Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl[C:21]1[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:36])[N:22]=1>CN(C=O)C>[Cl:36][C:23]1[N:22]=[C:21]([S:4][CH2:1][CH2:2][CH3:3])[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1
Reactant: CCCS
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)ccc1C(=O)NC1CCCCC1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of propane thiol (2.975 mL, 32.89 mmol)l in DMF (25 mL) was added slowly a solution of 1N NaHMDS in THF (33 ml, 33.00 mmol). The mixture was stirred for ten minutes at room temperature and then added slowly to a solution of 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide (Intermediate 1, 8.95 g, 32.89 mmol) in DMF (50 mL). The reaction was stirred at room temperature for two hours. The reaction was stopped and most of the THF and DMF was evaporated. The product was extracted with DCM (150 mL), washed with water (2×25 ml) and brine (25 mL). The solution was dried over MgSO4 and evaporated under reduced pressure to give a slightly pink solid. The solid was triturated in hexane and filtered; all of the coloured impurity went into solution to leave a white solid (7.84 g, 76%).
Reaction SMILES: [I-].C[N+]([CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:9])(C)C>O.C(OCC)(=O)C>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([C:8](=[O:9])[CH:7]=[CH2:6])[CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19]
Reactant: COc1cc(C(=O)CC[N+](C)(C)C)cc(OC)c1OC
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 2.5 h

Procedure:
The above iodide (355.9 g, 0.87 mol) was suspended in a mixture of water (3.56 L) and ethyl acetate (2.54 L) and heated under reflux with rapid stirring for 2-3 hours. The mixture was cooled and the pale yellow organic layer was removed. Fresh ethyl acetate (2 L) was added and the mixture was again heated under reflux for 1 hour and the process was repeated once again. The organic extracts were combined, washed with brine, dried (MgSO4), and evaporated to a yellow oil which was crystallized from hexane-ethyl ether to give 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one: mp 46°-47° C.; NMR (CDCl3) δ 3.94 (s, 3 OCH3), 5.92 (2 d, J=1.5 & 9.0 Hz, CH=CH2), 6.44 (2 d, J=1.5 & 16 Hz, CH=CH2), 7.18 (2 d, J=9.0 & 16 Hz, CH= CH2), 7.28 (ArH).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=1.O[N:32]1[C:36]2[CH:37]=CC=C[C:35]=2N=N1.C1(N)CC1>ClCCl>[CH3:35][CH:36]([NH:32][C:28]([C:26]1[N:27]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:14]4=[CH:15][C:16]5[O:20][CH2:19][O:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:2]2=[O:1])[O:24][CH:25]=1)=[O:30])[CH3:37]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Agent: NC1CC1
Solvent: ClCCl
Product: CC(C)NC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A solution of 2-((2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)methyl)oxazole-4-carboxylic acid (0.41 g, 1.0 mmol), N-hydroxybenzotriazole (0.20 g, 1.5 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5 mmol) in dichloromethane (10 mL) was stirred for 30 min, followed by the addition of cyclopropylamine (0.8 mL). The solution was stirred at ambient temperature for 16 h, diluted with dichloromethane (100 mL), washed with distilled water (2×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (gradient: 50% to 75%) to afford N-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide (0.40 g, 91%) as a colorless solid: mp 188-191° C.; 1H NMR (300 MHz, CDCl3) δ8.14 (s, 1H), 7.28-7.22 (m, 1H), 7.19 (d, J=6.8 Hz, 1H), 7.07 (dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.7 Hz, 2H), 6.49 (s, 1H), 6.16 (s, 1H), 5.85 (ABq, 2H), 5.04 (ABq, 2H), 4.81 (ABq, 2H), 2.82 (m, 1H), 0.85-0.77 (m, 2H), 0.64-0.58 (m, 2H); 13C NMR (75M Hz, CDCl3) δ177.2, 161.3, 158.1, 155.8, 149.0, 142.4, 141.8, 141.0, 136.6, 132.0, 129.1, 124.15, 124.10, 119.2, 108.6, 103.0, 101.6, 93.7, 80.2, 58.2, 37.1, 22.3, 6.60, 6.55; MS (ES+) m/z 446.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[N:23]([CH3:28])[N:24]=[CH:25][C:26]=3[Br:27])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:30][OH:31].Cl>C(O)C>[Br:27][C:26]1[CH:25]=[N:24][N:23]([CH3:28])[C:22]=1[C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[N:30][OH:31])[CH3:2])[CH:5]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: NO
Reactant: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Br)cnn1C
Agent: Cl
Solvent: CCO
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=NO)c2)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Compound 17 (54 mg, 0.12 mmol, see Example 1.24) was dissolved in ethanol (10 mL). Hydroxylamine hydrochloride (17 mg, 0.24 mmol) was added under Argon gas. The pH of the solution was then adjusted to pH=4 with 1N Hydrogen Chloride solution. The reaction was stirred overnight at room temperature and found to be complete by TLC and LC/MS. The ethanol was removed under reduced pressure. Then, the residue was worked up with EtOAc (2×20 mL) and Brine (20 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by HPLC to afford 8.8 mg (16%) of Compound 96: LCMS m/z (%)=458 (M+H79Br, 96), 460 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.48 (dd, J1=12 Hz, J2=4 Hz, 1H), 7.42 (s, 1H), 7.41 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.39 (d, J=4 Hz, 1H), 7.30 (t, 1H), 7.19 (d, J=8 Hz, 1H), 7.15 (s, 1H), 7.08 (dd, J1=12 Hz, J2=4 Hz, 1H), 6.88 (dd, J1=12 Hz, J2=8 Hz, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.OS(O)(=O)=O.O=S(=O)=O>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: COc1ccc(N)cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COc1ccc(N)cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
123 parts of fused p-anisidine are added dropwise over 30 minutes to 240 parts of 100% sulfuric acid, while keeping the temperature at 55°-60° C. After stirring for 15 minutes the p-anisidine is completely dissolved. This sulfuric acid solution is then run into 242 parts of 66% oleum over 30 minutes, while keeping the temperature at 30°-40° C. by cooling with an ice bath. Stirring is continued for 30 minutes at 40° C., after which time no more educt can be detected by HPLC. The batch is poured into 1000 parts of ice/water and the precipitated 4-methoxyaniline-3-sulfonic acid is filtered with suction and washed with 500 parts of ice/water, affording 179 parts of moist 97.0% 4-methoxyaniline-3-sulfonic acid, corresponding to a yield of 85%, based on p-anisidine. No more p-anisidine and no more 4-methoxyaniline-2-sulfonic acid is detectable by HPLC (<0.1%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:18]1[CH2:17][CH2:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])([C:10]([O:12][CH3:13])=[O:11])[CH2:19]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-(tert-butoxycarbonylamino)acrylate (16.5 g, 82.0 mmol) and N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (19.5 g, 82.0 mmol) in DCM (400 mL) was added dropwise TFA (0.32 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in DCM) to give methyl 1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine-3-carboxylate (21.7 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].I[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (207 mg, 1.05 mmol), sodium hydride (29 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added iodomethane (164 mg, 1.15 mol) then stirred for 2 h at room temperature. The reaction mixture was carefully quenched with water then extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine. MS (EI) for C8H7BrN2: 209, 211 (MH+, Br pattern).
Reaction SMILES: [NH2:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:11](Cl)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2)(=[O:13])[CH3:12]
Reactant: CC1(C)C2CCC1(N)CC2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)NC12CCC(CC1)C2(C)C

