Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][CH2:6]1)C.[CH3:20][O:21][C:22](=[C:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[O:23][Si](C)(C)C>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:15]([O:14][C:13]([NH:12][CH2:11][CH:8]1[CH2:7][CH2:6][N:5]([CH2:4][C:28]2([C:22]([O:21][CH3:20])=[O:23])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(O[Si](C)(C)C)=C1CCOCC1
Reactant: CCOCN1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 130.8 %

Procedure:
To a stirred solution of tert-butyl {[1-(ethoxymethyl)piperidin-4-yl]methyl}carbamate (4 g, 14 mmol, step 1 of Example 8) and [methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane (2.9 g, 13 mmol, step 2 of Example 8) in CH2Cl2 (30 mL) was added dropwise trimethylsilyl trifluoromethanesulfonate (0.24 mL, 1.3 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (150 mL), extracted with CH2Cl2 (30 mL×2), and the combined organic layer was dried over sodium sulfate and filtered. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1) to give 6.3 g (64%) of the title compound as clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@H:36]([OH:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:9][N:10]([CH2:18][CH:19]2[CH2:21][CH2:20]2)C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@H:36]([OH:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:28][CH2:29]2)=[O:23])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CN(CC4CC4)C(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate (0.0674 g, 0.1182 mmol) was dissolved in dioxane (0.5 mL) and treated with HCl in dioxane (0.7389 ml, 2.956 mmol) (4M). The reaction was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in vacuo. The residue was redissolved in MeOH and re-concentrated three times. This residue was resuspended in MeOH (0.2+0.1 mL) and added dropwise to a stirred flask of Et2O (10 mL). After stirring for 30 minutes, the solids were filtered, washed with Et2O, and dried under a blanket of nitrogen to give (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one as a white solid (60.2 mg, 94%.) LCMS (APCI+) [M+H]+ 470.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[K+].C(O[C:17]([S-])=[S:18])C.Cl>N1C=CC=CC=1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:12][C:17](=[S:18])[NH:1][C:2]=2[CH:7]=1)=[O:9]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
In a round bottom flask equipped with a mechanical stirrer, reflux condenser and drying tube were placed 2-amino-4-methoxycarbonylphenol (8,3 g, 0.05 mole), O-ethylxanthic acid potassium salt (8.8 g, 0.055 mole) and pyridine (125 mL). The mixture was stirred and heated at reflux for 2 hours and cooled to room temperature. The mixture was poured into ice and concentrated HCl (50 mL). The product was collected as a solid and washed thoroughly with water. The material was air dried to give 9.9 g (95%) of the 5-methoxycarbonylbenzoxazol-2-thione as a white powder, m.p. 218°-221° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][NH:7]2.[F:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15](N2C=CC(=O)NC2=O)[CH2:14]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[NH:2][CH3:1])[CH2:14]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CNc1ncnc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNc1ncnc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
6-Methylamino-9H-purine (0.41 g, 2.7 moles) (Sigma Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 moles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 2 days, 150 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (6:4). Solvent was removed and lyophilization yielded 0.45 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(methylamino)-9H-purine (73%): mp 100°-103° C.; TLC Rf 0.69 (Silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -23.8° C. (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 265 (15.6); at pH 13, 265 (16.0); 1H NMR (300 MHz, DMSO-d6) δ8.34 and 8.24 (2s, 2H, H2 and H8), 7.86 (b, 1H, NH), 6.41 (dd, 1H, H1', J=9.3 Hz, J=5.6 Hz), 5.37-5.37 and 5.52-5.56 (2m, 2H, OH5' and H3'), 4.25 (dt, 1H, H4', J=27.0 Hz, J=4.2 Hz), 3.60-3.64 (m, 2H, H5' and H5"), 3.03-3.16 (m, 1H, H2'), 2.92-2.99 (b, 3H, CH3), and 2.57-2.74 (m, 1H, H2"); MS (ci) 268 (M+1), 248 (M-F), 150 (MH2C5H8FO2).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([Cl:23])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:21]1[CH:22]=[C:17]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][N:13]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1
