Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(COC2C=CC(CO)=CC=2)=CC=1.C[O:20][C:21](=[O:49])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:34][CH:33]=2)=[CH:26][C:25]=1[CH3:48]>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH2:31][S:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]([OH:49])=[O:20])=[C:25]([CH3:48])[CH:26]=3)=[CH:33][CH:34]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(OC)cc3)cc2)cc1C
Agent: COc1ccc(COc2ccc(CO)cc2)cc1
Product: COc1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c(C)c3)cc2)cc1

Procedure:
Preparation of [4-(4-Methoxy-benzyloxy)-phenyl]-methanol (compound 33A) The title compound was prepared in the manner analogous to Example 14A using 1-chloromethyl-4-methoxy-benzene and 4-hydroxymethyl-phenol. MS m/z 227 (M-OH). Step 2. Preparation of 4-Methoxy-1-(4-chloromethyl-phenoxymethyl)-benzene (compound 33B) The title compound was prepared in the manner analogous to Example 3B using 33A. MS m/z 227 (M-Cl). Step 3. Preparation of {4-[4-(4Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (compound 33C) The title compound was prepared in the manner analogous to Example 1F using 33B and 2C. MS m/z 439 (M+1). Step 4. Preparation of {4-[4(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid (compound 33) The title compound was prepared in the manner analogous to Example 1 using 33C. mp 150-152° C.; HPLC: area %=96.69, r.t.=2.93 min., γ=214 nm, mobile phase=acetonitrile/water with 0.10% TFA; IR (KBr) cm−1: 2929, 1728, 1707, 1513, 1491, 1225; 400 MHz 1H NMR (DMSO-d6): δ 12.98 (br(s), 1H), 7.27-7.23 (m, 2H), 7.02-7.16 (m, 4H), 6.81-6.91 (m, 4H), 6.69 (d, 1H, J=8.6 Hz), 4.91 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 3.69 (s, 3H), 2.08 (s, 3H); MS m/z 423 (M−1). Anal. Calc'd for C24H24O3S: C, 67.90; H, 5.70; found: C, 67.48; H, 5.59.
Reaction SMILES: [OH2:1].[OH:2][C:3]1([C:8]#[N:9])[CH2:7][CH:6]=[CH:5][CH2:4]1>C(O)(=O)C>[OH:2][C:3]1([C:8]([NH2:9])=[O:1])[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: N#CC1(O)CC=CC1
Reactant: O
Solvent: CC(=O)O
Product: NC(=O)C1(O)CC=CC1
Reaction time: 8 h

Procedure:
To 5 ml. of a solution prepared by mixing one part of water and 9 parts of glacial acetic acid, and then cooling to 0°-10° C., is added 300 mg. of 1-hydroxy-3-cyclopentene-1-carbonitrile. To this is then added 5 ml. of a solution prepared by saturating glacial acetic acid with gaseous hydrogen bromide and cooling to 0°-10° C. The resulting mixture is allowed to stand at room temperature overnight. It is then evaporated to dryness in vacuo, and the residue is partitioned between ethyl acetate and 5% sodium bicarbonate solution. The ethyl acetate layer is separated, and then dried using anhydrous magnesium sulfate. Removal of the ethyl acetate by evaporation in vacuo affords 1-hydroxy-3-cyclopentene-1-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]3[CH:25]=[CH:26][CH:27]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:32]N1C(=O)CCC1=O>O1CCCC1>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]3[C:25]([Cl:32])=[CH:26][CH:27]=[C:17]3[CH2:16]2)=[O:14])=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-water cooled suspension of 5 mmol of 2-methyl-N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 5.5 mmol of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:3]1.CC1(C)C=CC=C(C(=O)CCC=C)C1>>[CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH2:5][C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:3]1
Reactant: C=CCCC(=O)C1=CC(C)(C)C=CC1
Agent: C=CCCC(=O)C1=CC=CC(C)(C)C1
Product: C=CCCC(=O)C1=CC(C)(C)CCC1

