Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]5[CH2:21][CH2:20]5)=[O:18])[N:15]=4)[CH:12]=3)=[C:4]([F:24])[CH:3]=2)=[O:41])[C:34]1=[O:43]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(2-chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (168 mg, 0.597 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (160 μL, 0.919 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 18 hr. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98→100/0), silica gel column chromatography (30 g, ethyl acetate/hexane=0/100→100/0) and preparative HPLC (acetonitrile/water=40/60→50/50, containing 0.1% trifluoroacetic acid) to give the title compound (101 mg, 37%) as a white solid.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[Pd]>[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Reaction time: 12 h
Yield: 55.5 %

Procedure:
TRISPA (200 g, assay 95% 148.48×10-3 moles) and trityl chloride (5 g 179.52×10-4 moles) in dichloromethane (600 ml) was hydrogenated at ambient temperature and atmospheric pressure in the presence of palladium on carbon catalyst (10%, 2.5 g). Uptake of gas was complete in 12 hours and then Amberlite IRA-93(OH) resin (40 g) was added and the suspension was stirred at ambient for 12 hours. Removal of the solids and solvent gave a residue (209 g: assay, 4-PAS 35.1%, 6-PAS 16.7%, tritane 55.5%). Toluene (150 ml) was evaporated from the residue which was then heated with toluene (1000 ml) at 70° for 5 mins. before cooling the mixture to about 15°. The toluene supernatant was decanted from the thick syrup which was then re-extracted with toluene (500 ml) as before. The syrup was passed on to the migration step and the toluene extracts were concentrated to dryness, the residue was digested in hot methanol (500 ml) and the tritane was allowed to crystallise out overnight. Recovered tritane: 103.1 g, 86.7%, m.p. 93°-6°. In a repeat of this experiment the volume of the first toluene extract was reduced to 500 ml and the methanolic mother liquor from the first tritane recovery was used to digest the tritane from the second experiment. This afforded tritane 115.8 g, 97.5%, m.p. 93°-5°.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[N:18][CH:19]=1
Reactant: Oc1cccc(F)c1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(Oc2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 110.6 %

Procedure:
To an N,N-dimethylformamide (100 mL) solution of 3-fluorophenol (3.30 g, 29.4 mmol) was added sodium hydride (1.41 g, 29.4 mmol, 50% in oil), which was stirred for 10 minutes at 0° C. 2,5-Dibromopyridine (4.64 g, 19.6 mmol) was then added to this mixture at 0° C., followed by 7 hours and 45 minutes of stirring at 110° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (5.81 g, quant.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3cccc(Cl)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-chloro-phenylamine to give N1-(3-chloro-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 380(MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][C:10]1([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:27][CH2:28]OS(C(F)(F)F)(=O)=O)(=O)=O>O1CCCC1>[C:3]([O:7][C:8]([N:9]1[CH2:28][CH2:27][N:14]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:13](=[O:19])[C:10]21[CH2:12][CH2:11]2)=[O:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(OCCOS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CCCNC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCN1CCN(C(=O)OC(C)(C)C)C2(CC2)C1=O
Reaction time: 1 h
Yield: 47.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 206 mg, 5.15 mmol) was added at 0° C. to a solution of (1-but-3-enylcarbamoyl-cyclopropyl)-carbamic acid tert-butyl ester (400 mg, 1.57 mmol) in tetrahydrofuran (8 ml), then after 15 min a solution of 1,2-bis(((trifluoromethyl)sulfonyl)oxy)ethane (Chem. Ber. 1981, 114, 810; 616 mg, 1.89 mmol) in tetrahydrofuran (1 ml) was added dropwise. After 1 h, another portion of sodium hydride (60% dispersion in mineral oil, 103 mg, 2.58 mmol) and after 15 min, 1,2-bis(((trifluoromethyl)sulfonyl)oxy)ethane (616 mg, 1.78 mmol) was added, and die reaction mixture was allowed to reach room temperature over 1 h, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (208 mg, 47%). Yellow oil, MS (ISP)=281.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:8]([CH2:9]O)=[CH:7][N:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:4]=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:9][C:8]1[C:3]([C:2]([F:22])([F:21])[F:1])=[N:4][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ncc(CCl)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.4 %

