Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:4][C@:5]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C[C@]12[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC[C@@H]1[C@H]1[C@H](C(C)=C)CC[C@]1(CNCCN1CCN(S(C)(=O)=O)CC1)CC2.[NH:99]1[CH2:104][CH2:103][CH:102]([CH2:105][OH:106])[CH2:101][CH2:100]1>>[OH:106][CH2:105][CH:102]1[CH2:103][CH2:104][N:99]([CH2:3][CH2:2][NH:1][CH2:4][C@:5]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:25])([CH3:26])[C:14]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:38][CH:39]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:100][CH2:101]1
Reactant: OCC1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCC(CO)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-ylmethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the procedure described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethylamino)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, using piperidin-4-ylmethanol as reagent in step 1. The product was isolated as a white solid (5 mg, 16.7%). LCMS: m/e 685.5 (MH+), 2.33 min (method 9). 1H NMR (400 MHz, METHANOL-d4) δ 7.90 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 5.28 (d, J=4.5 Hz, 1H), 4.74 (br. s., 1H), 4.63 (br. s., 1H), 3.74-3.38 (m, 8H), 3.07 (br. s., 2H), 2.98-2.85 (m, 2H), 2.48 (br. s., 1H), 2.21-1.93 (m, 4H), 1.90-1.64 (m, 11H), 1.63-1.40 (m, 10H), 1.39-1.24 (m, 4H), 1.23-1.09 (m, 4H), 1.04 (m, 6H), 0.94 (m, 6H).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1.CSC>C(Cl)Cl>[C:11]([O:10][C@@H:9]1[C@@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:34][C@H:8]1[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:51])(=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](S(=O)c2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 89.4 %

Procedure:
To a solution of 44 (1.24 g, 2.04 mmol) in 25 mL of CH2Cl2 at -78° C. is added a solution of 64% m-CPBA (550 mg, 2.04 mmol) in 10 mL of CH2Cl2. The reaction mixture is allowed to warm to -15° C., quenched with methyl sulfide (2.07 mL, 1.75 g, 6.8 mmol) and warmed to room temperature. The reaction mixture is then diluted with 25 mL CH2Cl2, washed with saturated NaHCO3 (50 mL), H2O (50 mL), saturated NaCl (50 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (30% EtOAc/hexane) to afford 1.14 g (89%) of the title compound 45 as a mixture of diastereomers: Rf 0.14 and 0.28 (10% EtOAc/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:33])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][C:29](O)=[O:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:34]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:33])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][C:29]([N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:34]=1
Reactant: O=C(O)COc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Reactant: CN1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)COc2ccccc2C(=O)Nc2ccc(C(=O)N3CCCCc4cc(Cl)ccc43)cn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-chloro-1-[6-(2-carboxymethoxybenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.25 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, to the reaction mixture is added N-methylpiperazine (0.11 ml), and thereto is added triethylamine (0.23 ml). The mixture is stirred at room temperature overnight, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1-{6-[2-(4-methyl-1-piperazinyl)carbonylmethoxybenzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (390 mg) as white powder.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O.CO.[OH-].[Na+]>[C:26]1([S:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=3[CH3:15])=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of [4-(4-benzenesulfonylamino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (38 mg, 0.08 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (10 mg, 0.25 mmol) in water (1 mL) and methanol (1 mL) plus sodium hydroxide solution (1 ml, 1.0 N) at room temperature. The resulting clear solution was stirred for 4 h and then the solvents were removed under vacuum. The residue was diluted with water (10 mL). The mixture was acidified with 1.0 N hydrochloric acid and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided the desired [4-(4-benzenesulfonylamino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (34 mg, 92%) as a light brown foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.43 (br. s, 1 H), 10.44 (s, 1 H), 7.88-8.02 (m, 1 H), 7.76-7.87 (m, 3 H), 7.50-7.71 (m, 3 H), 7.33 (t, J=7.7 Hz, 1 H), 7.24 (d, J=8.0 Hz, 2 H), 7.09 (d, J=8.0 Hz, 2 H), 6.58 (d, J=11.2 Hz, 1 H), 3.80 (br. s, 2 H), 2.00 (s, 3 H). HRMS calcd. for C25H19FNO4S [(M−H)−] 448.1024, obsd. 448.1022.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH3:3].[N+:22]([O-])([OH:24])=[O:23].Cl>C(O)(=O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]1=2)[CH3:3]
Reactant: CN(C)CCCN1c2ccccc2CCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCCN1c2ccccc2CCc2cc([N+](=O)[O-])ccc21
Temperature: 18 °C
Yield: 51.2 %

