Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13](=[O:15])[CH3:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale brown solid, m.p. 148° C. and MS: m/e=348 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-acetyl-benzenesulfonyl chloride.
Reaction SMILES: [H-].[Na+].C[C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:14][O:15][CH2:16]Cl.O.[CH3:19]N(C=O)C>>[CH3:14][O:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][C:9]([CH3:19])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CN(C)C=O
Reactant: COCCl
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 4.78 g, 0.12 -methyl-2-nitrophenol (known compound) (15.6 g, 0.102 mol) in DMF (50 ml) under nitrogen atmosphere under ice-cooling over a period of 30 minutes. The mixture was stirred at 0° C. for 30 minutes, and thereto was added dropwise chloromethyl methyl ether (9.3 ml, 0.122 mol). The reacion mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The concentrate was purified by column chromatography to give the ether compound (1). Yield 20.1 g (100%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:19](=[O:44])[N:18]([CH3:45])[C:17]=2[N:16]=1>CN(C=O)C.O>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:22]2[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:38])[CH3:39])[C:19](=[O:44])[N:18]([CH3:45])[C:17]=2[N:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
Step 1 Diethyl malonate (0.35 mL, 2.31 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% in oil, 0.74 g, 1.85 mmol) was added portion wise. The mixture was stirred for 15 min and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.92 mmol, intermediate 77) was added. The reaction was heated at 100° C. for 15 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column eluted with 20% ethyl acetate/hexanes to give diethyl-2-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)malonate (0.23 g, 40% yield) as a clear oil. LCMS retention time=5.015 min and 95% purity, LCMS MH+ 621. 1H NMR (DMSO-d6) δ 7.27 (dd, 4H, J=8 Hz and 72 Hz), 5.62 (d, 2H, J=12 Hz), 5.54 (s, 2H), 5.61 (s, 1H), 3.90-4.03 (m, 6H), 3.62 (t, 2H, J=8 Hz), 3.37 (s, 3H), 1.70-1.78 (m, 2H), 1.08 (t, 6H, J=8 Hz), 0.80 (s, 9H).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[C:50]1(O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl.O1CCOCC1.N1C=CC=CC=1>[O:1]([C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: Oc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCn1c(=O)c2[nH]c(C34CCC(Oc5ccccc5)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 0 °C
Yield: 15.1 %

Procedure:
To a solution of 60 mg of 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (0.167 mmol) in CH2Cl2 (2 ml) was added 27 μL of pyridine and the reaction mixture cooled to 0° C. To this was added 40 μL of triflic anhydride (0.24 mmol) in CH2Cl2 (1 ml). Maintained at 10° C. overnight. The reaction mixture was diluted with CH2Cl2 (5 ml) and washed with cold 1N HCl, sat'd NaHCO3 and brine. Dried over sodium sulfate and concentrated in vacuo to afford a yellow oil. The crude triflate was dissolved in 1,4-dioxane (3 ml) and 100 mg of phenol (1.08 mmol was added followed by heating at 80° C. overnight. The reaction mixture was concentrated down and the residue taken up in ethyl acetate (10 ml) washed with 1N KOH (5 ml), sat'd NaHCO3 (5 ml), 1N HCl (5 ml) and brine. The organic layer was dried over NaSO4 and concentrated in vacuo to a colorless oil which was purified by column chromatography (SiO2, 1:1 hexanes/EtOAc) to afford 11 mg of title compound as a white solid (MH+=437.29). The following compounds were prepared in an analogous manner after saponification of the methyl ester.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH2:31]Br)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:18]([C@H:23]1[CH2:24][CH2:25][C@H:26](/[CH:29]=[CH:30]/[CH2:31][O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:27][CH2:28]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@H]1CC[C@H](O)CC1
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](/C=C/CO[C@H]2CC[C@H](CCC)CC2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 g of sodium hydride and 25 ml of tetrahydrofuran was treated with 0.5 g of trans-4-propylcyclohexanol while gassing with nitrogen, stirred for a further 2 hours, then treated with 1.0 g of (E)-3-(trans-4-pentylcyclohexyl)allyl bromide and subsequently heated to 70° C. overnight. Thereafter, the reaction mixture was treated with 500 ml of water and extracted four times with 50 ml of hexane each time. The combined organic phases were washed twice with 500 ml of water each time, dried over magnesium sulphate, filtered and then concentrated. The residue was purified by chromatography on silica gel with toluene. The trans-4-propylcyclohexyl (E)-3-(trans-4-pentylcyclohexyl)allyl ether obtained was recrystallized from acetone at -25° C.. This gave 1.2 g of pure product with m.p. (C-I) 26° C..
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:22][Sn:23](Cl)([CH3:25])[CH3:24].[Cl-].[NH4+]>C1COCC1>[C:1]([C:5]1[O:6][C:7]([Sn:23]([CH3:25])([CH3:24])[CH3:22])=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2)co1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2ccc(F)cc2)c([Sn](C)(C)C)o1
Reaction time: 0.75 h

