Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si](C)(C)C)=[N:6][CH:7]=1.Br[C:15]1[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][CH:20]=1.CCN(CC)CC.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C)C=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(Br)c1
Reactant: Cc1ccc(C#C[Si](C)(C)C)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C#Cc2ccc(C)cn2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 5-methyl-2-trimethylsilanylethynylpyridine (5.32 mmol) in 25 mL degassed N,N-dimethylformamide was added successively 3-bromoanisole (6.96 mmol), CuI (0.57 mmol), Et3N (21.2 mmol) and trans-dichlorobis(triphenylphosphine)palladium (29 mmol). The resulting mixture was warmed to 70° C., Bu4NF (5.85 mmol) was added drop-wise, and the reaction was stirred at this temperature 2 h. After cooling, 20 mL of H2O was added and the resulting solution was extracted with EtOAc (4×20 mL). The organic layer was washed with saturated NaCl (3×20 mL), dried over Na2SO4 and evaporated to dryness. Purification of the residue by column chromatography provided M-5MPEP in 52% yield as a yellow oil. HCl salts were prepared by adding 2 M HCl/Et2O to a solution of free base in EtOAc and isolated by suction filtration. 1H NMR (CDC13) δ ppm: 2.20 (s, 3H, CH3); 3.67 (s, 3H, CH3); 6.79 (ddd, 1H, J=8.5, 2.5, 1.0 Hz, CHAr); 7.01-7.02 (m, 1H, CHAr); 7.07 (dt, 1H, J=8.5, 1.0 Hz, CHAr); 7.13 (t, IH, J=8.5 Hz, CHAr); 7.29 (d, 1H, J=7.5 Hz, CHAr); 7.33 (dd, 1H, J=7.5, 2.5 Hz, CHAr); 8.32 (s, 1H, CHAr). 13C NMR (CDCh) δ ppm: 18.8 (1C, CH3); 55.6 (1C, CH3); 88.8 (1C, C═C); 88.9 (1C, C═C); 115.9 (1C, CHAr); 116.9 (1C, CHAr); 123.8 (1C, Cq); 124.6 (1C, CHAr); 127.0 (1C, CHAr); 129.6 (1C, CHAr); 133.1 (1C, Cq); 137.0 (1C, CHAr); 140.8 (1C, Cq); 150.9 (1C, CHAr); 159.6 (1C, Cq). HCl salt mp 171-172° C. Anal. C 15H13NO HC1 0.2H20) C, H, N.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)=O)[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:5][C:6]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:7]=1[CH2:8][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)COc1ccc(Cc2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Yield: 72.2 %

Procedure:
In 2 ml of ethanol is dissolved 200 mg of 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetic acid. After adding 40 mg of 5% palladium-carbon, the mixture thus obtained is stirred at ambient temperature for one hour in a stream of hydrogen gas. The reaction mixture is filtered with Celite, and the solvent is distilled off under reduced pressure from the filtrate. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=4:1] to obtain 140 mg of 2-[5-(2,4-diisobutoxybenzyl)-2-isobutoxyphenyl]acetic acid as a colorless oily product.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:33].[OH-].[Na+]>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:4]2[CH:5]=[C:6]([N:9]3[CH2:14][CH2:13][S:12](=[O:15])(=[O:16])[CH2:11][CH2:10]3)[N:7]=[CH:8][C:3]=2[C:1]([NH2:2])=[O:33])=[C:18]([CH3:24])[CH:19]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 100.7 %