Procedure:
A solution of 1-amino-7,7-dimethylnorbornane (1.022 g) in pyridine (10 ml) was cooled in an ice-bath and stirred whilst acetyl chloride (1 ml) was added dropwise. The ice-bath was removed and the mixture was kept at room temperature until the reaction was complete. Dilution with water, acidification with dilute hydrochloric acid and extraction with ether afforded the crude product which was purified by filtration through a small column of neutral alumina and crystallization from ether-petroleum ether to give 1-acetamido-7,7-dimethylnorbornane m.p. 133°-134° (Kofler) after previous softening.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].Cl.[NH2:35][OH:36]>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=[N:35][OH:36]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(C=NO)c3)nc(OC)n2)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 117.9 %

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [700 mg, 1.84 mmol, Example 35(j)], sodium acetate (2.5 g, 18.4 mmol) and hydroxylamine hydrochloride (1.3 g, 18.4 mmol) in EtOH (95%, 20 mL) is stirred for 20 hours at 20° C. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered through a plug of silica, and concentrated to afford 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde oxime [0.86 g, Example 26]. LCMS: RT=2.53 minutes, MS: 397 (M+H). IC50=4.5 nM
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][O:2][C:3]1([C:9]([Cl:14])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: COC1(C(=O)O)CCCCC1
Solvent: CN(C)C=O
Product: COC1(C(=O)Cl)CCCCC1