Procedure:
Imipramine (26a, 1.925 g, 6.87 mmol) was dissolved in 32 mL acetic acid and cooled to 18° C., Conc. nitric acid (0.79 mL, 13 mmol) in 1.1 mL acetic acid was added dropwise, with stirring, keeping reaction at 17°-18° C., then reaction stirred at that temperature for an additional 20 minutes. The reaction was then poured into 130 mL of 0.15M HCl and washed with Et2O (2×85 mL), then pH adjusted to 13 with conc. NaOH and extracted with CHCl3 (4×100 mL). The CHCl3 extracts were combined, washed with 85 mL brine, dried over Na2SO4, and solvent removed in vacuo. The residue was purified by column chromatography, eluting with THF/Hex/NH4OH (70/30/0.4) to yield 1.145 g (51%) of the desired 2-nitroimipramine (26b) as a red oil. 1H NMR (200 MHz, CDCl3)d 8.0-7.9 (m, 2H), 7.3-7.0 (m, 5H), 3.9 (t, 2H), 3.2 (s, 4H), 2.3 (t, 2H), 2.1 (s, 6H), 1.7 (p, 2H); mass spec (FAB) (M+H)+ 326.
Reaction SMILES: [CH3:1][C:2]1([NH:21][C:22]2[N:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7]C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C.Br>C(O)(=O)C>[CH3:1][C:2]1([NH:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:27]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:7]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ncc(C(F)(F)F)cn1
Agent: Br
Solvent: CC(=O)O
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1N
Temperature: 90 °C

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)carbamate (1.04 g, 2.35 mmol) in acetic acid (8 ml) was added HBr (1.28 ml, 23.48 mmol). The reaction was heated sealed and heated at 90° C. overnight. To this was then added further HBr (1.28 ml, 23.48 mmol) and the reaction mixture heated at 90° C. for 24 hours. Further acetic acid (5 ml) and HBr (5 ml) was added and the reaction mixture heated to 90° C. for 5 hours. The reaction mixture was concentrated in vacuo and azeotropically distilled with toluene. The resulting residue was purified by SCX chromatography (2M ammonia in methanol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[CH2:13]([O:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])[CH3:14]
Reactant: O=Cc1c(O)cc(F)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(F)cc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of 2,4-difluoro-6-hydroxybenzaldehyde (4.340 g; 27.50 mmol), iodoethane (8.562 g; 54.90 mmol), and K2CO3 (4.553 g; 32.90 mmol) in anh. DMF (75 ml) was heated to 80° C., under nitrogen, for 45 min. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-4,6-difluorobenzaldehyde as an orange solid. LC-MS (conditions A): tR=0.70 min.; [M+H]+: 187.39 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 180 °C
Yield: 55.8 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 101 mg, 0.53 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 25; 185 mg, 0.53 mmol) and potassium carbonate (48 mg, 0.53 mmol) in anhydrous DMF (5 mL) was heated in a microwave at 180° C. for 10 min. The mixture was filtered. The filtrate was concentrated and purified using a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (148 mg, 56%).
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3]([O:5]C1C=CC=CC=1)=[CH2:4].[OH-].[K+].OOS([O-])=O.[K+].OS([O-])(=O)=O.[K+].C(CN(CC([O-])=O)CC([O-])=O)N(CC([O-])=O)[CH2:47][C:48]([O-:50])=[O:49].[Na+].[Na+].[Na+].[Na+].C(OC(=O)C)(=O)C.C(N(CC)CC)C>P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.CC(C)=O>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:4])[CH2:5][O:50][C:48](=[O:49])[CH3:47]
Reactant: C=C(Oc1ccccc1)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: O=S([O-])OO
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 35 °C
Reaction time: 1 h