Procedure:
A cooled (0° C.) solution of 0.081 g (0.25 mmol) of [4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol in 2.5 ml dichloromethane was treated with 0.04 ml (0.50 mmol) thionylchloride and stirred for 14 h at RT. The reaction was evaporated, dissolved in ether and twice in heptane and evaporated to give 0.077 g of pure 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH:11]([OH:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([NH:7][C:8](=[O:19])[CH2:9][CH2:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCC(O)c1ccccc1)NC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCC(=O)c1ccccc1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
A mixture of N-cyclohexyl-4-hydroxy-4-phenyl-butyramide (3.98 g, 15.2 mmol), prepared in the previous step, and pyridinium chlorochromate (4.94 g, 22.9 mmol) in 200 ml of methylene chloride was stirred at room temperature for 2.5 hours. The reaction was poured onto 400 g of silica gel (230-400 mesh) and the material eluted with methylene chloride-ethyl acetate. Isolation of the major component gave N-cyclohexyl-4-oxo-4-phenyl-butyramide (3.28 g, 83%) as a light green solid, mp 109-111° C.
Reaction SMILES: Cl[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@H:22]1([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]1>N1C=CC=CC=1.C(Cl)Cl>[C:16]1([C:2]2([O:28][CH2:27][C@H:26]3[O:29][C@@H:22]([N:30]4[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]4=[O:32])[CH2:23][C@@H:24]3[OH:25])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[O:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4Oc4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
585 mg (2 mmol) of 9-chloro-9-phenylxanthene were added to a solution of 484 mg (2 mmol) of thymidine in 20 ml of pyridine, and the resulting mixture was stirred at room temperature for 1 hour whilst shading it from light. The reaction mixture was then diluted with 200 ml of methylene chloride, and the diluted mixture was washed twice, each time with 200 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 35 g of silica gel (70-230 mesh), using methylene chloride containing from 0 to 2.5% by volume of methanol as the eluent, to give 647.8 mg (yield 65%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]([OH:7])=[O:6])[OH:4].[CH:8](OC(=O)C)=[O:9].[CH:14](O)=[O:15]>>[CH:8]([NH:1][CH2:2][C@@H:3]([C:5]([O:7][CH:14]=[O:15])=[O:6])[OH:4])=[O:9]
Reactant: NC[C@H](O)C(=O)O
Reactant: O=CO
Reactant: CC(=O)OC=O
Product: O=CNC[C@H](O)C(=O)OC=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a one liter round bottom flask containing 50 g of (S)-isoserine (0.476 mole) and 62.5 ml of formic acid was added in 30 min. a freshly prepared acetic formic anhydride solution * (5 eq.) at 0°-5° C. After examining the completion of reaction by H1 -NMR (approx. 2 hrs), the mixture was concentrated under vacuum at 40° C. to half of the original volume. 250 ml of isopropanol was added slowly with simultaneous cooling to effect crystallization. The slurry was stirred at 0° C. for one hour. The product, N,O-diformyl-(S)-isoserine, was filtered and washed with isopropanol. This afforded 64 g of N,O-diformyl-(S)-isoserine; 84% yield; m.p. 139.5°-141.5°; [a]D20 : -38° (1%, MeOH).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1N=NC(C)=CC=1)[CH2:4][CH2:3]2.Br[C:51]1[N:56]=[CH:55][CH:54]=[CH:53][N:52]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:51]1[N:56]=[CH:55][CH:54]=[CH:53][N:52]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Brc1ncccn1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ncccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 8.2 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromopyrimidine (0.016 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (8.0 mg, 8.2% yield) bis TFA salt. LCMS: m/e 651.5 (M+H)+, 2.27 min (method 11).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:35].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][C:21]([C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=3)=[O:35])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NCC(=O)c3ccc(OCC(=O)O)c(OCC(=O)O)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.8 %

Procedure:
To the solution of the compound prepared in Example 17 (a) (2 g) in THF (50 ml) was added an aqueous solution (50 ml) of sodium hydroxide (240 mg), and the mixture was stirred at room temperature for 20 minutes. After THF was evaporated under reduced pressure, the concentrated reaction mixture was acidified to pH 3.5 with 5N hydrochloric acid. Crystals deposited were collected by filtration and dried to give 1.21 g of [[4-[[[(5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]acetyl]-o-phenylene]dioxy]diacetic acid.
Reaction SMILES: [OH:1]O.[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=S)[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O>[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=[O:1])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OO
Reactant: Cn1c(=S)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.2 1 of 30% hydrogen peroxide were added dropwise at 0° C. over a period of 51/2 h, with stirring, to a suspension of 210 g of 6-benzyl-3-methyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[4,3-d]pyrimidin-4-one from b) in a solution of 78 g of NaOH in 4 1 of water. After subsequent stirring for 1/2 hour at 0° C., the pH of 9.7 was adjusted to 7.4 with conc. hydrochloric acid and the precipitate was filtered off, washed with water and dried. The above preparation was repeated and the precipitates were combined (396 g). These were purified by suspension in I 1 of water and dissolution with 33% sodium hydroxide solution (pH 13.5). Activated charcoal was added, with stirring, the mixture was filtered and the filtrate was adjusted to pH 10. The precipitate formed was filtered off with suction, washed with water and dried under reduced pressure to give 192 g of 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione, which was debenzylated by hydrogenolysis in d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C:14]1[S:15][C:16]([NH:24][C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[O:26])=[C:17]([C:19]([O:21]CC)=O)[N:18]=1)=[CH:8]2.[NH3:32].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C:14]1[S:15][C:16]([NH:24][C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[O:26])=[C:17]([C:19]([NH2:32])=[O:21])[N:18]=1)=[CH:8]2
Reactant: N
Reactant: CCOC(=O)c1nc(Nc2ccc3c(OC)cccc3c2)sc1NC(=O)c1ccsc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2cc(Nc3nc(C(N)=O)c(NC(=O)c4ccsc4)s3)ccc12
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of ethyl 2-[(5-methoxynaphthalen-2-yl)amino]-5-(thiophene-3-carboxamido)-thiazole-4-carboxylate (0.105 g, 0.23 mmol) in THF (5 mL) was added 7N NH3—MeOH (5 mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were collected by filtration and washed with MeOH to give 90 mg (92% yield) of the titled compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:23][N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][CH:27]=[N:28][C:29]=2[NH2:33])[CH2:11][CH2:12][O:13][CH2:14][P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])(C(C)(C)C)(C)C>C(O)(=O)C>[CH2:18]([O:17][P:15]([CH2:14][O:13][CH2:12][CH2:11][CH:10]([O:23][N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][CH:27]=[N:28][C:29]=2[NH2:33])[CH2:9][OH:8])([O:20][CH2:21][CH3:22])=[O:16])[CH3:19]
Reactant: CCOP(=O)(COCCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N)ncnc21)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(COCCC(CO)On1cnc2c(N)ncnc21)OCC
Yield: 78.5 %