Procedure:
76 g (480 mmoles) of 4 methoxycyclohexane carboxylic acid (cis/trans mixture) were boiled for 7 hours with refluxing in 350 ml of thionyl chloride to which several drops of dimethyl formamide had been added. The obtained 4 methoxycyclohexane carboxylic acid chloride was composed almost completely of the trans compound. After distilling off of the thionyl chloride the residue was incorporated into 75 ml of dry tetrahydrofuran. At a temperature of from 0° to 5° C. this solution was slowly added dropwise to a solution of 158.4 g (1440 mmoles) of hydroquinone in 650 ml of tetrahydrofuran and 375 ml of pyridine. When, after this addition, the mixture had attained room temperature, it was poured onto ice and concentrated sulphuric acid. Extraction with dichloromethane, evaporation of the dichloromethane, and, in succession, conversion of the evaporation residue to the crystallised form from an ethanol-water mixture and from toluene gave a yield of 24.45 g (20%) of pure trans 4 hydroxyphenyl 4'methoxycyclohexyl carboxylate. 24.3 g (97 mmoles) of the above compound were boiled, with refluxing, for 24 hours with 17.6 g of allyl bromide (145 mmoles) and 13.4 g (97 mmoles) of potassium carbonate in 350 ml of methylethyl ketone. After cooling the reaction mixture was poured into 1 .right brkt-top.of ice water, which was extracted with the aid of diethyl ether. After drying and evaporation of the diethyl ether 28.9 g (97%) of 4 allyloxyphenyl 4'methoxycyclohexyl carboxylate were obtained. To 28.7 g (99 mmoles) of said compound in 250 ml of dichloromethane there were added 32.9 g of chloroperbenzoic acid, and the mixture was stirred for 24 hours under an atmosphere of nitrogen. After being diluted with dichloromethane the reaction mixture was washed with sodium carbonate solution and water. After drying the dichloromethane was distilled off, and the residue was purified on a column filled with silica gel and eluted with a hexane-ethyl acetate mixture (75/25). The yield was 20.8 g (66%) of 4(2,3 epoxypropyl oxy)phenyl 4'methoxycyclohexyl carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)NC(C)C)n2C)cc1
Yield: 38.08 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-06) (250.0 mg, 38.08%) was synthesized as a brown solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) (600.0 mg, 1.36 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
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: O
Solvent: CCOCC
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: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][N:14]2[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:44]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:44][C:11]([C@@H:13]3[CH2:21][C:16]4([O:17][CH2:18][CH2:19][O:20]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1)OCCO2)C(C)C
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
In a 5 mL seal tube, methyl (S)-1-((S)-8-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (75 mg, 142 μmol) was combined with 1,4-dioxane (2 ml) to give a light yellow solution. Ammonium acetate (110 mg, 1.42 mmol) was added and it was stirred at 110° C. overnight. It was cooled and diluted with EtOAc(10 ml), filtered and concentrated in vacuo to afford methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a light brownish solid (70 mg, 96.8%). ESI-LRMS m/e calcd for C22H27BrN4O5 [M+] 507. found 508 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred suspension of 6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 990 mg, 5.15 mmol) in DMF (3.0 mL) is added K2CO3 (855 mg, 1.2 equiv.) followed by Mel (0.64 mL, 2.0 equiv.). The resulting solution is stirred overnight at room temperature. Water (20 mL) is then added and the reaction mixture is extracted with ethyl acetate (20 mL×2) and washed with saline (20 mL). The organic layers are collected and dried over MgSO4. Solvent is removed to yield the title compound as a yellow solid (956 mg, 90%). 1H NMR (300 MHz, DMSO) δ 8.16-7.26 (m, 3H), 3.30 (s, 3H), 3.00 (t, 2H), 2.61 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: Clc1ncccn1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Temperature: 90 °C
Yield: 88.4 %

Procedure:
A mixture of 2.52 g (14.8 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 1), 1.70 g (14.8 mmol) of 2-chloropyrimidine and 6.91 g (65.2 mmol) of sodium carbonate in 150 mL of water was heated at 90° C. for 16 h.; then cooled and extracted with chloroform (3×). The organic layer was dried (magnesium sulfate), filtered and evaporated to give 3.25 g (89%) of the title compound which was used without purification in subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][OH:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([O:19][CH2:18][C:17]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[N:26]=[CH:25][N:24]=1
Reactant: OCc1cc2ncccc2nc1-c1cccc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)ncnc1OCc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)methanol (65 mg, 0.256 mmol) in DMF (1.5 mL) was added sodium hydride (12.3 mg, 0.31 mmol, 60% suspension in oil) and the reaction was stirred at rt for 10 min. After this time 4-amino-6-chloropyrimidine-5-carbonitrile (39.5 mg, 0.256 mmol) was added and the reaction was stirred at rt for 30 min. After this time an additional portion of NaH (12.3 mg, 0.31 mmol, 60% dispersion in oil) was added and the reaction was heated at 50° C. for 2 h and at rt overnight. After this time the reaction was cooled to rt and partitioned between EtOAc (50 mL) and LiCl (20 mL, 1M aq. solution). The separated organic layer was washed with LiCl (20 mL, 1M aq. solution) and then it was dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by reversed-phase HPLC (10 to 60% acetonitrile in water) to give 4-amino-6-((2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)methoxy)-5-pyrimidinecarbonitrile as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.04 (1H, dd, J=4.2, 1.7 Hz), 8.61-8.66 (1H, m), 8.44-8.51 (1H, m), 8.28 (1H, s), 7.71 (1H, dd, J=8.6, 4.1 Hz), 7.36-7.56 (3H, m), 7.21 (1H, tdd, J=8.3, 8.3, 2.7, 1.2 Hz), 5.67 (2H, s), 5.62 (2H, br. s.): LC-MS (ESI) m/z 373.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl>O>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N2CCOCC2)CC1
Reaction time: 72 h

Procedure:
273 Grams of 4-chloro-3-morpholinosulfonylbenzoic acid (1.0 mole) were heated under reflux for 5 hours with 0.5 l of N-methylpiperazine. Subsequently the excess base was completely eliminated in vacuo, the residue was dissolved in 2 l of water, and the pH value of the solution was adjusted to 8 by means of 5N HCl. After standing for 3 days at room temperature, the crystalline precipitate was suction-filtered and was recrystallized from water.