Reactant: CCN1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 90 °C
Yield: 44 %

Procedure:
A solution of 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (185 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesium carbonate (1.02 g, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77.7 mg, 0.13 mmol) in dioxane (10 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was triturated with methanol and dichloromethane and filtered, washed with ether and dried to give 6-chloro-4-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one (138 mg, 44%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[C:19]([C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[C:22]([O:30][CH3:31])[CH:21]=2)[C:8]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:18][CH:17]=[N:16][CH:15]=3)[CH2:4][CH3:5])[CH3:2]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[C:19]([C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:30][CH3:31])[CH:21]=2)[C:8]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:18][CH:17]=[N:16][CH:15]=3)[CH2:4][CH3:5])[CH3:2]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3cnccc3c2c1-c1ccc(OC(C)C)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3cnccc3c2c1-c1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44.7 %

Procedure:
Titanium tetrachloride (0.85 ml) was added dropwise to a solution of the compound (1.0 g) obtained in Example 50A in dichloromethane (35 ml) under ice-cooling, and the mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was poured over ice-water, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed successively with an aqueous saturated solution of sodium bicarbonate and water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform (1:1, v/v) to yield ethyl 2-diethylaminomethyl-4-(4-hydroxy-3-methoxyphenyl)thieno[2,3-b:5,4-c']dipyridine-3-carboxylate (0.41 g, 44%), which was then recrystallized from ethyl acetate to yield colorless prismatic crystals having a melting point of 179 to 181° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]1)[NH:15][C:18](=[O:19])[C:17](=[O:21])[NH:16]2
Reactant: Nc1cc(Cl)c(-n2ccc(=O)cc2)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2Cl)cc1
Yield: 12.6 %

Procedure:
First, a mixture containing 1.93 g of 4-chloro-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, 2.21 g of oxalic acid, and 40 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 2 hours. The mixture was cooled and precipitated crystals were filtered to give 2.1 g of crude crystals of 6-chloro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione (melting point: >400° C.). Then, 500 mg of the crude crystals were recrystallized with dimethylformaldehyde and water to give 299 mg of 6-chloro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[O:30])=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1cn2cc(Sc3ccccn3)ccc2n1
Solvent: ClCCl
Product: COC(=O)Nc1cn2cc(S(=O)c3ccccn3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.300 g. (1 mmole) of 2-methoxycarbonylamino-6-(pyridylthio)-imidazo [1,2-a] pyridine in 50 ml. of methylene chloride is added 0.189 g. (1.1 mmoles) of m-chloroperbenzoic acid. The reaction is stirred at room temperature overnight, and the resultant solution is washed 3 times with saturated sodium bicarbonate solution. The methylene chloride layer is dried and evaporated to dryness in vacuo affording 2-methoxycarbonylamino-6-(2-pyridylsulfinyl) imidazo [1,2-a] pyridine, m.p. 231°-235° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH3:20])[CH2:12][N:13]([CH3:19])[CH2:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.C(#N)C.[H-].[Na+].[C:26](OC=O)(=[O:28])C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([C:10]2[N:11]([CH3:20])[CH2:12][N:13]([CH3:19])[CH2:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:26]=[O:28])=[CH:4][CH:3]=1
Reactant: CN1CC([N+](=O)[O-])=C(NCc2ccc(Cl)nc2)N(C)C1
