42FN2O4: 573.31. found: 573.08.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:35])[C:14]([CH3:34])=[C:15]([CH:20]3[CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21]3)[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl>CO.[C].[Pd]>[NH:22]1[CH2:23][CH:20]([C:15]2[O:16][C:17]3[C:12]([C:13](=[O:35])[C:14]=2[CH3:34])=[CH:11][CH:10]=[C:9]([OH:8])[C:18]=3[CH3:19])[CH2:21]1
Reactant: Cc1c(C2CN(C(=O)OCc3ccccc3)C2)oc2c(C)c(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C2CNC2)oc2c(C)c(O)ccc2c1=O
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of benzyl 3-[7-(benzyloxy)-3,8-dimethyl-4-oxo-4H-chromen-2-yl]azetidine-1-carboxylate (625 mg, 1.33 mmol) obtained in Example 1-2 in methanol (12 mL), 10% palladium-carbon (water content: 50%, 200 mg) was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere. Dichloromethane (20 mL) and methanol (20 mL) were added to the reaction solution, and the palladium-carbon was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain 297 mg of the title compound (yield: 91%).
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=2)[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:25]=2[C:38](O)=[O:39])=[CH:19][CH:18]=1.C(N)CC.O>C(Cl)Cl>[CH2:4]([NH:3][C:38]([C:25]1[N:26]([CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[C:27]2[C:32]([C:24]=1[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:39])[CH2:5][CH3:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)O)n(CCN(C)C)c3ccccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCN
Solvent: O
Product: CCCNC(=O)c1c(C(c2ccc(OCOC)cc2)c2ccc(OCOC)cc2)c2ccccc2n1CCN(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (728 mg, 3.80 mmol) was added to a solution of 3-{bis[4-(methoxymethoxy)phenyl]methyl}-1-(2-dimethylaminoethyl)indole-2-carboxylic acid (1.0 g, 1.90 mmol) obtained in Example 48 and propylamine (0.23 ml, 2.85 mmol) in 10 ml of methylene chloride, followed by stirring at room temperature for 3.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.2 g (quantitative) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([S:15]([CH2:18][CH:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:17])=[O:16])([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][C:12]([S:15]([CH2:18][CH:19]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])(=[O:17])=[O:16])([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(COC(=O)c1ccccc1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in paragraph (d) above, by reacting benzoyl chloride with benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate in pyridine there was obtained benzyl rac-α-[[[2-(benzoyloxy)-l,1dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 403 (M-benzyl)+.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:44])[C@@H:35]([NH2:43])[CH2:36][C:37]1[S:38][C:39]([Br:42])=[CH:40][CH:41]=1>>[Br:42][C:39]1[S:38][C:37]([CH2:36][C@H:35]([NH:43][C:26]([C:15]2[N:16]=[C:17]([CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[C:10]([O:9][C:8]2[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)[CH:19]=3)=[O:27])[C:34]([OH:33])=[O:44])=[CH:41][CH:40]=1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)s1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(Br)s4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 87.7 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester HCl (40.1 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 66.9 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C:11]3=[CH:12][CH2:13][C@@H:14]2[C:15](=O)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C([BH3-])#N.[Na+]>CC(O)=O.CO.[I-].[Zn+2].[I-]>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C:11]3=[CH:12][CH2:13][C@@H:14]2[CH2:15][CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(CC[C@H]3C4=CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H]1CC=C2[C@@H]3CCC4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 74 %

Procedure:
A solution of 5.2 g of 3β-acetoxy-pregn-14-en-20-one (Gambara, T. et al, Chem. Pharm. Bull., 1970, 18, 453) and p-toluensulphonyl hydrazide (3.5 g) in AcOH (50 mL) was stirred at room temp. for 3 hrs. The solvent was evaporated to dryness under reduced pressure: the residue obtained was dissolved in MeOH (200 mL) and zinc iodide (0.6 g) was added. To this solution sodium cyanoborohydride (1.5 g) was added portionwise and the temperature was raised to the boiling point of the reaction mixture. After 2 hrs the solvent was evaporated to dryness under reduced pressure, the crude product was dissolved in ethyl acetate and neutralised with 0.1 N NaOH; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 97/3 as eluant to give 3.7 g of 3β-acetoxy-pregn-14-ene as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[F:32])(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccccc3F)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.89 (1H, t, J=6.9 Hz), 7.45-7.06 (12H, m), 6.48 (1H, br.s), 3.46-3.36 (2H, m),2.77-2.71 (2H, m), 2.28 (3H, s), 2.21 (3H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN1CCOCC1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O1CCCC1>[CH2:34]([O:33][C:31]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)NCCCO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)NCCCOC(=O)OCC

Procedure:
3.14 g of N-(3-hydroxypropyl) hexadecanamide (10 mmoles) was suspended in 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g of N-methylmorpholine (11 mmoles) and 1.19 g of ethyl chloroformate (11 mmoles) were added and the resulting mixture was stirred for a further 3 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum. The residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness. The residue was crystallized from 30 ml of tert-butylmethyl ether. The crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried in a high degree of vacuum. The yield of the reaction was 92%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([NH2:37])(=[O:36])[CH3:35]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:37][C:34](=[O:36])[CH3:35])[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Temperature: 90 °C

Procedure:
To a solution of 400 mg of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) below in 12 mL of dioxane are successively added, under argon, 23.3 mg of palladium diacetate, 72 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine)[Xantphos], 1.18 g of caesium carbonate and 153 mg of acetamide. After heating for one hour at a temperature in the region of 90° C. and chromatography on a column of silica, eluting with a mixture of diethyl ether/ethyl acetate (gradient up to 100% of ethyl acetate), 370 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)acetamide are obtained in the form of white crystals, the characteristics of which are as follows: