Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)OC(C)(C)C)[CH2:17]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[NH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=23)[CH2:17]1
Reactant: CCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 203.6 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.22 g, 0.521 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase HPLC (0-50% ACN in water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide hydrochloride (0.190 g, 92.3% yield). 1H NMR (400 MHz, D2O) δ 8.14 (s, 1H), 7.28 (s, 1H), 3.88-3.84 (m, 1H), 3.54-3.37 (m, 2H), 3.19-3.13 (m, 2H), 2.42-2.37 (q, 2H), 2.11-2.08 (m, 1H), 1.80-1.76 (m, 1H), 1.66-1.54 (m, 2H), 1.10-1.06 (t, 3H). LCMS (APCI+) m/z 322 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[O:14][CH2:13][CH:12]([OH:15])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].CO.O>C(Cl)Cl>[C:16]([O:15][CH:12]1[CH:11]=[CH:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][CH2:13]1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(O)CO1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-ol (13.3 g, 57.7 mmol) and TEA (16.09 mL, 115 mmol) in DCM (200 mL) was added acetic anhydride (27.2 mL, 289 mmol), and the mixture was stirred at room temperature overnight. Methanol (˜3 mL) was added and the mixture was stirred for 30 min at room temperature before adding water and transferring to a separatory funnel. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and condensed. The crude material was purified on a 340G SNAP Biotage column (0-50% ethyl acetate in hexane) to give 6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetate (13.6 g, 49.9 mmol, 86% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 5.84-5.88 (m, 2H), 5.26-5.28 (m, 1H), 5.20-5.25 (m, 1H), 3.84 (dd, J=6.25, 1.95 Hz, 2H), 2.08 (s, 3H), 0.91 (s, 9H), 0.13 (d, J=1.17 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O[C:16]([S-])=[S:17])C.[K+].Cl>N1C=CC=CC=1>[S:17]=[C:16]1[NH:1][C:2]2=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=[C:11]2[O:12]1
Reactant: COC(=O)c1cccc(O)c1N
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2oc(=S)[nH]c12
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A mixture of methyl 2-amino-3-hydroxybenzoate from Step A (2.04 g, 12.2 mmol) and potassium O-ethylxanthate (1.37 g, 8.56 mmol) in pyridine (8 mL) was heated to reflux for 2 h, then cooled to room temperature and poured into a mixture of ice-water (45 mL) and conc. HCl (4.8 mL). The resulting precipitate was collected by filtration and washed with water, dried on vacuum to give methyl 2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (1.33 g, 52%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 10.40 (br s, 1H), 7.82 (dd, J 8.0, 1.0 Hz, 1H), 7.49 (dd, J 8.0, 1.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 4.01 (s, 3H); MS (ESI+) m/z 210 (M+H).
Reaction SMILES: [CH2:1]([N:9]1[C:17]([CH2:18]Br)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na].[OH:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:1]([N:9]1[C:17]([CH2:18][O:22][CH2:23][P:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:31])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOP(=O)(CO)OCC
Reactant: Nc1ncnc2c1nc(CBr)n2CCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CCc1ccccc1)OCC

Procedure:
A solution of N9-phenethyl-8-bromomethyladenine (1 mmol) in DMF was treated with a solution of diethyl hydroxymethylphosphonate sodium salt (1 mmol) in DMF at 25° C. for 1 h. Extraction and chromatography gave N9-phenethyl-8-diethylphosphonomethoxymethyladenine as a white solid. TLC: Rf=0.31, 10% MeOH—CH2Cl2.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8].C(OCC)(=O)[CH2:17][C:18]([O:20]CC)=[O:19].[H-].[Na+].Cl>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([CH2:2][CH2:17][C:18]([OH:20])=[O:19])=[C:7]([CH3:8])[O:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1CCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
4-Chloromethyl-3-(4-chlorophenyl)-5-methylisoxazole (1.21 g) was dissolved in tetrahydrofuran (50 ml) and added to a mixture of diethyl malonate (1.20 g), sodium hydride (60%, oil, 0.21 g) and tetrahydrofuran (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[3-(4-chlorophenyl)-5-methyl-4-isoxazolyl]propionic acid (1.20 g, yield 90%). The crystals were recrystallized from ethanol. melting point: 187–188° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[CH3:19][N:20]([CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH:30]([CH3:32])[CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:36]1[CH:35]=[CH:34][C:33]([CH:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][N:20]([CH3:19])[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[CH:38][CH:37]=1
Reactant: CC(C)C(CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN(C)C(=O)OC(C)(C)C)C(C)C)cc1
Yield: 14 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (440 mg, 1.4 mmol) was reacted with tert-butyl methyl(3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)carbamate (600 mg, 1.5 mmol) to afford the desired product (100 mg, 14%) as a yellow solid: ESI MS m/z 521 [C30H36N2O4S+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33](N3CCCC3)=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O.[Cl-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[N:25]1([C:34]2[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=2)[CH2:29][CH2:28][N:25]2[CH2:24][CH2:23][C@@H:27]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:26]2)[CH2:26][CH2:27][CH2:23][CH2:24]1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (132 mg, 3.3 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (10 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (600 mg, 3.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 42 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3-pyrrolidinophenethyl)pyrrolidin-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (225 mg, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][N:27](C(OCC3C=CC=CC=3)=O)[CH2:28][CH:29]=2)=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)C.C(OCC)(=O)C>CO.[Pd]>[NH:27]1[CH2:28][CH2:29][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:17])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Temperature: 50 °C
Yield: 80.6 %