Reactant: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1CC([N+](=O)[O-])=C(N(C=O)Cc2ccc(Cl)nc2)N(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a mixture of 0.27 g of 4-(6-chloro-3-pyridylmethylamino)-1,3-dimethyl-5-nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 13), 5 ml of dry THF and 5 ml of dry acetonitrile was added 0.0239 g of sodium hydride (60%, in oil) in small portions over 1 minute with ice cooling. After the mixture was stirred at room temperature for 30 minutes, a solution of 0.24 g of formic acetic anhydride in 1 ml of THF was added dropwise over a period of 4 minutes with ice cooling and the mixture was then stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography (eluent: dichloromethane-methanol (20:1)) to give 0.14 g of 4-[N-(6-chloro-3-pyridylmethyl)-N-formylamino]-1,3-dimethyl-5-nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 30) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C1COCC1.CN(C=O)C.O>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)(=[O:33])=[O:32])=[C:3]2[CH:16]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
Alternatively, to a stirred solution of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (3.76 g, 11.93 mmol) in THF (60 mL) and DMF (30 mL) was added sodium tert-butoxide (2.87 g, 29.8 mmol) and 3-chlorobenzenesulfonyl chloride (3.36 mL, 23.86 mmol). The reaction mixture was stirred at RT under nitrogen for ca. 30 min and was then diluted with water (ca. 30 mL) and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate/DCM, to afford the title compound (4.06 g). Alternatively, to a stirred solution of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (7 g, 22.21 mmol) in THF (100 mL) and DMF (50 mL) was added sodium tert-butoxide (5.34 g, 55.5 mmol) and 3-chlorobenzenesulfonyl chloride (6.25 mL, 44.4 mmol). The reaction mixture was then stirred at RT under nitrogen for ca. 30 min. The reaction mixture was quenched with saturated NH4Cl solution (ca. 200 mL) and extracted with DCM (ca. 80 mL×5). The combined organics were dried and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM, to afford material (8.24 g). 200 mg of the material was re-purified with a gradient of 0-30% ethyl acetate in DCM, to afford the title compound (115 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:25]([O:29][C:30]([C:32]1[S:36][C:35](Cl)=[N:34][CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl>CN(C=O)C>[C:25]([O:29][C:30]([C:32]1[S:36][C:35]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:34][CH:33]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=O)OC(C)(C)C)s3)cc(C)c21
Yield: 95.2 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol), Cs2CO3 (7.82 g, 24 mmol) and t-butyl-2-chloro-1,3-thiazole-5-carboxylate (2.64 g, 12 mmol) in DMF (20 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled down and acidified to pH 3 with 6N HCl, extracted with ethyl acetate and washed with water and brine. The organic layer was dried by Na2SO4 and concentrated. The residue was purified by column chromatography (silica, Hexanes/EA=8:2, then DCM/MeOH=9:1) affording the title compound (3.3 g, 89%) as a light yellow solid. 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.46 (d, 1H), 7.18 (d, 1H), 5.68 (dd, 1H), 4.21 (q, 2H), 3.11 (dd, 1H), 2.44 (m, 1H), 2.39 (s, 3H), 1.56 (s, 9H), 1.24 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH:17][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:13]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1ncccc1N
Yield: 71.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (9.4 g, 59 mmol), glycine ethyl ester hydrochloride (10.8 g, 77 mmol), and K2CO3 (21.3 g, 154 mmol) in toluene (100 mL) was refluxed overnight. The mixture was then filtered, concentrated, and subjected to chromatography (20% EtOAc/hexanes). The resulting yellow solid was dissolved in EtOH (300 mL), treated with Raney Ni (2 g) and hydrogenated at 40 psi H2 overnight. The mixture was filtered, concentrated and chromatographed (2-5% MeOH/CH2Cl2) to provide 34A (1.25 g, 14%) and N-(3-amino-2-pyridinyl)glycine ethyl ester (8.2 g, 71%).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[OH:10].[CH3:22][C@H:23]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:33]3[CH2:35][O:34]3)[CH:30]=2)[C:25](=[O:36])[O:24]1.CCN(C(C)C)C(C)C>C(O)C>[OH:34][CH:33]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:36])[O:24][C@@H:23]([CH3:22])[CH2:32]2)[CH2:35][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[CH2:8][C@H:9]([OH:10])[C:11]1[C:12]([CH3:21])=[C:13]2[C:14](=[CH:19][CH:20]=1)[C:15](=[O:18])[O:16][CH2:17]2