Procedure:
##STR5## 1-(3,3-Dimethyl-cyclohexa-1,4-dien-1-yl)-pent-4-en-1-one, 1-(3,3-dimethyl-cyclohexa-4,6-dien-1-yl)-pent-4-en-1-one and
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]([O:8][CH3:9])=[O:7].OS(O)(=O)=O.[CH3:23][OH:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:24][CH3:23])([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=C(C)COc1ccc(C(=O)OC)cc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OCC(C)(C)OC)c(OC)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
To methyl 3-methoxy-4-(2-methylallyloxy)benzoate (313 mg, 1.33 mmol) in MeOH (2.5 mL) was added H2SO4 (71 μL, 1.3 mmol) and the mixture was heated in a microwave vial at 100° C. for 15.5 h. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (208 mg, 59%). ESI-MS m/z calc. 268.1. found 269.5 (M+1)+; Retention time: 1.46 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 3.90 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O[CH:30]1[CH2:35][CH2:34][C:33]2([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:8][N:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=1[Cl:18])[CH:38]1[CH2:39][CH2:40][C:33]2([CH2:34][CH2:35][CH2:30][CH2:31][CH2:32]2)[CH2:36][CH2:37]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CCCCC3)CC2)cc1
Reactant: CCc1nccc(NOCc2ccccc2)c1Cl
Product: CCc1nccc(N(OCc2ccccc2)C2CCC3(CCCCC3)CC2)c1Cl
Yield: 95 %

Procedure:
Was prepared analogously to Example 7 from 4-(O-benzylhydroxylamino)-3-chloro-2-ethylpyridine (Example 52) and 3-tosyloxyspiro[5.5]undecane. Yield: 95%
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:27])=[O:26])[C:19](=[O:31])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:27])=[O:26])[C:19](=[O:31])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)cc1O
Reaction time: 8 h

Procedure:
To a solution of 29 (0.9 g, 2.26 mmol) in EtOH (15 mL) was added 10% Pd/C. The solution was then placed under vacuum and recharged with H2. The reaction mixture was stirred under H2 overnight. After filtration and removal of solvent, the residue was placed under vacuum for 10 h to give 30. Etherification of 30 was performed as set forth in Example 27.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22](F)=[CH:23][C:24]=3[O:29][CH3:30])[N:19]=2)[CH:15]=[C:14]([CH3:32])[N:13]=1>CS(C)=O>[CH3:32][C:14]1[CH:15]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:23][C:24]=3[O:29][CH3:30])[N:19]=2)[CH:17]=[C:12]([CH3:11])[N:13]=1
Reactant: OCCN1CCCC1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(OCCN2CCCC2)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-pyrrolidin-1-yl-ethanol (1.15 g, 10 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.20 g, 5.0 mmol) was added in portions and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.30 g, 1.0 mmol) and the reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was loaded onto a column and purified by column chromatography (silica gel 230-400 mesh; eluting with 5% 7.0 M ammonia in methanol solution in dichloromethane), to obtain the title compound as a white solid. Yield: 0.163 g (41.3%). MP 227-229° C. MS (ES) m/z: 395.15 (M++1). 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.66 (s, 6H), 2.63 (m, 4H), 1.83 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: CCC(=O)[O-]
Product: CS(=O)(=O)c1ccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1

Procedure:
This compound is prepared according to synthesis 229, from 200 mg (0.49 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 110 mg (0.55 mmol) of 4-methanesulfonylphenylboronic acid to give, after purification by chromatography on silica (eluent dichloromethane/methanol 95/5), 49 mg (32%) of 8-(4-methanesulfonyl-phenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][O:25][C:24]5=[O:29])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[N:33]([CH:36]([CH3:38])[CH3:37])=[C:34]=[O:35]>C(Cl)Cl>[F:32][C:4]1[CH:3]=[C:2]([NH:1][C:34]([NH:33][CH:36]([CH3:38])[CH3:37])=[O:35])[CH:31]=[CH:30][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][O:25][C:24]4=[O:29])=[CH:20][N:21]=3)[S:15][C:8]=12
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Temperature: 80 °C
Yield: 29.4 %

