Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].Br[CH:14]([CH3:17])[CH:15]=O>>[C:1]([O:4][CH2:5][C:6]1[C:7]2[N:8]([C:14]([CH3:17])=[CH:15][N:12]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(Br)C=O
Reactant: CC(=O)OCc1cccnc1N
Product: CC(=O)OCc1cccn2c(C)cnc12
Yield: 37.5 %

Procedure:
A mixture of 5.0 g (30 mmole) of 3-(acetoxymethyl)-2-pyridinamine and 4.8 g (35 mmole) of 2-bromopropanal spontaneously heated upon mixing. After cooling, the mixture was partitioned between aqueous potassium carbonate and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (using ethanol-dichloromethane as eluent) yielded 2.3 g of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C11H12N2O2 : C, 64.69; H, 5.92; N, 13.72. Found: C, 63.70; H, 5.85; N, 14.24). A mixture of 2.3 g (11 mmole) of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine and 1.65 g (11 mmole) of 2-mercaptobenzimidazole in 40 ml of 15% hydrogen bromide in acetic acid was heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. Chromatography yielded 2.1 g of the title compound. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CC[N:21]([CH:25]([CH3:27])C)[CH:22](C)C.N1CCC1.[NH4+].[Cl-]>C(Cl)Cl.CCOC(C)=O>[N:21]1([S:2]([C:5]2[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:22][CH2:27][CH2:25]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (0.3 g, 991 μmol; Buttpark Ltd.) in CH2Cl2 (1 mL) were added DIPEA (192 mg, 260 μL, 1.49 mmol) and azetidine (62.3 mg, 73.5 μL, 1.09 mmol). The clear, light yellow solution was stirred at room temperature for 4 hours and then poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, and evaporated. Light brown solid (0.316 g; 98%). MS (EI): m/z=323 [M].
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(OC)(OC)OC.[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][CH:40]=O)[CH:32]=[CH:31]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CO>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][CH2:40][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:32]=[CH:31]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CCC=O)ccc2c1
Reactant: CCCNCCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
Dipropylamine (363 mg) was dissolved in anhydrous methanol (20 ml) and then added with sodium cyanoborohydride (281 mg), trimethyl orthoformate (0.490 ml), and the compound (981 mg) obtained in Example 121-7, followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. After that, the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.28 g) as a brown liquid.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13](=[O:14])[C:8]2=[CH:7][NH:6]1)(C)(C)C>FC(F)(F)C(O)=O>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[N:10]=[C:9]2[N:5]=[N:6][CH:7]=[C:8]2[C:13](=[O:14])[N:12]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc2n(C(C)(C)C)[nH]cc-2c(=O)n1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccccc1C1=NC(=O)C2=CN=NC2=N1
Yield: 79.9 %

Procedure:
A mixture of 1-tert-butyl-6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one 1/100 hydrate (0.68 g, 2.1 mmol) and trifluoroacetic acid (50 ml) was heated on a steam bath for 3.5 hours. The reaction mixture was stripped to dryness and the residue was purified by column chromatography on silica gel eluting with ether to afford 0.45 g (79%) of 6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one 1/4 hydrate, m.p. 170°-171° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]([O:23][CH2:24][CH3:25])=[CH2:22])CCC.[F-].[K+]>CN(C)C=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[CH2:22])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Yield: 50.3 %

Procedure:
A degased solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (7 g, 26.82 mmol), tributyl(1-ethoxyvinyl)stannane (9.51 mL, 28.16 mmol) and bis(triphenylphosphine)-palladium chloride (0.376 g, 0.54 mmol) in dimethylformamide (200 mL) was heated under argon at 100° C. for 1.5 h. The mixture was poured into a solution of potassium fluoride (20 g) in water 250 mL, and the mixture was extracted with MTBE (300 mL). The organic phase was washed with water, dried over sodium sulfate, and filtered through a pad of silica gel. The residue was crystallised from heptane (50 mL) to yield the title compound (4.0 g). The mother liquor was concentrated in vacuum and purified by column chromatography on silica gel, using a gradient of 0-15% ethyl acetate in heptane as eluent to yield additional amount of the title compound (2.9 g), total yield being 6.45 g (81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21]C(OCC2C=CC=CC=2)=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(Cl)Cl.C1COCC1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH2:21])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCN)cc1
Yield: 76.2 %

