Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([CH:21]([CH2:23][CH3:24])[OH:22])#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][CH:21]([OH:22])[CH2:23][CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 5 hours with 1.09 g (13 mmol) of ethynyl-ethyl carbinol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-1-pentynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 178°.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:41]1[C:42]2[C:37](=[CH:36][CH:35]=[CH:34][C:33]=2[S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:22][CH2:23][CH2:24][CH2:25][N:26]=3)=[CH:15][CH:16]=2)[C:6]([OH:43])=[O:5])(=[O:31])=[O:32])[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2cccnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3cccnc23)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
72 mg (0.11 mmol) of (2S)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 54 mg. MS (ES+): m/e=553 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Br)c(O)c1C(=O)O
Temperature: 100 °C
Yield: 121.9 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett, 2007, 17, 2817, 5.41 g) and lithium hydroxide monohydrate (9.23 g) was suspended in dioxane (100 mL) and water (100 mL) and heated at 80° C. overnight. The temperature was then increased to 100° C. for 4 hours. Further lithium hydroxide monohydrate (4.61 g) was added and the reaction mixture was heated at 100° C. for a further 1 hour. After cooling, the mixture was concentrated in vacuo and the residue was acidified to pH3 with formic acid and extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered and the filtrate was concentrated in vacuo to give 6-amino-3-bromo-2-hydroxybenzoic acid (6.22 g) as a black/grey solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O.O>[Br:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To 3-(trifluoromethyl)benzaldehyde (5 gm, 28.72 mmol) in sulfuric acid (13.5 ml) at 60° C., N-bromosuccinimide (6.13 g, 34.45 mmol) was added in 3 portions. After 2 h, the reaction mixture was cooled, diluted with cold water and filtered. Filter cake was washed with hexane. Volatiles were removed under reduced pressure and the crude residue of 3-bromo-5-(trifluoromethyl)benzaldehyde was carried to the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O-:23])=[O:22])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[N:4]=1.[K+].[CH2:25]([O:27][C:28]([O:30][CH:31](Cl)[CH3:32])=[O:29])[CH3:26].O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23][CH:25]([O:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26])=[O:22])=[N:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[N:6]=1
Reactant: CCOC(=O)OC(C)Cl
Reactant: COc1cc(OC)nc(Oc2ccc(N(C)C)nc2C(=O)[O-])n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)OC(C)OC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.0 g (5.6 mmol) of potassium 3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-dimethylaminopicolinate and 0.8 g (5.7 mmol) of 1-(ethoxycarbonyloxy) ethylchloride were suspended in 5 ml of dimethylformamide, and were stirred at room temperature for 6 hours. The reaction mixture was poured into water, and was extracted with ethyl acetate twice. The organic layer was then washed with water and dried, and the solvent was distilled off to obtain a viscous product which was then column-purified to obtain an aimed compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]2[CH2:11][CH2:10]2)=[C:5]2[C:12]([O:18][CH3:19])=[C:13](Cl)[C:14]([F:16])=[CH:15][N:4]2[C:3]1=[O:20].[CH3:21][NH:22][C@H:23]([C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:24]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]2[CH2:11][CH2:10]2)=[C:5]2[C:12]([O:18][CH3:19])=[C:13]([N:27]3[CH2:28][CH2:29][C@@H:25]([C@@H:23]([NH:22][CH3:21])[CH3:24])[CH2:26]3)[C:14]([F:16])=[CH:15][N:4]2[C:3]1=[O:20]
Reactant: CN[C@@H](C)[C@@H]1CCNC1
Reactant: COc1c(Cl)c(F)cn2c(=O)n(N)c(=O)c(C3CC3)c12
Product: CN[C@@H](C)[C@@H]1CCN(c2c(F)cn3c(=O)n(N)c(=O)c(C4CC4)c3c2OC)C1
Yield: 34.1 %

Procedure:
The title compound (0.04 g) was prepared from 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxypyrido[1,2-c]pyrimidine-1,3-dione (0.09 g, 0.30 mmol [Example 12]), and methyl-((S)—(R)-1-pyrrolidin-3-ylethyl)amine (0.11 g, 0.90 mmol) using the general procedure of Example 4. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H), 5.42 (s, 2H), 3.89-3.58 (m, 5H), 3.22 (s, 3H), 2.67-2.58 (m, 1H), 2.46 (s, 3H), 2.22-2.02 (m, 2H), 1.80-1.61 (m, 2H), 1.21 (d, 3H), 1.10-1.00 (m, 1H), 0.84-0.76 (m, 1H), 0.52-0.44 (m, 1H), 0.40-0.32 (m, 1H). MSCI: m/z=392 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]12[CH2:18][CH:17]1[CH2:16][CH2:15][S:14][C:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:12]2.[H][H]>CO.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]23[CH2:18][CH:17]2[CH2:16][CH2:15][S:14][C:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[N:12]3)[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc([N+](=O)[O-])ccc3F)CC2CCS1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(N)ccc3F)CC2CCS1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
tert-Butyl (1SR,7SR)-1-(2-fluoro-5-nitrophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A7a) (68 mg; 0.18 mmol) was dissolved in 20 ml methanol under argon and 10% palladium on carbon (Pd/C) (28 mg, 15 mol %) was added. The atmosphere of the reaction system was replaced with hydrogen, followed by stiffing at 23° C. for 3 hours. More 10% Pd/C (67 mg) was added and stiffing was continued under hydrogen atmosphere for 20 hours. The reaction mixture was filtered and evaporated to give the tert-butyl (1SR,7SR)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (53 mg; 85%) as a grey foam which was used in the next step without further purification. MS (ISP): m/z=352.3 [(M+H)+].
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCOCC2)c1C
Temperature: 25 °C
Yield: 32.7 %

