Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[CH2:19]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[C:15]1[Cl:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 1-benzyl-2,3-dichloro-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 419 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1COCC1>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 20 h
Yield: 302 %

Procedure:
A solution of tert-butyl (1-(5-chloropyridin-2-yl)piperidin-4-yl)carbamate (1.15 g, 3.70 mmol) in HCl in Dioxane (4M, 5 mL) and THF (5 mL) was stirred at rt for 6.5 h. 4M HCl in Dioxane (2 mL) was added and the reaction mixture stirred for another 20 h. The reaction mixture was filtered, the residue was washed with EtOAc and dried to give the title compound (1.06 g, 100%) as a solid. 1H NMR (500 MHz, CD3OD): 8.10 (s, 1H), 8.06 (d, 1H), 7.52 (d, 1H), 4.36 (d, 2H), 3.62-3.54 (m, 1H), 3.42 (dt, 2H), 2.18 (d, 2H), 1.82 (dq, 2H); 13C NMR (CD3OD): 151.4, 144.4, 134.6, 120.0, 114.7, 45.2, 29.1; Mass Spectrum: M+H 212.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: F[B-](F)(F)CCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(CCc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), potassium trifluoro(phenethyl)borate (76 mg, 0.361 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-phenethyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 25-40% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (21 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (br s, 2H), 1.65 (br s, 2H), 1.68-1.81 (m, 2H), 1.84 (br s, 2H), 2.83-3.04 (m, 2H), 3.14-3.41 (m, 2H), 4.22-4.43 (m, 3H), 6.65 (d, J=6.82 Hz, 1H), 7.08-7.33 (m, 4H), 7.37 (br s, 1H), 7.54 (br s, 1H), 7.70 (br s, 3H), 8.31 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H25FN4O, 369. found, 369.
Reaction SMILES: [Cl-].[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].I[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][NH:19][C:20]([N:22]1[CH2:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][C:24]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:23]1=2)=[O:21])=[O:17].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CC(C)=O>[O:41]1[CH2:42][CH2:43][N:38]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][NH:19][C:20]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:23]2=3)=[O:21])=[O:17])[CH2:39][CH2:40]1
Reactant: O=C(CCCCI)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C1COCCN1
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [I-]
Solvent: CC(C)=O
Product: O=C(CCCCN1CCOCC1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
To a solution of 0.5 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide (U.S. Pat. No. 3,534,019) and 19.6 parts of acetonitrile is added 0.298 part of sodium bicarbonate followed by 0.6 part of 5-chloropentanoyl chloride. The solution is stirred for 48 hours at room temperature, after which time the solvent is removed under reduced pressure and the resulting residue is purified by recrystallization from ethyl acetate-cyclohexane to afford 1-(5-chloropentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, which has a melting point at about 148°-149° and is structurally represented by the following formula ##STR9## 14.8 Parts of the above chloride is reacted with 7.94 g of sodium iodide in 145 parts by volume of acetone containing a catalytic amount of sodium thiosulfate. The reaction mixture is stirred in the dark and refluxed for 5 hours and allowed to stand at room temperature. The solvent is removed and the residue taken up in benzene containing 1% sodium thiosulfate. The benzene is washed with aqueous sodium chloride and dried over sodium sulfate to provide an approximately 50--50 mixture of 1-(5-iodopentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine and the (5-chloropentanoyl) derivative. 8 Parts of this mixture is reacted with 1.65 parts of morpholine in 80 parts by volume of acetone for 48 hours. The acetone is removed and 10% hydrochloric acid and benzene is added to the benzene layer. The benzene layer is separated and the aqueous acid layer is made basic with 5% potassium hydroxide and then extracted wtih benzene. The benzene layer is washed with sodium chloride solution and dried over sodium sulfate. The solvent is removed and the residue is crystallized from ethyl acetatecyclohexane to provide 1-(5-morpholinopentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine melting at 107°-114° C. and having the following structural formula ##STR10##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]1[C:9]([F:24])=[CH:8][CH:7]=[CH:6][C:5]2=1.[OH-].[Na+]>CCO.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]1[C:9]([F:24])=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1ccccc1-n1c2ccc(Br)cc2c2cccc(F)c21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1-n1c2ccc(Br)cc2c2cccc(F)c21

