Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[NH:21][C:20](=[O:26])[CH:19]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:24][N:23]1[C:18]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)=[CH:19][C:20](=[O:26])[NH:21][C:22]1=[O:25]
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Reactant: Cn1c(Cl)cc(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(N2CCN(CCCOc3ccccc3)CC2)cc(=O)[nH]c1=O
Reaction time: 12 h
Yield: 68.1 %

Procedure:
1.3 g of 1-(3-phenyloxypropyl)piperazine and 0.5 g of 6-chloro-1-methyl-2,4(1H,3H)-pyrimidinedione were dissolved in 15 ml of isopropanol, and 2.7 ml of triethylamine was then added. Next, the solution was heated under reflux with stirring for 12 hours and then allowed to stand for cooling, and the solvent was distilled off. The resultant residue was dissolved in 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain an oily product. This oily product was purified through a silica gel column chromatograph (chloroform/methanol=30/1 in volume ratio), thereby obtaining 0.73 g of 1-methyl-6-[4-(3-phenoxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[N:24]=[CH:25][C:18]=12>CC(N(C)C)=O>[CH2:2]([N:9]1[CH2:12][CH:11]([O:13][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([C:26]4[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=4)[N:24]=[CH:25][C:18]=23)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC1CN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
1-Benzyl-azetidin-3-ol hydrochloride salt (0.59 mmol, 117 mg) and sodium hydride were dissolved in dimethyl acetamide (2 mL) and stirred at room temperature for 30 minutes. 4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.49 mmol, 150 mg) was added slowly and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was quenched with water followed by an extraction with ethyl acetate. Removal of organic solvents in vacuo and purification by flash chromatography provided compound A23 as a white solid (88 mg, 41%). 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.90 (s, 1H); 8.53 (s, 1H); 8.30 (d, 2H); 8.16 (d, 2H); 7.43 (m, 5H); 6.19 (m, 1H); 4.59 (m, 2H); 4.42 (d, 1H); 4.00 (d, 1H); 3.65 (d, 1H); 3.35 (m, 1); 3.30 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[O:7][CH:8]=1.NC(CC1C=CC=CC=1)CC(O)C(NC(OCC1SC=NC=1)=O)CC1C=CC=CC=1.[NH2:50][C@@H:51]([CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH2:52][C@H:53]([OH:72])[C@@H:54]([NH:62][C:63]([O:65][CH2:66][C:67]1[O:71][N:70]=[CH:69][CH:68]=1)=[O:64])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(Cl)Cl>CO>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([NH:50][C@@H:51]([CH2:73][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[CH2:52][C@H:53]([OH:72])[C@@H:54]([NH:62][C:63]([O:65][CH2:66][C:67]1[O:71][N:70]=[CH:69][CH:68]=1)=[O:64])[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:19])[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[O:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)O)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Agent: NC(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OCc1cncs1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)co1
Yield: 64 %

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanine and replacing 2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 92:8 CH2Cl2:CH3OH, the desired compound (Rf 0.48, 92:8 CH2Cl2:CH3OH) in 64% yield. 1H NMR (DMSO-d6) δ 1.08 (d, 3H), 1.24 (d, 6H), 1.50 (m, 2H), 2.82 (s, 3H), 3.0 (m, 1H), 4.25 (s, 2H), 4.60 (d, 1H), 5.05 (s, 2H), 6.20 (br d, 1H), 6.32 (d, 1H), 7.20 (m, 11H), 7.50 (br d, 1H), 7.78 (s, 1H), 8.51 (d, 1H). Mass spectrum: (M+H)+=661.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13](SC)[N:12]=1)=[O:10].O>CCO.[Ni]>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)[OH:10]
Reactant: CSc1nccc(C(=O)c2cccc(C)c2Br)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(O)c2ccncn2)c1Br

