Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH4+].[Cl-].C1C=CC2N(O)N=[N:9]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH2:33]([O:40][N:41]([C@H:54]1[CH2:59][N:58]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C@H:57]([C:67](O)=[O:68])[CH2:56][CH2:55]1)[S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.CCOC(C)=O>[CH2:33]([O:40][N:41]([C@H:54]1[CH2:59][N:58]([C:60]([O:62][C:63]([CH3:64])([CH3:65])[CH3:66])=[O:61])[C@H:57]([C:67](=[O:68])[NH2:9])[CH2:56][CH2:55]1)[S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 99 %

Procedure:
NH4Cl (1.39 g, 26.18 mmol), HOBt (3.53 g, 26.18 mmol), EDCI (5 g, 26.18 mmol), and DIPEA (8.44 g, 65.45 mmol) were added to a solution of (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (10 g, 18.7 mmol) in DMF (90 mL) The mixture was stirred at rt for 17 hrs, then, EtOAc (500 mL) was added. he mixture was washed with saturated sodium chloride (6×), dried over Na2SO4, and concentrated. The residue was washed with petroleum ether/EtOAc (95:5, 200 mL) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoylpiperidine-1-carboxylate (9.9 g, 99%) which was used in the next step. ESI-MS (EI+, m/z): 535.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 mL). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 uL, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzamide (64 mg, 0.144 mmol). 1H NMR (CDCl3-d) δ 2.12(m, 4H), 3.67(m, 2H), 3.99(s, 3H), 4.17(m, 2H), 4.99(m, 1H), 7.03(s, 1H), 7.04(s, 1H), 7.14(d, J=8.2 Hz, 1H), 7.53(m, 3H), 7.94(d, J=7.8 Hz, 1H), 8.33(s, 1H), 8.58(s, 1H), 8.63(d, J=8.2 Hz, 1H). LC/MS: MH+=444.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6](O)(=[O:8])=[O:7].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C.O>[CH3:5][S:6]([C:17]1[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][C:16]=1[CH3:19])(=[O:8])=[O:7]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 12 %

Procedure:
Under a nitrogen atmosphere, thionylchloride (4ml, 58 mmol) and methanesulphonic acid (9 mL, 146 mmol) were refluxed for 90 min. 4-Nitrotoluene (4 g, 29 mmol) and triflouromethanesulphonic acid (200 uL, 3 mmol) were added and the mixture was allowed to stand for 48 hours at 120° C. The mixture was cooled to 0° C. and water (50 mL) was carefully added, followed by addition of ethyl acetate (150 mL). The organic phase was separated and extracted with a saturated solution of sodium hydrogencarbonate (2×50 mL) and water (2×50 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethylacetate, 1:1) to give 0.75 g of 2-methylsulfonyl-1-methyl-4-nitrobenzene.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:22]=[CH:23][CH:24]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cccc(Cl)c1
Product: O=c1[nH]c2nccc(Nc3cccc(Cl)c3)c2c2ccccc12
Yield: 69.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-chloroaniline (83 mg, 0.65 mmol) to provide 191 (96 mg, 68% yield) as a white solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:14]1[CH2:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:4].CCN(CC)CC.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:14]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH2:2][C:3]2=[O:4])[CH2:16][CH2:15]1
Reactant: COc1cccc(N(C(=O)CCl)C2CC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)N(C1CC1)C(=O)C2
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)-acetamide (1.25 g, 5.2 mmol), Pd(OAc)2 (0.06 g, 0.26 mmol), Et3N (0.79 g, 1.10 mL, 7.8 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (0.155 g, 0.52 mmol) in toluene (6.0 mL) was stirred at 80° C. overnight. After cooling to room temperature the mixture was purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide 1-cyclopropyl-6-methoxy-1,3-dihydro-indol-2-one as a solid (0.89 g, 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[C:17]([CH:19]1[CH2:21][CH2:20]1)#[CH:18]>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.[Cu]I.C(N(CC)CC)C>[CH:19]1([C:17]#[C:18][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:21][CH2:20]1