Procedure:
MeOH (70 mL) was added to a flask containing 4-{1-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethylidene}-pent-2-enedioic acid dimethyl ester (2.39 g, 8.05 mmol). NaOMe solution (1.8 mL, 8.05 mmol, 4.375 M in MeOH) and N-bromosuccinimide (1.72 g, 9.66 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-50% EtOAc/hexanes) to give 906 mg of the title compound. MS: (+) m/z 366.16, 368.17 (M+Na, 79/81Br).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[C:17](O)(=O)C.C(N)=N>CCO.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=3)[CH:17]=[N:16][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1Nc1ccnc(Cl)c1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1cc(-n2cnc3ccc(Br)nc32)ccn1
Temperature: 25 °C

Procedure:
6-Bromo-N*2*-(2-chloro-pyridin-4-yl)-pyridine-2,3-diamine (step 2)(1 eq, 1.22 mmol, 634 mg) is dissolved in EtOH (15 mL) and treated formamidine acetate (5 eq, 6.105 mmol, 634 mg). The reaction is heated at reflux for 3 hours allowed to cool to room temperature. The mixture is diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×10 ml). The organic portions are combined, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica eluting at 5-10% EtOAc in hexane affords the title compound; [M+H]+=310.
Reaction SMILES: CO.[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:7][C:6](=[O:17])[C:5]=1[S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>CN(C)C=O>[CH2:35]([O:36][C:37](=[O:39])[CH2:38][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:7][C:6](=[O:17])[C:5]([S:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:4]([OH:3])[CH:9]=2)=[CH:15][CH:14]=1)[CH3:34]
Reactant: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Reaction time: 3 h

Procedure:
To a methanol solution (3 ml) of the 4-hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium carbonate (0.955 g, 2.94 mmol). The reaction was stirred for 3 hrs. and is then concentrated in vacuo. Next, dimethylformamide (15 mL) is added and the residue is reconcentrated in vacuo to dryness. The solid is then diluted with dimethylformamide (3 mL) and bromoethylacetate (0.491 mL, 2.94 mmol) is added. The slurry is then stirred for 3 hrs. The reaction is quenched by dilution with ethyl acetate (100 mL). The organic layer is washed in succession with; 1 N HCl, water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2 -230 to 400 mesh) using a gradient of 15% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to 30% ethyl acetate/30% hexanes/40% methylene chloride.: m.p. 169-171° C.; 1H NMR (400 MHz, DMSO-d6) δ1.20 (t, 3 H), 2.75 (t, 2 H), 2.96 (t, 2 H), 4.16 (q, 2 H), 4.87 (s, 2 H), 6.69 (s, 1 H), 7.06 (d, 2 H), 7.19 (m, 5 H), 7.73 (d, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:23])=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.O[C@@H:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C@H:27]([C:41]([O:43][CH3:44])=[O:42])[CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:44][O:43][C:41]([CH:27]1[CH2:26][CH:25]([O:23][C:7]2[C:6]3[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)[CH:8]=2)[CH2:30][CH2:29][N:28]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:42]
Reactant: COC(=O)[C@@H]1C[C@H](O)CCN1C(=O)OCc1ccccc1
Reactant: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirred solution of compounds 203b (1 g, 1 eq.) and 12 (1.39 g, 1.2 eq.), and triphenylphosphine (1.34 g, 1.5 eq.) in anhydrous THF (40 mL) at 0° C. was added DIAD (1.02 mL, 1.5 eq.). The reaction mixture was stirred at room temperature for 2 hrs. THF was then removed under reduced pressure and the residue was purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 13 as a white solid in 52% yield. MS (ESI, EI+) m/z=616 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]2)=[O:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]2)=[O:12])=[O:8])=[CH:25][CH:26]=1)(=[S:27])[NH2:2]
Reactant: COC(=O)COC1CCN(C(=O)CNC(=O)c2ccc(C#N)cc2)CC1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)COC1CCN(C(=O)CNC(=O)c2ccc(C(N)=S)cc2)CC1
Reaction time: 24 h