Procedure:
To a solution of benzyl 4-{4-[({2-[(tert-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (269 g, 524 mmol; prepared as described in Method 2 below) in methanol (3000 ml) was added 10% palladium on charcoal (10 g). The reaction mixture was placed under 5 bar pressure of hydrogen gas and heated to 50° C. for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the solvent evaporated under reduced pressure. The resultant foam was triturated under diethyl ether and filtered to give a white solid. This product was ground finely and stirred with 95:5 diethyl ether/ethyl acetate then collected by suction filtration. This solid was washed with diethyl ether, isohexane and dried in vacuo to afford the title compound (167 g, 81%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.57 (m, 2H), 1.72 (m, 2H), 2.61 (t, 2H), 2.69 (m, 1H), 3.07 (m, 2H), 7.18 (m, 2H), 7.40 (d, 2H), 7.53 (d, 2H), 7.91 (d, 2H), 8.70 (br s, 1H), 9.82 (br s, 1H); Mass Spectrum: M+H+ 396.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[OH:18])[CH2:7][CH2:6]2)[O:4]CC1.O.[NH+]1C=CC=CC=1>CC(C)=O>[OH:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2O)CC1
Yield: 99.8 %

Procedure:
A flask equipped with magnetic stirrer was charged with 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol (11.3 g, 45.2 mmol), acetone (250 ml) and water (50 ml). To the stirred solution was added pyridinium ptoluenesulfonate (1.14 g, 4.52 mmol) in one portion and the reaction mixture was then heated under reflux for 8 hr. After allowing the reaction mixture to cool to room temperature, most of the acetone was removed in vacuo and the remaining mixture was partitioned between ethyl acetate (200 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine (30 ml), dried (MgSO4), filtered and concentrated under reduced pressure to afford an off-white powder. After washing the powder with dichloromethane (100 ml) and removal of excess solvent under reduced pressure, the title compound (9.30 g, 100%) was obtained as an off-white powder. m/z (ES+) 207 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@@H:38]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:39]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.40 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.17 g) and (R)-2-chloropropionic acid methyl ester (0.15 g) was stirred at 40° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume) to afford title compound as a cream solid, 0.21 g.
Reaction SMILES: [CH:1](OC=C)=[CH2:2].[N+:6]([C:9]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:10][OH:11])([O-:8])=[O:7].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([O:11][CH2:10][C:9]([N+:12]([O-:14])=[O:13])([N+:15]([O-:17])=[O:16])[N+:6]([O-:8])=[O:7])=[CH2:2]
Reactant: C=COC=C
Reactant: O=[N+]([O-])C(CO)([N+](=O)[O-])[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=COCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Yield: 25.9 %

Procedure:
Following the procedure described in Examples I and II, divinyl ether and 2,2,2-trinitroethanol (X) were reacted for 60.25 hours in methylene chloride in the presence of red mercuric oxide and trifluoroacetic acid. A 25.9% yield of 2,2,2-trinitroethyl vinyl ether was obtained after elution with carbon tetrachloride through the neutral alumina (pH 7.3) column, followed by column chromatographic removal of 2,2,2-trinitroethanol in hexane through 60/200 mesh SiO2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O>[C:21]([O:13][CH:10]1[CH2:11][CH2:12][CH:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8][CH2:9]1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: NC1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCC(NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
In a nitrogen atmosphere, 115 g of methanesulfonyl chloride was added dropwise to a mixture of 115 g of 4-aminocyclohexanol, 212 g of triethylamine and 1,000 g of N,N-dimethylformamide at −20° C. The mixture was stirred for one hour, after which 105 g of methacryloyl chloride was added dropwise at −20° C. The mixture was gradually warmed to room temperature and then stirred for 5 hours. The reaction mixture was subjected to conventional aqueous work-up and purified by column chromatography, obtaining 196 g of 4-[(methylsulfonyl)amino]cyclohexyl methacrylate. The yield was 75% based on the 4-aminocyclohexanol.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12.[OH-].[Na+].[CH3:15]I>O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:15])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12
Reactant: Cc1n[nH]c2nc(S)nc(O)c12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc(O)c2c(C)n[nH]c2n1
Temperature: 5 °C
Reaction time: 0.29 h