Procedure:
To a solution of (2-bromo-3-methylphenyl)(2-(methylthio)pyrimidin-4-yl)methanone (0.10 g, 0.309 mmol) in EtOH (10 mL) was added Raney 2800 nickel, slurry, in water (0.022 mL, 3.41 mmol) and the resulting mixture was reflux until starting material was consumed (2 h). The mixture was brought to RT and decanted. The remaining Ni was extracted with DCM/NH3 (2M in MeOH). The combined organic layers were concentrated and the residue obtained was extracted with DCM and the extracts were combined and concentrated to afford a yellow oil as (2-bromo-3-methylphenyl)(pyrimidin-4-yl)methanol which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11]I.[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CI
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In 100 ml of DMSO were dissolved 10 g of 2,3,5-trimethylphenol and 10.4 ml of methyl iodide. Under ice-cooling, 5.6 g of 60% sodium hydride in oil was added, and the mixture was stirred at room temperature for 10 hours. After addition of water, the extraction with ether was carried out. The ether layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation leaves the oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:15][CH2:16]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3ccccc3[N+](=O)[O-])CC2)n1
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (20 mg, 0.09 mmol) and 1-bromo-2-nitrobenzene (22.8 mg, 0.11 mmol) was stirred at 90° C. for 0.5 h, then at 110° C. for 1 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 3:7 to 4:6) affording the title product (8.3 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li]C(CC)C.C([N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O)(OC(C)(C)C)=O>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([S:2](/[CH:1]=[C:35]3/[NH:34][CH2:38][CH2:37][CH2:36]/3)(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[C:13]([O:20][CH3:21])[CH:14]=1)[CH3:19]
Reactant: CCc1ccc(Oc2ccc(S(C)(=O)=O)cc2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)/C=C3\CCCN3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone (0.44 mmol; 136 mg), in anhydrous THF (1 mL), under argon, cooled to 0° C., was added sBuLi (1.2M in cyclohexane; 0.89 mmol; 0.74 mL). After stirring for 30 min, a solution of 1-BOC-2-Pyrrolidinone (0.44 mmol; 0.08 mL) in anhydrous THF (1 mL) was slowly added. The reaction was stirred at 0° C. for 30 min. then slowly warmed up to room temperature overnight. The mixture was quenched with water and NH4Cl sat. (3 mL), extracted with ethyl acetate (2*3 mL), to yield a light yellow oil (164 mg), used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[OH-].[NH4+:39]>>[NH2:39][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.257 mmol) and ammonium hydroxide (3 mL, 77 mmol), the title compound was obtained as a tan solid (47 mg, 31% yield). MS (ESI): 565 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[C:1]([O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COc1cc(CO)ccc1O
Reactant: CCCCCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
Decanoic acid (2.00 g, 11.61 mmol), vanillyl alcohol (1.74 g, 11.27 mmol), and Novozym 435 (100 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 20 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (50 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were removed by filtration. The filtrate was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (3.41 g) of vanillyl decanoate and decanoic acid as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 94.1%. The mixture contained 6.0 wt % of decanoic acid relative to vanillyl decanoate.
Reaction SMILES: Cl.O.[NH2:3]N.Cl.[CH2:6]([O:8][C:9](=[O:22])[C:10](=[CH:18][N:19](C)C)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:7]>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[NH:3][N:19]=[CH:18][C:10]=1[C:9]([O:8][CH2:6][CH3:7])=[O:22])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1C(=O)OCC
Temperature: 60 °C
Yield: 31 %

Procedure:
Under an atmosphere of argon, hydrazine monohydrate hydrochloride (1.91 g, 28 mmol) and HCl (36.5% in water, 2.8 ml) were added to a solution of 2-dimethylaminomethylene-3-oxo-succinic acid diethyl ester (6.8 g, 28 mmol, obtained by the method of Hanzlowsky et al., J. Heterocyclic Chem. 2003, 40(3), 487-498) in ethanol (100 ml). The mixture was heated to 60° C. (3 h). The solvent was evaporated, and the residue was taken up in dichloromethane and washed (water). The organic layer was dried (Na2SO4), the solvent was evaporated and the title compound (1.81 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=383.3 [M+H+].
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:15][CH2:16][CH2:17][CH3:18].ICCCC>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)NS(=O)(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCCCI
Product: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
N-tert-Butylthiophene-2-sulfonamide (5 g, 0.0228 mol, see Example 1(a) above) was dissolved in THF (43 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 38.5 mL, 0.062 mol) was added via a syringe. The reaction mixture was stirred at −78° C. for 30 min and then at −40° C. for 2 h. Iodo-butane (5.19 mL, 0.046 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature, quenched with NH4Cl (aq) and extracted with EtOAc. The combined organic phase was washed with brine, dried and concentrated in vacuo. The crude product was purified on column chromatography (Hex:EtOAc 10:1) to give the sub-title compound in 46% yield (2.92 g, 0.011 mol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([CH2:25][OH:26])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH3:29]>CN(C)C=O.[Ag]=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([CH2:25][O:26][CH3:29])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethyl-cyclohexyl)carbamic acid tert-butyl ester (1.8 g) was dissolved in N,N-dimethylformamide (15 mL). Iodomethane (50 mL) was added, followed by silver oxide (5.52 g), and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite and the solids were washed with ethyl acetate. The filtrate was washed sequentially with water and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to provide (1R,3R,4S)-(4-benzyloxycarbonylamino-3-methoxymethylcyclohexyl)carbamic acid tert-butyl ester as a colorless gum (1.78 g). MS found: (M+H)+=393.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[CH3:17][N:18]([CH3:20])[NH2:19]>CCO>[CH3:17][N:18]([CH3:20])[N:19]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: CN(C)N
Reactant: N#Cc1ccc(CC2CCCCC2=O)cc1
Solvent: CCO
Product: CN(C)N=C1CCCCC1Cc1ccc(C#N)cc1