Reactant: C#CC1CC1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#CC1CC1)c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A 1 L three-necked round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (31.2 g, 111 mmol; Intermediate 1) and triethylamine (500 mL). The flask was degassed with three vacuum/N2 cycles, followed by the addition of Pd(PPh3)2Cl2 (7.7 g, 11 mmol) and CuI (2.1 g, 11 mmol) under N2 atmosphere. The flask was again degassed with three vacuum/N2 cycles. Ethynylcyclopropane (70% in toluene, 20.9 g, 222 mmol) was then added via syringe and the reaction mixture was stirred at 80° C. for 16 hours. Upon completion, the solvent was evaporated. The residue was diluted with dichloromethane (600 mL), washed with water (2×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was further purified on silica gel column (1:100-1:20 EtOAc/petroleum ether) affording the title compound (27.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.82 (s, 1H), 7.70 (d, 1H), 7.39 (m, 1H), 5.84 (dd, 1H), 3.91-3.87 (m, 1H), 3.78-3.73 (m, 1H), 2.52-2.37 (m, 1H), 2.05-1.94 (m, 2H), 1.76-1.72 (m, 1H), 1.60-1.52 (m, 3H), 0.92-0.87 (m, 2H), 0.78-0.73 (m, 2H); LCMS: 267 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[N:6][CH:7]=1.N(OCCC(C)C)=O.[CH3:17][CH:18]([OH:20])[CH3:19]>Cl>[Br:8][C:4]1[CH:3]=[C:2]([O:20][CH:18]([CH3:19])[CH3:17])[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)O
Agent: CC(C)CCON=O
Agent: Cl
Product: CC(C)Oc1cncc(Br)c1

Procedure:
A slurry of 5-amino-3-bromopyridine (1.29 g, 7.46 mmol) in 6M HCl solution (5 mL) was stirred 30 min at ambient temperature. The mixture was concentrated under high vacuum, and the residue was vacuum dried for 15 h at 50° C., affording a tan solid. The solid was slurried in 2-propanol (25 mL), and treated with isoamyl nitrite (1.70 g, 15.00 mmol). The mixture was stirred and heated under reflux for 1.5 h. The solution was concentrated by rotary evaporation, and the residue was partitioned between diethyl ether and 1M NaOH solution. The aqueous layer was separated and extracted with ether. The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing an orange oil (2.03 g). The oil was purified by vacuum distillation, collecting the fraction with bp 105-115° C. at 9 mm Hg. The distilled product was further purified by column chromatography on silica gel, eluting with 10→20% (v/v) diethyl ether in hexane. Selected fractions, based upon TLC analysis (Rf 0.40 in hexane-ether, (4:1, v/v)) were combined and concentrated by rotary evaporation to give 566.0 mg (35.2%) of a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[OH:14])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: OC1CCCCC1c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCCC1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
bii) Alternatively, to a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (7.5 g, 39 mmol) in dry DMSO (67 mL) was added triethylamine (27 mL, 190 mmol) under argon and the resulting mixture cooled to 0° C. and then a solution of sulfur trioxide pyridine complex (18.4 g, 116 mmol) in dry DMSO (98 mL) was added dropwise over 15 min. After 1 h, the mixture was diluted with water (200 mL) and the product extracted with DCM (2×100 mL). The combined organic extracts were then dried over sodium sulfate, followed by filtration and evaporation. Purification by filtration through silica gel, eluting with ethyl acetate:hexane (1:4) afforded the title compound (7.1 g, 95%) as white crystals. MS: m/e=192.1 (M).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].Br[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:31]([OH:33])=[O:32].[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:23]4)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-[(1-methylethyl)oxy]-5-[3-(1,2,3,4-tetrahydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 3, 28.8 mg, 0.080 mmol), methyl 3-bromopropionate (35 μl, 0.32 mmol) and Cs2CO3 (130 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature for 1 h, and then irradiated to 60° C. for 5 min in the microwave. More methyl 3-bromopropionate (35 μl, 0.32 mmol) was added and the suspension was stirred at room temperature for 3.5 h, and then irradiated to increasing temperatures in the microwave until 150° C. for 30 min was achieved. The suspension was filtered and concentrated in vacuo then purified by MDAP to give the title compound as a yellow film (5.9 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 8.42 (1H, d), 8.33 (1H, dd), 8.21 (1H, br. s), 8.04 (1H, d), 7.35 (1H, t), 7.24 (1H, d), 7.13 (1H, d), 4.80 (1H, sept), 3.99 (2H, s), 3.72 (3H, s), 3.38 (2H, t), 3.12-3.06 (4H, m), 2.78 (2H, t), 1.48 (6H, d); m/z (ES) 447 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.O1CCCC1>[Pd].C(O)C>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[CH:2][N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccncc1OCC2