Procedure:
{4-[4-(2-Benzyloxycarbonylaminoethoxy)phenyl]butyl}carbamic acid tert-butyl ester 15 (61.8 g) was stirred in ethanol (500 ml) with 10% palladium on carbon (6 g, wet), under one atmosphere of hydrogen. After stirring for more than 6 h, TLC (silica gel, methylene chloride/THF, 20:1) indicated reaction completion. The complete reaction was flushed with nitrogen, and suction filtered through a pad of Celite, and the pad washed with methylene chloride. The residue (41 g) after evaporation of the methylene chloride was applied to an 800 g pad of silica gel, and sequentially eluted with a mixture of THF and methylene chloride (1.4 L, 2:1), and a mixture of methylene chloride, methanol, and concentrated ammonium hydroxide (30:10:1, 2 L). The fraction containing the product was collected. Evaporation afforded the pure product 16 (32.8 g, 74% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.50 (br s, 2H), 1.55 (m, 4H), 2.56 (t, 2H), 3.12 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:29]1[CH:33]=[CH:32][C:31]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)=[CH:30]1
Reactant: OB(O)c1ccoc1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccoc4)cc2-3)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 1.7 mmol), Furan-3-boronic acid (0.28 g, 2.5 mmol), Na2CO3 (2 M, 3.9 mL), and Pd(PPh3)2Cl2 (15 mg, 0.13 mmol) in toluene/ethanol (1:1, 12 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Furan-3-yl-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 67% yield.
Reaction SMILES: C([C:4]1([CH2:19][CH2:20][CH:21]=O)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2C=[CH:16][CH:17]=[CH:18][C:5]1=2)CC.Cl.[CH3:24][NH:25][CH3:26].C([BH3-])#N.[Na+].[CH2:31]1[CH2:35]O[CH2:33][CH2:32]1>CO>[CH3:24][N:25]([CH3:26])[CH2:33][CH2:32][CH2:31][C:35]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]([CH2:19][CH2:20][CH3:21])[C:5]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CNC
Reactant: C1CCOC1
Reactant: CCCC1(CCC=O)c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCC1c2ccccc2CCc2c(CCCN(C)C)cccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
Dissolved 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5yl]-propanal (0.75 g, 2.56 mmol) in 5 mL of dry THF and 10 mL of dry methanol. Added 3A sieves, dimethylamine hydrochloride (1.05 g, 12.82 mmol), and sodium cyanoborohydride (0.161 g, 2.56 mmol). Stirred to room temperature for 24 hours. Added saturated NaHCO3, and filtered through celite. Extracted filtrate with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% MeOH--CH2Cl2 then 10% MeOH--CH2Cl2. Combined appropriate fractions, and evaporated to give 0.53 g (65% yield) of 10,11-dihydro-N,N-dimethyl-5-propyl-5H-dibenzo[a,d]cycloheptenepropanamine as an oil. Dissolved free base in dichloromethane, and added 28.8 weight % HCl-ethanol until acidic. Evaporated to give hydrochloride salt as a foam.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[CH2:22][C:23]1[N:24]([CH3:49])[C:25]2[C:30]([N:31]=1)=[C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[N:28]=[C:27]([N:38]1[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]1[CH2:47][CH3:48])[N:26]=2)=O)(C)(C)C>C(Cl)Cl>[C@H:19]12[CH2:21][C@H:16]([NH:15][CH2:20]1)[CH2:17][N:18]2[CH2:22][C:23]1[N:24]([CH3:49])[C:25]2[C:30]([N:31]=1)=[C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[N:28]=[C:27]([N:38]1[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]1[CH2:47][CH3:48])[N:26]=2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (122 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 520 mg) in DCE (10 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 85:15) to give (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid. TFA (3 mL) was added to a solution of (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 85:15) to afford 395 as a white solid (153 mg, 63%). LCMS (Method G): RT=5.78 min, M+H+=474. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.26 (m, 2 H); 4.34 (m, 4 H); 4.00 (d, J=13.6 Hz, 1 H); 3.92-3.83 (m, 8 H); 3.70 (s, 1 H); 3.45 (s, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.25 (d, J=10.2 Hz, 1 H); 2.97-2.91 (m, 2 H); 2.70 (d, J=10.2 Hz, 1 H); 1.85 (d, J=10.1 Hz, 1 H); 1.70 (d, J=10.1 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].N(C(OCC)=O)=NC(OCC)=O.[OH:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]O>O1CCCC1.C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:44][C:43]1[CH:42]=[C:41]([OH:40])[CH:48]=[CH:47][CH:46]=1
Reactant: OCc1cccc(O)c1
Reactant: Oc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1cccc(COc2ccccc2Cl)c1
Reaction time: 1 h
Yield: 50.9 %