Procedure:
4-hydroxy-6-mercapto-3-methylpyrazolo[3,4-d]pyrimidine (14 g) was dissolved in a solution of 10 g. of sodium hydroxide in 300 ml. of water. The solution was cooled to 5° C. and shaken with 12 g. of methyl iodide. After 15-20 minutes, the solution was charcoaled, filtered and acidified with acetic acid to yield 12 g. of crude product. Recrystallization in acidic acid gave the product. MS (ES+): 197.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32](O)=[O:33])=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:79][CH2:80][CH2:81][N:82]([CH2:86][CH2:87][OH:88])[CH2:83][CH2:84][OH:85]>CN(C)C=O>[OH:85][CH2:84][CH2:83][N:82]([CH2:86][CH2:87][OH:88])[CH2:81][CH2:80][NH:79][C:32]([C:5]1[C:6]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1)=[O:33]
Reactant: NCCN(CCO)CCO
Reactant: COc1cc(-c2csc3c(C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(C(=O)NCCN(CCO)CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 20 mL scintillation vial was charged with 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (0.070 g, 0.148 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.067 g, 0.177 mmol), 1-hydroxybenzotriazole hydrate (0.024 g, 0.177 mmol) and N,N-dimethylformamide (1.5 mL). To the suspension was added diisopropylethylamine (0.100 mL, 0.592 mmol) and 2-[(2-aminoethyl)(2-hydroxyethyl)amino]ethanol (0.024 mg, 0.162 mmol). The vial was flushed with nitrogen gas prior to capping, and the reaction mixture was shaken at room temperature for 12 hours. Upon completion of the reaction, methylene chloride (2 mL) and saturated sodium bicarbonate solution (2 mL) were added. The solution was filtered through an Empore™ cartridge, and the solvents removed under reduced pressure. The residues were taken up in a minimal amount of methanol and eluted (gravity) through a Si-carbonate™ cartridge (2 gram, 6 mL). The organic solution obtained was concentrated and the resulting residue triturated with water to give N7-2-[di(2-hydroxyethyl)amino]ethyl-4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)carbonyl]aminophenyl)thieno[3,2-c]pyridine-7-carboxamide as a precipitate. The title compound was collected and dried by vacuum filtration (15 mg, 14%). LCMS (Conditions a) Rt 2.62 min., 603.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.51 (s, 1H), 8.39 (t, J=5.5 Hz, 1H), 7.99 (dd, J=7.8 Hz, 8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.20 (d, J=1.6 Hz, 1H), 7.15 (dd, J=7.8 Hz, 7.2 Hz, 1H), 7.07 (dd, J=8.2 Hz, 1.6 Hz, 1H), 4.41 (t, J=5.8 Hz, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.44 (q, J=5.8 Hz, 4H), 3.34 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 2.61 (t, J=5.8 Hz, 4H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].C(N(CC)CC)C.[Si:17]([O:24][CH2:25][CH:26](O)[CH2:27][N:28]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[C:35]2[C:30]([N:31]([CH3:47])[C:32](=[O:46])[N:33]([CH3:45])[C:34]2=[O:44])=[CH:29]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH3:1][S:2]([O:5][CH:26]([CH2:27][N:28]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[C:35]2[C:30]([N:31]([CH3:47])[C:32](=[O:46])[N:33]([CH3:45])[C:34]2=[O:44])=[CH:29]1)[CH2:25][O:24][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:18])[CH3:19])(=[O:4])=[O:3]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonic anhydride (0.679 g, 3.90 mmol) in 1,2-dichloroethane (3.0 mL) was added dropwise to a solution of DMAP (0.016 g, 0.130 mmol), triethylamine (0.544 ml, 3.90 mmol) and 6-(3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.6 g, 1.300 mmol) in 1,2-dichloroethane (10 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours, then diluted with water (10 mL). The phases were separated and the aqueous phase was extracted with DCM (3×10 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)CCC>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.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1ccco1
Yield: 27 %

Procedure:
A DMF solution of 2-nitrobromobenzene (2.02 g), 2-tributylstannylfuran (3.31 mL), and tetrakis(triphenylphosphine)palladium was heated at 97° C. under N2 overnight. The mixture was evaporated to a small volume. The residue was suspended in 40 mL of water. This mixture was extracted with two 50 mL portions of Et2O. The combined extracts were dried and evaporated. This oil was purified by chromatography on silica gel with 10% EtOAc/hexanes to yield 0.51 g (27%) of 2-(2-nitrophenyl)furan. [This compound was reported in Smith et al.; J. Am. Chem. Soc. 1953, 75, 6335.]
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH2:28]([N:30]([CH2:40][CH3:41])[CH2:31][C:32]1[N:33]=[C:34]([N+:37]([O-])=O)[NH:35][CH:36]=1)[CH3:29].CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH2:28]([N:30]([CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[CH:14][CH:15]=2)=[O:5])[NH:35][CH:36]=1)[CH2:40][CH3:41])[CH3:29]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CCN(CC)Cc1c[nH]c([N+](=O)[O-])n1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1c[nH]c(NC(=O)c2ccc(-c3c(F)c(OC)cc(OC)c3F)c3nccnc23)n1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture at 70° C. for 7 h and using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1). Diethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 18.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Title compound: ESI-MS: 497.0 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.18 (DCM/MeOH/NH3aq, 91.5:7.5:1).