Procedure:
A solution of 1.5 g of methyl [[1-[N-(p-cyanbenzoyl)glycyl]-4-piperidinyl]oxy]acetate in 215 ml of pyridine/triethylamine 40:3 is saturated with hydrogen sulphide and left at room temperature for 24 hours. After removing the solvent, the residue is taken up in ethyl acetate and washed with saturated sodium chloride solution. The organic extracts are dried and concentrated. After chromatography of the residue on silica gel with ethyl acetate followed by ethyl acetate/methanol, there are isolated 1.34 g of methyl [[1-[N-[p-(thiocarbamoyl)benzoyl]-glycyl]-4-piperidinyl]oxy]acetate, MS (FAB): 394 (M+H)+.
Reaction SMILES: N1C=CC=NC=1.[CH2:7]([O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[NH:21][C:20]([O:31][CH3:32])=[N:19][C:18]=1[CH2:33][CH3:34])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:7]([O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[N:21]([C:36]([O:38][CH3:39])=[O:37])[C:20]([O:31][CH3:32])=[N:19][C:18]=1[CH2:33][CH3:34])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)Cl
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: c1cncnc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Yield: 67.5 %

Procedure:
(−)-5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-methoxycarbonyl]pyrimidine. To a well stirred solution of (−)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAc as the eluting system to obtain 0.45 g (78% yield) of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
To a solution of the compound from Step F (457 mg, 1.63 mmol) in anhydrous pyridine (3.5 mL) was added tert-butyldimethylsilyl chloride (370 mg, 2.45 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted with ethyl acetate (40 mL) which was washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to an oil that was subjected to chromatography on silica gel eluting with 10% MeOH in CH2C2. The appropriate fractions were collected, evaporated, and dried under high vacuum to furnish the title compound as a colorless foam (516 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:14]2[CH:15]=[CH:16][C:17]([C:2]3[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][C:13]=2[F:12])=[CH:29][N:30]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: OCCOc1ncccc1Br
Product: Nc1ncc(-c2ccc(-c3cccnc3OCCO)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-((3-bromopyridin-2-yl)oxy)ethanol and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C17H15FN4O2, 326.12; m/z found, 326.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.3, 2H), 8.15 (dd, J=4.9, 1.8, 1H), 7.84 (dd, J=7.4, 1.8, 1H), 7.65-7.52 (m, 3H), 7.08 (dd, J=7.4, 5.0, 1H), 6.87 (s, 2H), 4.80 (s, 1H), 4.40-4.32 (m, 2H), 3.70 (t, J=5.0, 2H).
Reaction SMILES: [C@@H:1]1([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[O:12][C@H:6]([CH:7]([C:9]([OH:11])=[O:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:23](O)[CH3:24]>>[CH2:23]([O:10][C:9]([CH:7]([OH:8])[C@H:6]1[O:12][C@@H:1]([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[O:11])[CH3:24]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)O)[C@@H](O)[C@H]1O
Reactant: CCO
Product: CCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 78 %

Procedure:
In an analogous manner, by the reaction of free adenosine-5'-carboxylic acid with ethanol, there is obtained adenosine-5'-carboxylic acid ethyl ester in a yield of 78% of theory (m.p. 204°-205° C.) and by the reaction of free adenosine-5'-carboxylic acid with n-butanol, there is obtained adenosine-5'-carboxylic acid n-butyl ester in a yield of 54% of theory (m.p. 167° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[S:34]([CH3:33])(=[O:36])=[O:35])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.05 h

Procedure:
N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 22) (0.50 g) was dissolved in DCM (10 m) and cooled to 0-5° C. in an ice bath. Triethylamine (0.55 ml) was added followed by dropwise addition of methylsulphonyl chloride (0.11 ml) and the mixture was allowed to warm to ambient temperature over 2 hours. The solution was concentrated then the solid was dissolved in DCM (5 ml) and water (5 ml) was added. The solution was loaded onto a Varian Chem Elut column and after 3 minutes was washed through with DCM (20 ml). The DCM layer was then concentrated and the solid washed with ether and filtered to give the title compound (0.58 g) as a solid. NMR (CDCl3): 1.7 (s, 6H), 2.2 (s, 3H), 3.4 (s, 6H), 7.2 (s, 4H), 7.4 (d, 1H), 7.5 (d, 1H), 8.4 (d, 1H), 8.5 (d, 1H); MS (ESP−): 533; EA: found: C, 44.4; H, 4.5; N, 5.1%; C20H23ClN2O7S3 requires C, 44.9; H, 4.3; N, 5.2%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16]C)=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[NH2:18].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:12]1[N:11]=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[N:9]=[C:8]2[C:13]=1[NH:14][C:15](=[O:16])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCCCl
Reactant: C1CCNCC1
Product: CC(C)Oc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(5-chloropentyl)-2-[(1-methylethyl)oxy]-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccccc2)nc2cccnc21
Reaction time: 0.12 h

Procedure:
N-[3-(benzoylamino)-2-pyridinyl]glycine ethyl ester, 10.32 g (0.034 mole) in two divided portions was heated in glass in a Wood's metal bath at 190° C. under a flow of nitrogen, one portion for 15 min and the other for 7 min. The green glassy residues were dissolved in methylene chloride, combined, and stirred together with 90 g of Florisil® for 1 hr. The mixture was filtered, and the filtrate evaporated to an oil, which crystallized. The solid was recrystallized from hexanes to give a crystalline solid, which was dried under high vacuum at room temperature overnight to give 3.67 g (38%) of cyrstals, m.p. 93°-95° C.