Procedure:
Dissolve 2-tert-butyl-4-(4-fluorophenyl)oxazole (0.61 g, 2.77 mmol) in THF (15 ml) and add tert-butyl lithium (3.3 ml, 1.7 M) at −78° C. Stir the mixture for 45 min. Add trimethylstannanyl chloride (0.58 g, 2.90 mmol) and allow the temperature to reach RT. Stir for 2 h and add an ammonium chloride solution (200 μL, pH=8 with ammonia) and concentrate.
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].C(OC=O)C.[CH3:12][CH:13]([C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14]>C1COCC1.C(OCC)C>[OH:5][CH:2]=[C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:15](=[O:21])[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)CCC(=O)C(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC=O
Solvent: CCOCC
Product: CC(C)CC(=CO)C(=O)C(C)C
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 31.1 %

Procedure:
To a solution of KOtBu (15.6 g, 139 mmol) in THF (200 mL) is added ethylformate (27.4 g, 370 mmol). During the addition, the mixture is cooled with a water bath to 10° C. Strong gas evolution occurs. The mixture is stirred until the gas evolution ceases (5 min) and is then cooled to −5° C. To this mixture a solution of 2,6-dimethyl-heptan-3-one (20 g, 141 mmol) and ethylformate (13.7 g, 185 mmol) in THF (20 mL) is added slowly during 30 min. The reaction mixture is stirred for 2 h and allowed to slowly warm to rt. The reaction is diluted with diethyl ether (200 mL) and washed with 1 N aq. HCl (2×100 mL). The organic extract is dried (Na2SO4), filtered and evaporated to give 1-hydroxy-2-isobutyl-4-methyl-pent-1-en-3-one (7.35 g) as a brown resin; LC-MS: tR=0.91 min, [M+1]=171.21.
Reaction SMILES: C([N:20]1[CH2:25][CH2:24][CH:23]2[S:26][C:27](=[O:29])[CH:28]=[C:22]2[CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[S:26]1[CH:23]2[C:22]([CH2:21][NH:20][CH2:25][CH2:24]2)=[CH:28][C:27]1=[O:29]
Reactant: O=C1C=C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C2CNCCC2S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 204.9 %

Procedure:
A mixture of 2.85 g of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno [3,2-c]pyridin-2-one (see Japanese Provisional Patent Publication No. 246148/1986), 1.36 g of p-toluenesulfonic acid monohydrate and 50 ml of tetrahydrofuran was stirred at 50° C. for 2 hours. The precipitated solid was filtered, washed with 10 ml of tetrahydrofuran and then dried to obtain 2.28 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2one.p-toluenesulfonate (yield based on 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one: 93%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Cl[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=O>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=5[N:1]=4)=[CH:5][C:6]=3[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Reactant: O=C1CCCCC1Cl
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 144) and 2-chlorocyclohexanone (239 mg 1.8 mmol) in EtOH (anhydrous, 8 mL) was stirred at 70° C. for 48 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:2) gave 45 mg (43%) of the title compound as a clear oil. LC-MS: RT=4.69 min; (M+H)+ 534.3.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1Oc1ccccc1
Yield: 78.3 %

Procedure:
Prepared according to the procedure of Example 1 using 3-phenoxy-4-methoxybenzoic acid (0.3 g, 1.2 mmol), oxalyl chloride (0.19 g, 1.5 mmol), and aniline (0.22 g, 2.4 mmol) to afford the product (0.3 g); m.p. 200-201° C. after recrystallization from ethanol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:16]1[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]3[CH:10]=[N:9]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: FC(F)(F)c1cccnc1-n1ncc2c(I)ccnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ncccc1C(F)(F)F

Procedure:
To a 48 mL pressure bottle containing Intermediate 73A (495 mg, 1.269 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (569 mg, 2.241 mmol), potassium acetate (571 mg, 5.82 mmol) and anhydrous DMSO (10 mL). The reaction mixture was purged with argon, treated with PdCl2(dppf).CH2Cl2 (56 mg, 0.077 mmol), and heated to 85° C. for 2 h 15 min to give conversion to the desired product. LC/MS (Condition B): ret. T=2.5 min, (M+H)+ 309.07.
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2].[CH3:20]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CS(C)=O>[CH2:1]([C:3]1([CH3:20])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCC1c2ncccc2C(=O)N(C)c2cccnc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CS(C)=O
Product: CCC1(C)c2ncccc2C(=O)N(C)c2cccnc21
Reaction time: 0.05 h