Procedure:
67 g (219 mmol) of 6-bromo-1-fluoro-9-(2-nitrophenyl)-9H-carbazole are dissolved in 820 ml of EtOH, 143 g (755 mmol) of ZnCl2 are added at room temperature, and the mixture is heated under reflux for 6 h. The mixture is allowed to come to room temperature over the course of 1 h, 20% NaOH is added, and the phases are separated. The solvent is then removed, and the residue is purified by chromatography. The yield is 44 g (125 mmol), corresponding to 72% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](OC)=[C:7](OC)[CH:8]=2)[C:3]=1[CH:16]=[O:17].CN(C)C=O.P(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:16]=[O:17]
Reactant: COc1cc2ccc(Br)c(C=O)c2cc1OC
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=CC1=C(Br)CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-Bromo-6,7-dimethoxy-1-napthaldehyde (10). Dimethylformamide (3.0 g, 41 mmol) was added dropwise to solution of phosphorus tribromide (3.3 mL, 35 mmol) in dry chloroform (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h to give pale yellow suspension. A solution of compound 8 (2.0 g, 9.7 mmol) in chloroform was added to the yellow suspension and the mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added dropwise until no effervescence was obtained. The resulting mixture was extracted with dichloromethane, dried (Na2SO4) and evaporated to provide the respective 2-bromo-3,4-dihydro-1-napthaldehyde derivatives as yellow solids. Each of the 2-bromo-3,4-dihydro-1-napthaldehyde derivatives were chromatographed on silica gel using a 3:1 mixture of hexanes:ethyl acetate as the eluent to give the 2-bromo-3,4-dihydro-1-napthaldehydes in an 87% yield. The 2-bromo-3,4-dihydro-1-napthaldehyde (2.4 g, 8.1 mmol) and DDQ (2.2 g, 97 mmol) was refluxed in toluene (50 mL) for 15 h. After cooling to room temperature, the mixture was subjected to filtration through a celite bed and the filtrate was evaporated to dryness. The residue obtained was chromatographed on 75 g silica gel using a 3:1 mixture of hexanes:ethyl acetate as eluent to give the 2-bromo-1-napthaldehyde in a 95% yield; 1H NMR δ 4.00 (3H, s), 4.05 (3H, s), 7.07 (1H, s), 7.54 (1H, d, J=8.5), 7.79 (1H, d, J=8.5), 8.71 (1H, s), 10.74 (1H, s); 13C NMR δ 56.3, 56.6, 104.2, 107.0, 126.5, 128.8, 129.4, 129.8, 129.9, 134.3, 150.4, 153.1, 195.9; HRMS calcd for C,3H11O3Br: 293.9891; found: 293.9896.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:36]([N:35]([CH2:32][CH2:33][CH3:34])[C:11](=[O:12])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCNCCC
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCN(CCC)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.6 μL N-propylbutylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.31 min. (m/Z=304.2, 388.2, 410.2).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[C:15]1(=O)[CH2:20]CCC[CH2:16]1.N>CO>[N+:11]([C:4]1[CH:5]=[C:6]2[CH2:20][CH2:15][CH2:16][C:7]2=[N:2][CH:3]=1)([O-:13])=[O:12]
Reactant: O=C1CCCCC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CCC2
Temperature: 70 °C