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3CC(O)c2ccc3c(c2)C[C@H](C)OC3=O)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of 5-{(1R)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one [INTERMEDIATE 36](100 mg, 0.35 mmol) in ethanol (2 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 24) (71 mg, 0.35 mmol) and Hunig's base (61 uL, 0.35 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield the pure respective diastereomers as a faster eluting isomer D1 (LCMS: m/z 493.2 (M+H)+) and slower eluting diastereomer D2 (LCMS: m/z 493.2 (M+H)+).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[NH:25][C:23]2[C:24]3[C:15](=[N:16][NH:17][C:18](=[O:26])[C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH:14]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:14]2[C:15]3=[N:16][NH:17][C:18](=[O:26])[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]=43)[NH:25][CH:13]2[C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)=[CH:32][CH:31]=1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1nccn1Cc1ccccc1)C2c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ncc[nH]1)C2c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
A mixture of 8-(1-benzyl-1H-imidazol-2-yl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (200 mg, 0.46 mmol) and palladium hydroxide (200 mg) in methanol (4 mL) was purged with hydrogen and stirred at 60° C. for 18 hr. Then the mixture was filtered, evaporated to remove the solvent, and washed the solid with ethyl acetate to obtain the title compound (150 mg, yield 94%). LC-MS (ESI) m/z: 348 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.93 (d, J=8.4 Hz, 1H), 5.21 (d, J=8.4 Hz, 1H), 7.10 (t, J=8.4 Hz, 2H), 7.21-7.30 (m, 3H), 7.37 (s, 1H), 7.45-7.49 (m, 3H), 4.58 (d, J=10 Hz, 1H), 7.62-7.67 (m, 1H), 7.87 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH2:24]([N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([CH3:34])=[N:27]1)[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:31]([C:29]3[C:28]([CH3:34])=[N:27][N:26]([CH2:24][CH3:25])[CH:30]=3)=[O:32])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: CCn1cc(C(=O)O)c(C)n1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: CCn1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c(C)n1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=469.2.
Reaction SMILES: [F:1][C:2]1[C:3]([F:16])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[NH:6][C:5]2=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1.Cl.[CH3:18]O>>[CH3:18][O:14][C:13]([C:11]1[CH:12]=[C:2]([F:1])[C:3]([F:16])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[NH:6][C:5]=12)=[O:15]
Reactant: CO
Reactant: CC1COc2c(F)c(F)cc(C(=O)O)c2N1
Agent: Cl
Product: COC(=O)c1cc(F)c(F)c2c1NC(C)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.1 g (9.1 mmol) of 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid Example 31) in 50 mL of methanol is cooled to 0° C. and saturated with hydrogen chloride gas. The reaction is stirred at room temperature for 18 hours, recooled to 0° C. and resaturated with hydrogen chloride gas. After stirring an additional 24 hours at room temperature, the solvent is removed in vacuo and the residue is partitioned between dichloromethane/5% aqueous sodium bicarbonate (200:100 mL). The organic layer is separated, washed with 5% aqueous sodium bicarbonate, water, dried (MgSO4), filtered, and concentrated in vacuo affording 1.9 g of the title compound. 1H NMR (400 MHz, CDCl3): 7.27 (bs, 1H), 7.24 (m, 1M), 4.26 (m, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.62 (m, 1H), 1.22 (d, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[CH2:9]O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[CH2:9][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: ClCc1cc(Cl)cc(Cl)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 12.5 g of thionyl chloride in 20 ml of chloroform is added dropwise, at RT, to a solution of 14.5 g of 3,5-dichlorobenzyl alcohol in 150 ml of chloroform, followed by heating at 40-50° C. for 8 hours and stirring at RT overnight. The mixture is concentrated under vacuum to give 16 g of the expected product, which is used without further processing.