Reaction time: 3 h

Procedure:
A mixture of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (82.7 mg, 0.250 mmol), palladium on carbon 10% (0.1:0.9, Palladium:carbon black, 83 mg) and triethylamine (0.104 mL, 0.750 mmol) in 5.0 ml of ethanol and 5.0 ml of tetrahydrofuran (5.0 mL, 62 mmol) was hydrogenated at 1 atm for 3 hours. The catalyst was filtered out, the filtrate concentrated, the residue purified by RP HPLC, acetonitrikle gradient to give 233. Yield 32 mg (43%). MS (ESI+): 297.2. 1H NMR (500 MHz, DMSO) δ 8.40 (s, 1H), 8.30 (d, J=5.2, 1H), 8.25 (d, J=5.2, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 5.87 (dt, J=13.0, 6.6, 1H), 4.60 (dd, J=13.1, 5.5, 4H), 1.49 (d, J=6.6, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13]([CH3:22])([C@@H:14]3[CH2:21][C@@H:15]3[C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:23])[CH2:6][CH2:5]1.[CH3:24][C@@H:25]1[C:42]2[C@:37]([CH3:45])([C@@H:38]3[CH2:44][C@@H:39]3[C:40](=[O:43])[CH:41]=2)[C@@H:36]2[C@H:27]([C@H:28]3[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C:31](=[O:46])[CH2:30][CH2:29]3)[CH2:26]1.C1[C@@H]2C(=O)C=C3[C@](C)([C@H]12)[C@@H]1[C@H]([C@H]2[C@@](CC1)(C)C(=O)CC2)CC3>>[CH3:21][C@H:14]1[C@@:13]2([CH3:22])[C:18]([CH2:19][C@H:2]([CH3:1])[C@@H:3]3[C@@H:12]2[CH2:11][CH2:10][C@@:8]2([CH3:9])[C@H:4]3[CH2:5][CH2:6][C:7]2=[O:23])=[CH:17][C:16](=[O:20])[CH2:15]1.[CH3:44][C@H:38]1[C@@:37]2([CH3:45])[C:42]([C@@H:25]([CH3:24])[CH2:26][C@@H:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30][C:31]2=[O:46])=[CH:41][C:40](=[O:43])[CH2:39]1
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)[C@H]1C[C@H]12
Reactant: C[C@@H]1CC2=CC(=O)[C@H]3C[C@H]3[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@@H]1CC(=O)C=C2C[C@H](C)[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Product: C[C@@H]1CC(=O)C=C2[C@@H](C)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C

Procedure:
Substituting 7α-methyl-1β,2β-methylene-4-androstene-3,17-dione and 6α-methyl-1β,2β-methylene-4-androstene-3,17-dione for the 1β,2β-methylene-4-androstene-3,17-dione above results in the preparation of 1β,7β-dimethyl-4-androstene-3,17-dione and 1β,6α-dimethyl-4-androstene-3,17-dione.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]#[N:22])[CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[OH2:23].[OH-].[Li+]>CO.O1CCCC1.O>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:21]([NH2:22])=[O:23])[N:9]=[N:8][N:7]=1
Reactant: O
Reactant: CC(=O)OCc1nnnn1-c1cc(C#N)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cc(-n2nnnc2CO)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of {1-[3-cyano-5-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 30, 3.33 g) in methanol (10.0 mL), tetrahydrofuran (20 mL) and water (10.0 mL) was cooled in an ice-water bath before the addition of lithium hydroxide monohydrate (0.449 g, 10.7 mmol). The reaction was stirred at 0-5° C. for 2 hours. The reaction was diluted with water (30 mL) and the organic solvent removed under vacuum. The suspension was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried and the solvent removed to yield a white solid. The solid was triturated with diethyl ether (2×25 mL), the solvent decanted and the residue dried under vacuum to yield the intermediate 3-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-5-(trifluoromethyl)benzamide as a white solid (1.37 g).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][C:22]=1[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][C:22]=1[F:31]
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)c(F)c1