Procedure:
17α-hydroxy-20-phenoxy-pregna-4,9(11), 20-trien-3-one (20.0 grams, 49.5 mmoles) is slurried in a mixture of pH 8 potassium phosphate buffer (100 ml, 0.1M PO4 ≡) and water (100 ml). Acetone (20 ml) methylene chloride (200 ml) and polyethylene glycol (3.0 g avg. MW=300) are added and the two phase mixture heated to 35° C. and adjusted to pH 8.5 with potassium hydroxide. OXONE® (2KHSO5.KHSO4.K2SO4), 30 g, 48.8 mmoles) is dissolved in water (110 ml) containing (10 ml of a 5% by weight solution of sodium edetate) and the (Na4EDTA) solution added dropwise over 1 hour with vigorous agitation while maintaining the pH at 8.3 to 8.5 When the reaction is complete, the phases are separated hot and the aqueous phase extracted twice with 50 ml of methylene chloride. The combined organics are washed twice with 100 ml of aqueous 5% sodium hydroxide and clarified thru through solka flok (10 g). The solvent is removed by distillation and replaced with tetrahydrofuran to a final volume of 150 ml. Water (3 ml) containing fluoboric acid (0.3 ml of 50%) is added to hydrolyze the epoxide at 45-50° C. After 1 hour, acetic anhydride (30 ml, 318 mmoles), triethylamine (0.35 ml, 2.63 mmoles) and N,N-dimethylaminopyridine (0.1 g, 0.47 mmoles) are added at 55° C. to acetylate the 21-alcohol. When complete, tetrahydrofuran is replaced with acetone by atmospheric distillation to a final volume of 100 ml. 17α-hydroxy-21-acetoxypregna-4,9(11)-diene-3,20-dione was isolated by filtration and drying under vacuum at 60° to yield 16.7 g.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:15]([CH2:14][CH2:13][Cl:12])=[O:16]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(CCCl)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the known Schotten-Baumann procedure using 3-(trifluoromethyl)-aniline and 3-chloro-propionyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[O:21]([C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34]O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:34][CH2:33][O:32][C:31]2[CH:36]=[CH:37][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:29][CH:30]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-phenoxyphenoxy)ethanol (1.5 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 1.1 g of alpha-oxo-4-[[2-(4-phenoxy-phenoxy)ethyl]oxy]benzeneacetic acid methyl ester, mp 97°-98° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]>ClCCl>[C:31]([C:33]1[CH:34]=[C:35]([S:39]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0° C. was added 3-cyanobenzenesulfonylchloride (100 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with water. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound. 1H NMR (400 MHz, CDCl3) δ7.97 (s, 1H), 7.93-7.91 (d, 1H), 7.83-7.81 (d, 1H), 7.62-7.58 (m, 1H), 7.11-7.09 (d, 2H), 6.89-6.86 (d, 2H), 4.06-4.03 (m, 3H), 3.77-3.72 (m, 2H), 3.56-3.51 (m, 2H), 3.08 (br s, 2H), 2.70-2.67 (m, 2H), 3.08 (br s, 4H), 2.08-2.01 (m, 4H), 1.85-1.82 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CS(O[CH2:31][C:32]1([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]1)(=O)=O>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:13])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:8][N:9]2[CH2:31][C:32]2([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][O:36][C:35]([CH3:38])([CH3:39])[O:34][CH2:33]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(COS(C)(=O)=O)COC(C)(C)OC1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a solution of the product of Example 13, Step B (0.11 g; 0.32 mmol) in anhydrous DMF (0.6 ml) 60% NaH in mineral oil (0.02 g; 0.5 mmol) was added and the mixture was stirred for 1 h at room temperature under N2. To it, a product of Step A (0.13 g; 0.383 mmol) was added and the resulting mixture was stirred for 3 days at ˜55° C. under N2, cooled to room temperature and diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, CH2Cl2/EtOAc 8:2) to give the title compound (0.07 g; 37%) as a colourless solid. 1H-NMR (CDCl3) 1.23 (s, 9H); 1.46 (s, 3H); 1.53 (s, 3H); 3.71 (d, 2H, J=11.8 Hz); 3.84-3.94 (m, 15H); 4.12 (s, 1H); 4.76 (s, 2H); 6.96 (dd, 1H, J=2.2, 8.8 Hz); 7.06 (s, 2H); 7.16 (d, 1H, J=2.2 Hz); 7.44 (s, 1H); 8.24 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH2:8][N:7]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:9][CH2:8][N:7]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(OS(=O)(=O)C(F)(F)F)=CCN1c1ccc(OC)cc1
Reactant: COc1ccc(B(O)O)cc1
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: [Cl-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC(c2ccc(OC)cc2)=CCN1c1ccc(OC)cc1
Temperature: 75 °C

Procedure:
To a suspension of 38.0 g of (S)-1-(4-methoxy-phenyl)-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester, 18.1 g of 4-methoxyphenylboronic acid, 6.45 g of lithiumchloride in 300 ml of dimethoxyethan are added 100 ml of ethanol, 160 ml of 2N sodium carbonate solution and 2.22 g of tetrakis(triphenylphosphine)palladium. The reaction mixture is heated to 75° C. for 3-6 hours and allowed to cool to room temperature overnight. The reaction mixture is filtered and the filtercake is redissolved in dichloromethane and water. The suspension is filtered again and the organic phase is concentrated under reduced pressure to afford the title compound as a colourless solid. Rf=0.25 (EtOAc-heptane 1:4); Rt=5.00.