Procedure:
To a solution of 5,11-dihydro-11-ethyl-5-methyldipyrido[3,2-b:2',3'-e]azepine-6-one (0.10 g) in DMSO (1 mL) stirred under nitrogen was added potassium tert-butoxide (1M in tetrahydrofuran, 0.5 mL). After 3 minutes, methyl iodide (0.1 mL) was added, and the mixture was stirred for 10 minutes. Ethyl acetate was added, and the mixture was washed with water, dried, filtered, and evaporated. The residue was fractionated by preparative layer chromatography (developer chloroform/ethanol) to give 5,11-dihydro-11-ethyl-11-methyl-5-methyldipyrido[3,2-b:2',3 '-e]azepine-6-one (0.006 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4]1.Cl.[CH2:33](Cl)[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.CN(C=[O:52])C>>[CH3:27][N:26]1[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:29])[N:18]=[C:17]1[S:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][O:1][C:33](=[O:52])[C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:8][CH2:7]2)=[O:10])=[CH:31][CH:30]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(CO)CC4)cc3)n(C)c(=O)c12
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(COC(=O)c5ccncc5)CC4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In DMF (15 ml) was dissolved 2-[4-(4-hydroxymethylpiperidylcarbonyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (415 mg), and following addition of isonicotinyl chloride hydrochloride (270 mg), triethylamine (0.40 ml) was added over 5 minutes. The mixture was stirred at room temperature for 3 hours, after which it was concentrated. The residue was washed with water, saturated aqueous NaHCO3 solution, and saturated aqueous NaCl solution in that order, dried, and concentrated. The residue was recrystallized from hexane/ethyl acetate to provide the title compound as colorless solid (241 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8].I.N1C=C[CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:4])[O:10][C@@H:9]2[C@H:11]3[O:12][C:18]([CH3:19])([CH3:17])[O:14][C@H:13]3[O:8][C@@H:7]2[CH2:6][O:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(C)=O
Reactant: c1ccncc1
Agent: I
Product: CC1(C)OC[C@H]2O[C@@H]3OC(C)(C)O[C@@H]3[C@H]2O1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.6 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-xylose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 5 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene and the benzene solution was washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure and the residue was further distilled under reduced pressure, whereby 12.8 g (83.6%) of 1,2:3,5-di-O-isopropylidene-α-D-xylofuranose was obtained as a fraction boiling at 94°-97° C./3 mmHg.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[N:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]2=[C:23]([C:30](O)=[O:31])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:30]([C:23]1[CH:22]=[N:21][N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=12)=[O:31]
Reactant: O=C(O)c1cnn2cccnc12
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
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: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cccnc12
Yield: 85.1 %

Procedure:
To a solution of (3R)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 10) (80.0 mg, 0.259 mmol) in DMF (4 ml) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42.3 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol), HBTU (98 mg, 0.259 mmol) and DIPEA (0.136 ml, 0.778 mmol) and the reaction mixture was stirred at rt for 1.5 hours. The DMF was evaporated in vacuo then DCM (5 ml) was added and the whole washed with saturated aq. NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP to give the title compound (100 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5](Cl)([Cl:8])(=[O:7])=[O:6].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.Cl>C(OCC)(=O)C.C(#N)C>[ClH:8].[N:10]1([S:5]([N:1]=[N+:2]=[N-:3])(=[O:7])=[O:6])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A modification of a published procedure was used (19). A suspension of 6.53 g NaN3 (25, 100 mmol, Aldrich, >99.5%) and 100 mL acetonitrile (Aldrich, 99.8% anhydrous) in a 500-mL round-bottom flask was cooled in an ice water bath under a flow of nitrogen. Then was added 8.15 mL sulfuryl chloride (100 mmol, TCI American, >98.0%) in 20 mL) anhydrous acetonitrile drop-wise to the ice-cooled suspension. The mixture was stirred overnight at room temperature, after which we cooled the white suspension to −0° C. with ice water and added 13.03 g imidazole (191 mmol, TCI America, >98.0%). The resulting white slurry was warmed to room temperature, then stirred for 3 h. It was diluted with ethyl acetate (200 mL) and separated and discarded the aqueous layer. The organic layer was washed twice with deionized water (2×100 mL), then twice with saturated aqueous NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4 overnight and filtered. Ethanolic HCl solution (196 mmol) was added drop-wise to the filtrate while stirring at ice-water temperature. After the addition of −3 mL, a large amount of white solid appeared. The mixture was kept in an ice bath for 15 min, then at room temperature for 30 min, after which it was filtered. The filter cake was washed with ethyl acetate (3×100 mL) to obtain 126 as a colorless solid (8.65 g, 49.9%), m.p. 99-101° C. IR (KBr) 2173, 1383 and 1160 cm−1. 1H NMR (500 MHz, D2O) δ 7.61 (dd), 8.02 (dd), 9.39 (dd); 13C NMR (125. MHz, D2O) δ=120.0, 123.5, 137.6. Element Analysis Calculated C, 17.19; H, 1.92; N, 33.41. Found: C, 17.38; H, 1.98; N, 32.97.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].CCN(C(C)C)C(C)C.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1-c1ncco1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccccc1-c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 2-Oxazol-2-yl-benzoyl chloride (104 mg, 0.5 mmol), DIEA (0.26 mL, 1.5 mmol) in 2 ml of DCM was added N,O-dimethylhydroxylamine hydrochloride (59 mg, 0.6 mmol). The mixture was stirred at room temperature for 2 hours, washed with dilute HCl solution followed by brine. Concentration of the organic layer afforded 100 mg of N-Methoxy-N-methyl-2-oxazol-2-yl-benzamide as a sticky light yellow liquid. MS: (M+H)/z=233.1.