Procedure:
A mixture of 5-cyano-4-(4-fluoro-2-methylphenyl)-2-(1,1-dioxo-thiomorpholin-4-yl)pyridine (14.80 g, 42.85 mmol), 15 mL of toluene, and 15 mL (27.6 g, 281 mmol) of concentrated sulfuric acid was heated in a 500-mL flask at 70° C. for 12 hours. The mixture was cooled and quenched with 150 mL cold H2O. A solution of 22.8 g (570 mmol) of sodium hydroxide in 200 mL of H2O was added dropwise at 25–30° C. over 15 minutes. The precipitate was filtered, washed with H2O, and dried to afford 15.68 g (100.7%) of 4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine-3-carboxamide as a colorless solid (2 wt % toluene remains).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]1)(=[O:4])=[O:3]
Reactant: OC1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
Methanesulphonyl chloride (1.95 ml, 25.3 mmol) was added dropwise to an ice-cooled, stirred solution of 3(R,S)-pyrrolidinol (1.0 g, 11.5 mmol), triethylamine (3.5 ml, 25.3 mmol) and 4-dimethylaminopyridine (70 mg, 0.575 mmol) in dichloromethane (10 ml) under nitrogen. The resulting slurry was stirred at room temperature for 24 hours, then diluted with dichloromethane (50 ml), washed successively with saturated aqueous sodium bicarbonate solution (50 ml) and water 50 ml), dried (Na2SO4) and filtered. Dilution of the filtrate with ethyl acetate provided the title compound (1.67 g) as a white crystalline solid. Rf 0.84 (SS 1). Found: C,29.89; H,5.12; N,5.74. C6H13NO5S2 requires C,29.62; H,5.39; N,5.76%.
Reaction SMILES: [F:1][C:2](=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[CH:30][CH:29]=1>CS(C)=O.C(N(CC)CC)C.O>[F:1][C:2]([C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[CH:4]=1)=[C:20]1[CH2:25][CH2:24][N:23]([C:35]([NH:34][C:31]2[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[O:36])[CH2:22][CH2:21]1
Reactant: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(NC(=O)N2CCC(=C(F)c3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a solution of 2-(3-(fluoro(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine (110 mg, 0.312 mmol) and phenyl 6-methoxypyridin-3-ylcarbamate (76.2 mg, 0.312 mmol) in DMSO (5 mL) under a N2 atmosphere was added 5 drops of triethyl amine and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water several times to remove the excess DMSO. The title compound was crystallized from hexane and diethyl ether to give the pure title compound (70 mg). 1H NMR (500 MHz, CDCl3): δ 2.5 (brs, 2H), 2.6 (brs, 2H), 3.5 (brs, 2H), 3.6 (brs, 2H), 4.0 (s, 3H), 6.7 (d, 1H, J=9 Hz), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.3 (m, 3H), 7.4 (t, 1H, J=8.5 Hz), 7.9 (m, 1H), 8.1 (s, 1H), 8.4 (s, 1H); 13CNMR (125 MHz, CDCl3): 25.5, 27.7, 29.7, 44.0, 44.3, 53.8, 60.4, 110.3, 111.6, 114.2, 114.3, 121.3, 121.4, 121.7, 122.0, 122.5, 124.7, 125.3, 129.6, 129.9, 133.6, 133.8, 134.1, 136.8, 138.5, 145.3, 145.4, 149.9, 151.8, 153.0, 155.2, 160.3, 165.4; m/z (503.3 M+ H+); HPLC: 97.6%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(Br)c2occc12
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1ccc(C(F)(F)F)c2ccoc12
Yield: 38.3 %

Procedure:
Beginning with 1.5 gm (5.7 mMol) 4-trifluoromethyl-7-bromobenzofuran and 1.26 gm (6.2 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 0.85 gm (39%) of the desired compound were recovered essentially as described in EXAMPLE 3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.C(N(CC)CC)C.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][OH:44])=[CH:38][CH:37]=1>C(#N)C>[OH:44][CH2:43][CH2:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[N:13]=[C:9]([CH3:8])[S:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:37][CH:38]=1
Reactant: OCCc1ccc(CBr)cc1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CCO)cc4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
To a solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.791 g) and triethylamine (0.697 mL) in acetonitrile (10 mL) was added 2-(4-(bromomethyl)phenyl)ethanol (example 16, step a) and the resulting mixture stirred overnight. The solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was separated and extracted with ethyl acetate (2×25 mL). The combined organic solutions were washed with brine (25 mL), dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.76 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)CCCl
Reactant: COc1ccc(N)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)CCCl)cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3,4-Dimethoxyaniline (0.3 mole), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 5 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3,4-dimethoxyphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[CH:25]([NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)=[O:26]>N1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:2]=1[NH:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:27][CH:25]=[O:26])[CH2:29][CH2:30]1
Reactant: N[C@H]1CC[C@H](NC=O)CC1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2F)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC=O)CC2)cc1OC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 2-fluoro-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (200 mg) and trans-4-formamidocyclohexylamine (170 mg) in pyridine (2 mL) was stirred for 4 hours at 50° C. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N HCl and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 5% methanol in chloroform. The obtained product was recrystallized from acetone (2 mL) to give N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohexyl)amino]-5-nitrobenzamide as yellow crystals (164 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.O1CCCC1.C([Li])(C)(C)C.[B:29](OC)([O:32]C)[O:30]C>CCCCC>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:29]([OH:32])[OH:30])[CH:3]=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CCCCCCc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-7-hexyl-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 53, 1.32 g, 4.26 mmol), anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane and trimethyl borate, the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:47])=[C:41]([CH:46]=1)[C:42]([O:44]C)=[O:43]>>[C:42]([C:41]1[CH:46]=[C:37]([CH:38]=[CH:39][C:40]=1[CH3:47])[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)([OH:44])=[O:43]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COC(=O)c1cc(CCl)ccc1C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)O)c2)cc1

Procedure:
Analogously to Method D, 1.68 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.700 g of methyl 5-chloromethyl-2-methylbenzoate are reacted. The title compound is obtained as a white foam. Rf=0.07 (1:2 EtOAc-heptane); Rt=5.65.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:31])[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pd]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:31])[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C(=O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
25 g of 2-(4-benzylpiperidino)-4'-benzyloxypropiophenone are debenzylated in 200 ml of ethanol and 10 ml of acetic acid, in a Parr apparatus, in the presence of 1 g of 10% palladium-on-charcoal under a pressure of 0.1 MPa for 3 hours. The product obtained is isolated by filtering off the catalyst and evaporating off the solvent.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][C:29]([Br:31])=[CH:30][C:25]=1[CH2:24][O:23][CH2:22][CH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCOCc2cc(Br)ccc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Br)cc1COCCC1CCCNC1
Temperature: 0 °C