Procedure:
A solution of 9-[1-(t-butyldimethylsilyloxy)-4-(diethoxyphosphorylmethoxy)but-2-oxy]adenine (360 mg, 0.72 mmol) in 80% acetic acid (15 ml) was stirred at 85° C. for 3 h. The solvents were evaporated under vacuum and co-evaporated with toluene. The residue was chromatographed on silica, eluting with chloroform-methanol 10:1, affording 9-[4-(diethoxyphosphorylmethoxy)-1-hydroxybut-2-oxy]adenine (220 mg, 79%) as a white solid, m.p. 86°-88° C. νmax (KBr) 3350, 3140, 1660, 1600 and 1540 cm-1 ; δH (CDCl3) 1.36 (6H, t, J6.8 Hz, 2×CH3CH2), 2.03 (1H, m, HOCH2CHCH2), 2.23 (1H, m, HOCH2CHCH2), 3.66 (2H, m, CH2OH)), 3.86 (4H, m, CH2OCH2P), 4.21 (4 H, m, 2×CH3CH2), 4.48 (1H, m, CHON), 5.32 (1H, br.s, D2O exchangeable, OH), 6.02 (2H, br.s, D2O exchangeable NH2), 8.24 (1H, s, H-2/H-8), 8.34 (1H, s, H-2/H-8). Found: C, 43.33; H, 6.27; N, 17.81%; M+ 389.1469. C14H24N5O6P requires C, 43.19; H, 6.21; N, 17.99%; M+ 389.1464.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:5]=1.IC.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:23])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCCN(C)c1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(C)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1

Procedure:
Dissolve 2-methanesulfonylamino-6-(methylpropylamino)-isonicotinic acid methyl ester (87 mg, 2.89 mmol) and iodomethane (0.27 mL, 4.33 mmoles) in DMF (10 mL). Add potassium carbonate (639 mg, 4.62 mmol) and tetrabutylammonium bromide (93 mg, 0.98 mmol) and stir at room temperature 1 h. Dilute with ethyl acetate (80 mL), wash with 10% aqueous potassium carbonate (2×15 mL), 0.1 N citric acid (2×15 mL), 1 N lithium chloride (2×15 mL) and saturated aqueous sodium chloride (15 mL).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>>[OH:29][C@@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#C[C@](C)(O)c1cc(C)on1
Product: Cc1cc([C@@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1
Yield: 9 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2S)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (34 mg, 9%).
Reaction SMILES: C([S:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[C@H:23]([CH2:39][O:40][NH:41][C:42](=[O:44])[CH3:43])[CH2:22]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>CO.O.[N+]([O-])([O-])=O.[Ag+]>[SH:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[C@H:23]([CH2:39][O:40][NH:41][C:42](=[O:44])[CH3:43])[CH2:22]1
Reactant: CC(=O)NOC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NOC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.42 h
Yield: 72.5 %

Procedure:
To a solution of (2S,4S)-4-tritylthio-2-acetylaminooxymethyl-l-p-nitrobenzyloxycarbonylpyrrolidine (7a:452 mg) in methanol (9 ml) under ice cooling are dropwise added pyridine (149 μl) and then a solution of silver nitrate (289 mg) in a mixture of water (1.5 ml) and methanol (15 ml), and the mixture is stirred for 25 minutes. Separating silver salt is collected by filtration, washed with methanol, ether, and petroleum ether, and dried. To a suspension of this crude silver salt in a mixture of dichloromethane (3.5 ml) and methanol (3.5 ml) is introduced hydrogen sulfide gas for 5 minutes. The resulting silver sulfide is filtered off and washed with a mixture of methanol and dichloromethane. The filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-mercapto-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (8a:198 mg) as a pale yellow foam. Yield: 73%.