Procedure:
A reaction mixture consisting of amine 200 (100 mg, 0.222 mmol) and 2-isocyanatopropane (434 mg, 5.10 mmol) in DCM (3 mL) was heated to 80° C. in a sealed flask overnight. The mixture was then cooled to RT and purified by Biotage (SiliaFlash 12 g cartridge, 0-12% MeOH/CHCl3) to afford after the separation title compound 201 (35 mg, 29.4% yield) as beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.67 (s, 1H), 8.55 (d, 1H, J=1.8 Hz), 8.50 (d, 1H, J=5.3 Hz), 8.33 (s, 1H), 8.25 (d, 1H, J=8.2 Hz), 7.84 (dd, 1H, J1=2.2 Hz, J2=8.2 Hz), 7.69 (dd, J1=2.5 Hz, J2=13.7 Hz), 7.35 (t, 1H, J=9.0 Hz), 7.12-7.10 (m, 1H), 6.62 (d, 1H, J=5.1 Hz), 6.14 (d, 1H, J=7.4 Hz), 4.50 (s, 2H), 4.21 (t, 2H, J=5.1 Hz), 3.77-3.72 (m, 1H), 3.30-3.28 (m, 2H), 1.97-1.92 (m, 2H), 1.10 (s, 3H), 1.08 (s, 3H). MS: 536.4 (MH)+
Reaction SMILES: Br[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>CO>[F:35][C:36]([F:44])([F:45])[C:37]1[CH:38]=[CH:39][C:40]([NH:41][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[CH:42][CH:43]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)[C@H](Br)C(=O)O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
1.5 Grams (8.3 mmol) of the (S)-2-bromo-3-methylbutanoic acid is titrated with 8 ml of 1 M potassium hydroxide in methanol to a phenolphthalein endpoint. The solution is evaporated under high vacuum at 40° for 1 hour, and 0.51 g (2.33 mmol) of the resulting salt is heated together with 1.52 g (9.43 mmol) of 4-trifluoromethylaniline at 90°-95° under nitrogen for 1 hour. Heating is discontinued and the reaction worked up immediately by partition between ether/5% sodium hydroxide. The layers are separated and the organic phase is extracted with 5% sodium hydroxide (2×). The aqueous layers are combined and washed with ether (2×), then acidified with ice and conc. HCl and extracted with ether (3×). The latter ether extracts are washed with brine, dried over magnesium sulfate, filtered and evaporated, giving (S)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:31])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24]C(=O)C(F)(F)F)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])=[O:31])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NC(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-trifluoroacetylaminophenyl)ethyl]piperidine obtained in Example 63 and 141 mg of potassium carbonate were suspended in a mixed solvent of 3 ml of methanol and 3 ml of water, and the mixture was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:16]=[CH:15]C(C(O)=O)=[CH:10][C:9]=1[F:17].CN(C=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:1]([C:2]([Cl:4])=[O:3])=[CH:10][C:9]=1[F:17]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl dichloride (6.1 g, 48 mmol) was added to a solution of 4-bromo-3-fluoro-benzoic acid (7 g, 32 mmol) in DCM (80 mL) at 0° C. followed by DMF (0.2 mL) and the reaction mixture was stirred at RT for 2 h and then concentrated under vacuum to provide crude 4-bromo-3-fluoro-benzoyl chloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][CH2:8][CH2:9][NH2:10].[Cl:11][CH2:12][CH2:13]N.C(N(CC)CC)C>ClCCl.O1CCCC1>[Cl:7][CH2:8][CH2:9][N:10]([CH2:13][CH2:12][Cl:11])[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(CCCl)CCCl
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
14.3 ml (185 mmol) of methanesulfonyl chloride are added slowly to a solution of 15 g (84 mmol) of commercial bis(2-chloroethylamine) hydrochloride and 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran previously stirred for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is then stirred at ambient temperature for 18 h, extracted with dichloromethane, and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is washed with diisopropyl ether, filtered and then dried under vacuum. 15.3 g (82%) of N,N-bis-(2-chloroethyl)methanesulfonamide are obtained in the form of a solid.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@@H:8]([OH:9])[C@H:4]2[CH2:3][NH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=1.C(N(CC)CC)C>C(O)C>[F:18][C:17]([F:20])([F:19])[C:13]1[N:12]=[C:11]([N:2]2[CH2:3][C@@H:4]3[C@H:8]([OH:9])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O[C@@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C