Procedure:
At 0° C. to 616 mg (2.35 mmol) of triphenylphosphine and 400 μL (3.84 mmol) of 2-chlorophenol in 20 niL of methylene chloride was added 370 mL (2.35 mmol) of diethyl azodicarboxylate followed by dropwise addition of a solution of 233 mg (1.9 mmol) 3-hydroxybenzyl alcohol in 2 mL of tetrahydrofuran. The reaction mixture was stirred at 0° C. to ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (methylene chloride/hexane (2:1 to 4:1)) to provided 227 mg (44% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.39 (dd, 1 H, J=1.6, 7.8 Hz), 7.25 (t, 1 H), 7.15-7.21 (m, 1 H), 6.88-7.01 (m, 4 H), 6.79 (dd, 1 H, J=2.5, 8.1 Hz), 5.12 (s, 2 H), and 4.97 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@H:28]2[CH3:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)#[N:2].CS(C)=[O:44].OO.[OH-].[Na+]>CO.CC#N>[C:1]([C:3]1[N:4]=[CH:5][C:6]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C@H:28]2[CH3:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:44])[NH2:2]
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C(N)=O)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
tert-Butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (312) (430 mg, 0.74 mmol) was dissolved in MeOH (25 mL), DMSO (4.4 mL), and TEA (0.22 mL, 1.6 mmol). The solution was cooled to 0° C., and a pre-mixed solution of 30% H2O2 (175 μL, 1.5 mmol) and 4N NaOH (384 μL, 1.5 mmol) was added. The reaction was stirred for 1 hour at 0° C. An additional amount of the pre-mixed solution 30% H2O2 (175 μL, 1.5 mmol) and 4N NaOH (384 μL, 1.5 mmol) was added, and the reaction was stirred for an additional hour at 0° C. MeCN (10 mL) was then added and the solution was stirred for 10 minutes at room temperature. The solvents were removed under reduced pressure, and the residue was subjected to silica flash column chromatography (MeOH/DCM) to give tert-butyl (2R,3R)-1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (313) (430 mg, 0.74 mmol, 97% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCOCC1.O.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>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]3)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: O=C1CCc2cc(Br)ccc2C1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCc2cc(-c3ccc([N+](=O)[O-])cc3)ccc2C1
Yield: 50.6 %

Procedure:
Pd(PPh3)4 (0.0736 g, 0.06 mmol) was added to a solution of 6-bromo-2-tetralone (1.5 g, 6.66 mmol) in 50 mL of 1,4 dioxane-H2O (3:1) mixture under argon atmosphere, followed by cesium carbonate (6.49 g, 19.99 mmol) and 4-nitrophenyl boronic acid (1.32 g, 7.99 mmol). The reaction mixture was degassed for 5 min. The reaction mixture was refluxed for 4 h and solvent removed under reduced pressure. The residue partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulphate, filtered and removed under reduced pressure. The product was purified by flash chromatography using 18% ethyl acetate in hexane to afford title compound (0.9 g, 50%) as solid. 1H NMR (300 MHz, CDCl3): 8.31 (d, J=9.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.5 (m, 2H), 7.27 (s, 1H), 3.66 (s, 2H), 3.16 (t, J=6.9 Hz, 2H), 2.61 (t, J=6.9 Hz, 2H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C:7](=[CH:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([O:19][C:12]1[CH:13]=[CH:14][C:15]2[C@@H:16]3[C:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[CH:3]=[CH:4][CH2:5]4)=[CH:8][CH2:9][C:10]=2[CH:11]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]12C=CC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra-1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 mL, 32 mmol) and acetic anhydride (0.36 mL, 3.8 mmol) was stirred 6 h, after which 30 mL of ethyl acetate were added. The mixture was washed with three 10 mL portions of 1N hydrochloric acid+10 mL of saturated sodium bicarbonate+10 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24. (NA-1994A-286A)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH:30]([CH3:34])[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH:30]([CH3:34])[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(CC#N)N1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CC#N)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 53.1 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.33 g, 45.4 mmol), 3-(4-amino-piperidin-1-yl)-butyronitrile (hydrochloride salt) (50.0 mmol), diisopropylethylamine (24.5 ml, 141 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 18 h. The mixture was cooled to 25° C. and was concentrated to approximately 25 ml volume. This material was partitioned between water (200 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (11.3 g, 53% over 3 steps) as a yellow-orange foam. LCMS (Method G, ESI): RT=0.70 min, m+H=469.3. This material was used in the next step below without additional characterization.
Reaction SMILES: [CH2:1]([NH+:4](CCC)[CH2:5][CH2:6]C)[CH2:2]C.[C:11](=[S:13])=[S:12].[CH2:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].C(NCC)C>>[CH2:1]([N:4]([CH2:5][CH3:6])[C:11](=[S:13])[S-:12])[CH3:2].[CH2:14]([NH+:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]
Reactant: CCCN(CCC)CCC
Reactant: S=C=S
Agent: CCC[NH+](CCC)CCC
Solvent: CCNCC
Product: CCN(CC)C(=S)[S-]
Temperature: 50 °C

Procedure:
Preparation of tripropylammonium salt of diethyl dithiocarbamateis as follows: 76 grams (1 mole) carbon disulfide and 143 grams (1 mole) tripropylamine are mixed at 10° C. under nitrogen. 80.5 grams (1.1 mole) diethylamine is added slowly and drop wise to the mixture and the mixture is maintained at a temperature below 30° C. Then the mixture is heated to 50° C. for 1 hour. The solution is then stripped out under vacuum to remove the excess amine and for the removal of low volatiles to obtain final product. The acid number (normally below 30) is measured to check the acidity. The product purity (ranging between 85-95%) is measured by LC-MS and NMR.