Procedure:
In a 1-ml round bottom flask 1-(t-butoxycarbonyl)-3-[2-(2-fluoro-5-bromobenzyloxy)ethyl]piperidine (0.495 g) was dissolved in methylene chloride (4 ml) under a nitrogen atmosphere. The solution was cooled to 0° C. and trifluoroacetic acid (1 ml) was slowly added dropwise. The resulting mixture was stirred for thirty minutes at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting residue was used as is.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])[C@:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[C@@H:6]1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].[OH-].[K+]>C1COCC1.CO>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([C@H:8]2[CH2:9][N:5]([CH2:4][C:3]([OH:33])=[O:2])[C@@H:6]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@:7]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CN1C[C@H](c2cccc(Cl)c2F)[C@@](C#N)(c2ccc(Cl)cc2F)[C@@H]1CC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 8, rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid methyl ester (115 mg, 0.23 mmol) in THF/MeOH (1.8/0.6 mL) was treated with 2N KOH (0.6 mL) at rt overnight to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (108.5 mg, 97.0%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29]C)=[O:28])[CH2:4][C@@H:3]1[OH:31].[ClH:32]>O1CCOCC1.O>[ClH:32].[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([OH:29])=[O:28])[CH2:4][C@@H:3]1[OH:31]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CCN[C@@H]1C[C@]2(C)[C@@H](C(=O)O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](O)C[C@]3(C)[C@H]21

Procedure:
Methyl 2β,3α-dihydroxy-11α-(3-methylbutylamino)5α-androstane-17β-carboxylate (750 mg) in dioxan (20 ml) was treated with concentrated hydrochloric acid (3 ml) and water (10 ml) and heated on a steam bath for 5 days. The cooled mixture was diluted with water (200 ml) and acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate (3×). The extracts were washed with brine, dried and evaporated to give a foam (426 mg). This was purified by preparative t.l.c. in chloroform/methanol (4:1) to give the title compound (146 mg), [α]D +17° (in dimethyl sulphoxide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16]C(C)(C)C)=O)[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.C(OC([NH:41][C@@H:42]([CH:46]1[CH2:48][CH2:47]1)C(O)=O)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:46]1([C@H:42]([NH2:41])[C:14]([N:12]2[CH2:13][C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:10][C@H:11]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:16])[CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 1.00 g, 2.80 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via benzene azeotrope (1×50 mL), then dissolved in DMP (30 mL). (2S)-[(tert-butoxycarbonyl)amino](cyclopropyl)ethanoic acid (0.903 g, 4.20 mmol, 1.50 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.805 g, 4.20 mmol, 1.50 equiv), 1-hydroxy-7-azabenzotriazole (0.571, 4.20 mmol, 1.50 equiv) and triethylamine (1.95 mL, 14.0 mmol, 5.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 5 days. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in a 4:1 mixture of dichloromethane and trifluoroacetic acid. The resulting solution was allowed to stand for 25 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL), and the combined organic layers were washed with aqueous sodium bicarbonate solution (2×100 mL), then brine (100 mL), and dried over sodium sulfate and concentrated to provide (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7) as a white solid. 1H NMR (500 MHz, CD3OD) major rotamer: δ 7.41 (t, 2H, J=7.6 Hz), 7.33 (m, 3H), 7.26 (m, 1H), 7.18 (m, 1H), 7.09 (m, 1H), 6.46 (s, 1H), 5.91 (m, 1H), 5.02 (d, 2H, J=13.9 Hz), 4.96 (ddd, 1H, J=13.9, 4.4, 1.7 Hz), 3.08 (d, 1H, J=7.6 Hz), 1.04 (m, 1H), 0.52 (m, 3H), 0.37 (m, 1H). LRMS m/z (M+H) 355.0 found, 355.2 required.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>CCOCC>[F:15][C:4]([F:3])([F:14])[C@H:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: O[C@H](c1ccc(F)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
NaH (11.87 g, 296.7 mmol) was added to Et2O (700 mL) at 0° C. under N2 followed by addition of an Et2O solution of 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethanol (44.3 g, 228.2 mmol). The reaction mixture was stirred for 10 min at 0° C. then 1 h at room temperature. Trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) in Et2O was added at 0° C. under N2 and the reaction mixture was stirred 10 min at 0° C. then 3 h at room temperature. The solvent was removed under the reduced pressure and H2O (100 mL) was added slowly. The aqueous layer was extracted by hexane and the combined organic layer was dried over MgSO4. The solvent was removed under the reduced pressure to give trifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (70 g) as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:28]([NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]([CH3:31])[CH3:30]>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)CNCC(C)C
Product: CC(C)CN(CC(C)C)C(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 70.7 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.24 mmol) and diisobutyl-amine (0.29 g, 2.24 mmol) were used to afford 0.74 g of the required product. 1H NMR (DMSO-d6): δ 0.72 (6H, d), 0.88 (6H, d), 1.82 (1H, m), 2.00 (1H, m), 3.06 (2H, d), 3.24 (2H, d), 6.98 (2H, d), 7.04 (1H, t), 7.22 (4H, d), 7.89 (4H, d).