Procedure:
(3aR,4R,6aS)-Octahydrocyclopenta[c]pyrrol-4-ol (1.65 g, 12.97 mmol) from Example 29, 2-bromo-6-(trifluoromethyl)pyridine (3.66 g, 16.22 mmol) and triethylamine (7.23 mL, 51.9 mmol) were combined in ethanol (7.23 mL). The reaction was heated at 80° C. for 24 hours and the solvent was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-40% ethyl acetate/hexane as eluent to give the title compound and the title compound of Example 31: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.47 (t, J=7.9, 1H), 6.94 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 6.38 (d, J=4.1, 1H), 4.47-4.38 (m, 1H), 4.12 (dd, J=11.0, 4.3, 1H), 3.70-3.63 (m, 1H), 3.53 (t, J=10.0, 1H), 3.38 (dd, J=10.4, 4.6, 1H), 2.80-2.73 (m, 1H), 2.72-2.64 (m, 1H), 1.97-1.74 (m, 3H), 1.64-1.56 (m, 1H); MS (ESI+) m/z 273 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=2)=[N:18][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N([O-])=[O:28].[Na+].[OH-].[Na+]>O>[CH2:6]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:26]=[CH:25][C:23]([OH:28])=[CH:22][CH:21]=2)=[N:18][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=N[O-]
Reactant: CCCCCCCCc1ccc(-c2ccc(N)cc2)nc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Temperature: 5 °C
Yield: 35.2 %

Procedure:
10 ml of 3N sulphuric acid were treated while stirring with 1.8 g of p-(5-octyl-2-pyridyl)aniline. The mixture was cooled to 5° C. and then treated dropwise at 0°-5° C. within about 3 minutes with a solution of 0.442 g of sodium nitrite in 2 ml of water. The brown mixture obtained was poured into 100 ml of water and heated to reflux for 30 minutes while stirring. The reaction mixture was subsequently cooled to room temperature, adjusted to about pH 5 with 7 ml of 3N sodium hydroxide solution and extracted once with 200 ml of methylene chloride and once with 100 ml of methylene chloride. The organic phases were washed with 150 ml of dilute sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. The residue (1.867 g) was separated by chromatography on 250 g of silica gel at 0.4 bar with methylene chloride and methylene chloride/acetone. Recrystallization of the resulting red-brown oil in diethyl ether/hexane at 0° C. gave 0.635 g of p-(5-octyl-2-pyridyl)phenol as beige crystals. Working-up of the mother liquor gave 0.355 g of crude p-(5-octyl-2-pyridyl)phenol as a brown oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1(SCC)[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2]>C(C1C=CC=CC=1CC)C>[CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 190 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A suspension of 4.0 g of 17,17-bis(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4-dien-3-one (prepared as described above) in 60 ml of diethylbenzene is stirred at 190° C. (oil bath temperature) for 1 hour. The solution is cooled to 0° C. and the solid that precipitates is filtered. This is redissolved in 1:9 hexane-chloroform and chromatographed on a 60 g-silica gel column. Elution with 1:9 hexane-chloroform gives 3.35 g of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 2.8 g of the title compound, melting point, 282°-283° C., dec.
Reaction SMILES: [CH:1]1([N:7]([CH3:16])[C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[ClH:26].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:35][CH2:36][CH2:37][NH2:38])=[CH:30][CH:29]=1.C(OCC)C>CN(C=O)C>[ClH:26].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[CH2:35][CH2:36][CH2:37][NH:38][C:9](=[O:11])[C@@H:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:16])[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:30][CH:29]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 76.2 %

Procedure:
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (0.300 g, 1.32 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.690 mL, 3.96 mmol) and solid O-benzotriazol-1-yl-N,N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.501 g, 1.32 mmol). The resulting reaction mixture was stirred at that temperature for 40 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.393 g, 1.32 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.51 g (75%) of the pure titled compound as a white foam; mp 73-83° C. APCI-MS m/z 471.4 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]4[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]4)=[O:24])[CH:21]=3)[C:16]([S:38][CH3:39])=[CH:15]2)=[N:12][CH:13]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(O)(C)(C)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:39][S:38][C:16]1[C:17]2[C:22](=[CH:21][C:20]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[N:14]([C:11]2[N:10]=[CH:9][C:8]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:13][N:12]=2)[CH:15]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: 90 °C

Procedure:
Potassium carbonate (1.16 g, 8.45 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.2 g, 0.28 mmol) were added under an argon atmosphere and at room temperature to a solution of 223b) (1.5 g, 2.8 mmol) and phenyl boronic acid (0.69 g, 5.63 mmol) in tert-butanol/water (10:1, 66 mL). The resulting mixture was heated at 90° C. for 2 h, then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the remnant purified by flash column chromatography [silica gel, dichloromethane with 2% methanol] and then triturated with ether. White solid. Yield: 1 g (67% of theory)