Product: O=C(Cc1ccc(Cl)c(F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(4-chloro-3-fluorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.70-11.79 (m, 1H), 8.39-8.44 (m, 1H), 7.88-8.05 (m, 2H), 7.71-7.76 (m, 1H), 7.63 (s, 4H), 7.57 (t, J=8.1 Hz, 1H), 7.44 (dd, J=10.5, 1.9 Hz, 1H), 7.25 (dd, J=8.3, 1.9 Hz, 1H), 3.75 (s, 2H); MS (ESI+) M/Z 442 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16][OH:17])[O:11][C:10]([CH3:22])([CH3:21])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:18]([CH3:19])[CH3:20])[CH2:15][CH2:16][O:17][C:37](=[O:40])[CH2:38][CH3:39])[O:11][C:10]([CH3:21])([CH3:22])[N:9]2[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCC[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
1.0 g (2.43 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 50 ml of methylene chloride is treated with 0.38 ml (2.7 mmol) of triethylamine and 0.24 ml (2.7 mmol) of propionyl chloride and stirred at room temperature for 12 hours. After the usual working-up the crude product is purified by flash chromatography on silica gel with a 1:5 mixture of ether and petroleum ether, whereby there is obtained 1.0 g (88%) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-isopropyl-4-(propionyloxy)butyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 452 (M-CH3)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13]Cl)[CH3:10].O>CN(C=O)C>[CH3:10][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:8]
Reactant: CC(C)CC(O)(CCl)c1ccccc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(O)(Cn1cncn1)c1ccccc1
Temperature: 25 °C

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to 100% sodium hydride (0.03 mol, 0.72 g) in dry DMF (30 ml) and stirred at room temperature until the effervescence ceased. 2-Methyl-4-phenyl-5-chloro-pentan-4-ol (0.01 mol, 2.1 g) in dry DMF (10 ml) was added dropwise at room temperature and then the solution was stirred at 100° for 6 hours. On cooling to room temperature the solution was poured into water to precipitate out a solid which was recrystallised from petroleum (60°-80°)/chloroform giving the title compound (60%) as a white crystalline solid, m.p. 94°-95°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>CS(C)=O.C(OCC)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:22][CH2:21]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CNCC1CCc2cccc(-c3ccccc3Cl)c2O1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
To a suspension of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.30 mmol) in dimethylsulfoxide (0.5 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 1.5 mL, 3.0 mmol) and the mixture heated to 60° C. in a sealed vial for 24 hours. The cooled reaction mixture was then diluted with diethyl ether (10 mL), washed with water (5×5 mL) and saturated brine (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave 69 mg (79%) of N-{[8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}-N-methylamine. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (3 drops). The resulting white precipitate was filtered to afford 74 mg (76%) of N-{[8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}-N-methylamine hydrochloride as a white solid. HRMS: calcd for C17H18ClNO+H+, 288.11497. found (ESI, [M+H]+), 288.1143.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[S:28])[NH2:27])[N:25]=1>C(#N)C.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:27]=[C:26]([C:24]3[N:25]=[C:21]([CH3:20])[S:22][CH:23]=3)[S:28][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(N)=S)cs1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Solvent: CCO
Product: CSc1ccc(-c2sc(-c3csc(C)n3)nc2-c2ccc(F)cc2)cc1
Yield: 48.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone (9.69 g, 28.6 mmol) (Example 1, Step 3) and 2-methylthiazole-4-thiocarboxamide (3.90 g, 24.7 mmol) in 35 mL of acetonitrile and 20 mL of ethanol was heated to reflux for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid. The crude solid was purified by flash chromatography over silica gel eluting with 1:1 hexane:ethyl acetate. The appropriate fractions were combined and the solvent removed in vacuo to provide pure 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-[2-(methyl)-4-thiazolyl]thiazole (4.79 g; 49%): mp 132.5°-135° C. 1H NMR (CDCl3) 300 MHz 7.89 (s, 1H), 7.55 (m, 2H), 7.25 (d, J=8.5Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 7.01 (t, J=8.8Hz, 2H), 2.78 (s, 3H), 2.49 (s, 3H). 19F NMR (CDCl3) -113.80 (m). Mass spectrum M+H+ =399.