Procedure:
A mixture of 1-methyl-3,5-dinitropyridin-2(1H)-one (B) (947 mg, 4.76 mmol), cyclohexanone (0.5 mL, 5.70 mmol) and ammonia solution (1 M) in methanol (50 mL) was heated to 70° C. for 3 h under N2. TLC showed complete consumption of starting material. The reaction mixture was removed in vacuo and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford crude which was purified by column chromatography to afford 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (C). (340 mg, 44%)
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](OC)=[O:16])=[CH:11][C:10]=2[CH:19]2[CH2:23][CH2:22][CH2:21][C:20]2([CH3:25])[CH3:24])[CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[F:27][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([F:26])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[CH:19]2[CH2:23][CH2:22][CH2:21][C:20]2([CH3:24])[CH3:25])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCCC1c1cc(CO)ccc1-c1cc(C(F)F)ccc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
To a cooled solution of 66.51A (0.8631 g, 2.293 mmol) in dry THF (15.4 mL) at 0° C. was added LAH (1.0 M in THF) (4.6 mL, 4.6 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction (gas evolution occurred). The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-100% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to a colorless oil as 66.51B (617.1 mg, 77% yield). MS ESI (pos.) m/e: 331.0 (M−H2O)+. Chiral separation of 66.51B was accomplished on a Chiracel-OD column (4% IPA in hexane) to provide 66.51C (peak 1) and 66.51D (peak 2). Both enantiomers were used to synthesize example compounds, and both enantiomers gave active compounds.
Reaction SMILES: C([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:24][Si:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C@@H:9]([O:44][Si:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:8][CH2:7]2)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[C:58]1([Si:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:44][C@H:9]2[CH2:8][CH2:7][C@@:6]3([CH2:5][OH:4])[C:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][CH2:17][C@@H:18]3[O:24][Si:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:10]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CC(=O)OC[C@]12CC[C@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43CO)[C@@H]1CC[C@@H]2O[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To an ether solution of 3β,17β-di-(triphenylsiloxy)androst-4-en-19-ol acetate is added a suspension of lithium aluminum hydride in ether. After refluxing for a period of one hour, water is cautiously added, the ether solution is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue when purified from an acetone-hexane mixture results in the preparation of the desired 3β,17β-di-(triphenylsiloxy)androst-4-en-19-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:32])=[O:33])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (90 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.61-1.74 (m, 4H); 1.92-2.08 (m, 4H); 2.11 (q, 1H, J=12 Hz); 2.78-2.84 (m, 1H); 3.68 (td, 1H, J=12, 4 Hz); 3.78 (t, 1H, J=12 Hz); 3.88-3.96 (m, 1H); 4.02-4.10 (m, 1H); 4.49-4.67 (m, 5H); 4.71 (d, 1H, J=12 Hz); 7.19-7.27 (m, 2H); 7.28-7.33 (m, 1H); 8.09 (s, 1H). LC-MS: 453.04 (M+1).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[CH2:9]1[O:11][C@@H:10]1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:11][C@H:10]([CH2:12][OH:13])[CH2:9][N:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: OC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccn(C[C@H](O)CO)c(=O)n1
Yield: 43.1 %

Procedure:
Reaction of cytosine (2.2 g, 19.8 mmol) with (R)-glycidol (88% ee, 1.51 ml, 22.8 mmol) in the presence of anhydrous potassium carbonate (40 mg, 0.289 mmol) in dry DMF (20 ml) at 72° C. for 5 hours, as described in Example 1, furnished the title compound (88% ee) in 43.1% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3]1.Cl.[Cl:15][C:16]1[C:17]([CH2:22][NH2:23])=[N:18][CH:19]=[CH:20][N:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH2:22][NH:23][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=3)=[O:13])=[N:18][CH:19]=[CH:20][N:21]=1
Reactant: Cn1ncc2c1CCCC2C(=O)O
Reactant: NCc1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cn1ncc2c1CCCC2C(=O)NCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.9 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylic acid (6 g, 33 mmol) and (3-chloropyrazin-2-yl)methanamine hydrochloride (6 g, 33 mmol) in 200 mL of DCM was added TEA (9 g, 88 mmol) dropwise. The resulting mixture was stirred at room temperature for 5 mins, and then HATU (12.5 g, 33 mmol) was added to the solution in portions at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added, the DCM layers was separated, and washed with brine, dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF=5/1 v/v %) to afford N-((3-chloropyrazin-2-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxamide (1.5 g, 15%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:38])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[N:20]=[C:19]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@H:31]4[CH3:36])[N:18]=3)[CH:13]([CH3:37])[CH2:12]2)=[N:9][CH:10]=1)=[O:4]>[OH-].[Na+].CCO>[Cl:38][C:7]1[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[N:20]=[C:19]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH:31]4[CH3:36])[N:18]=3)[C@H:13]([CH3:37])[CH2:12]2)=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1COCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(C(=O)O)nc3Cl)C[C@H]2C)n1

Procedure:
Stir a solution of 3′-chloro-4-[6-(4-fluoro-phenyl)-2-(3-(R)-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (500 mg) in a mixture of 10% NaOH (6 mL) and EtOH (20 mL) at room temperature for 16 h. Bring the mixture to pH 4 with 6 N HCl and extract the solution with EtOAc. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:13]([NH:29][C:30]1[CH:31]=[C:32]([C:35](O)=[O:36])[S:33][CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[CH2:13]([NH:29][C:30]1[CH:31]=[C:32]([C:35]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:36])[S:33][CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)NS(=O)(=O)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide during 30 minutes at room temperature. Stirring is continued for 30 minutes. In the meantime, a mixture of 36.2 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid in 100 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated and to the resulting oil residue is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and then filtered. The filtrate is poured into 2 l. of water and 250 ml. of saturated sodium chloride solution. The product is collected by filtration and then dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried and evaporated. The residue is crystallized from toluene to yield the product as a white solid.