Procedure:
A solution of 4-[(2-oxocyclohexyl)methyl]-benzonitrile (7 g) (0.033 mol) and anhydrous N,N-dimethylhydrazine (9.2 ml) (3,7 eq.) in EtOH (100 ml) was refluxed for 8 h. After cooling, the reaction mixture was concentrated to dryness. The residue was partitioned between tBuOMe and water, the organic phase washed twice with water, dried over magnesium sulfate, and concentrated to yield 4-[[2-(dimethylhydrazono)cyclohexyl]methyl]-benzonitrile (6.1 g) as a orange oil. 1H NMR (CDCl3): 7.55 (2H, d), 7.30 (2H, d), 3.15 (1H, dd), 2.9-2.15 (6H, m), 2.3 (6H, s), 1.8-1.3 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[C:21]([CH3:31])[CH:20]=1>>[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22](/[CH:23]=[CH:24]/[C:25]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[C:21]([CH3:31])[CH:20]=1
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CCC)c1=O
Yield: 45 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.5 g (11.1 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.51 g (12.17 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.98 g (yield 45%) of Compound 45 as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1COCC1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][NH:29][C:27]([C:23]1[CH:22]=[C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:26]=[CH:25][N:24]=1)=[O:28]
Reactant: Nc1ccc(O)cc1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 4-aminophenol (1 g, 9.2 mmol) in DMF (20 mL) was added 1M potassium tert-butoxide in THF (9.7 mL, 9.7 mmol) at room temperature. After 2 h, (4-chloro(2-pyridyl))-N-methylcarboxamide (1.6 g, 9.2 mmol) and potassium carbonate (0.64 g, 4.6 mmol) were added and then the reaction mixture was heated to 80° C. for 6 h. After cooling, the reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate. The solvent was removed in vacuo. The residue was purified by column chromatography to afford 4-(4-amino-phenoxy)-pyridine-2-carboxylic acid methylamide (2.2 g, 80%) as a light-brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.89 (s, 1H), 8.78 (q, J=5 Hz, 1H), 8.50 (d, J=6 Hz, 1H), 7.61-7.54 (m, 4H), 7.38 (d, J=3 Hz, 1H), 7.29 (d, J=9 Hz, 2H), 7.19-7.12 (m, 3H), 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=2)[N:5]=[C:6]([Cl:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[C:30]([O:9][C:8]([C:7]2[C:6]([Cl:11])=[N:5][C:4]3=[N:12][N:13]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:14]=[C:3]3[C:2]=2[NH2:1])=[O:10])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: COc1ccc(Cn2cc3c(N)c(C(=O)O)c(Cl)nc3n2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc3c(N)c(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)c(Cl)nc3n2)cc1
Yield: 89 %

Procedure:
To a cold (0° C.) solution of 4-amino-6-chloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (952 mg, 2.86 mmol) and pentafluorophenol (830 mg) in DMF was added a solution of DCC (620 mg, 3 mmol) in EtOAc (9 mL). After work up the crude product was purified by flash column (silica gel, EtOAc/hexane, 1:1) to give the desired product (1.27 g) as a white solid. LC: 4.64 (Gradient 1), MH+: 499.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3](OC(=O)C(C)C)[CH3:4].[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][CH2:4][O:21][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Product: CSC(=O)OCCOC(=O)c1ccccc1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with benzoic acid in Step B affords O-(benzoyloxyethyl) S-methyl thiocarbonate (215) as an oil.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[N:21]1([C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Nc1ccc2ccc(N3CCCC3)nc2n1
Reactant: O=C(O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(N3CCCC3)nc2n1)c1ccccc1
Temperature: 4 °C
Yield: 90 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with benzoic acid (6.5 g), N,N'-carbonyldiimidazole (8.6 g) and 2-amino-7-(1-pyrrolidinyl)-1,8-naphthyridine (8.6 g). The product obtained by precipitation in water (13 g; m.p. 110° C.) is dissolved in boiling acetonitrile (85 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (15 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(1-Pyrrolidinyl)-1,8-naphthyridin-2-yl]benzamide (11.5 g), m.p. 130° C., is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.Br[CH2:23]CCCC(C)(C1C=CC(C)=CC=1)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[CH:19][CH:20]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Yield: 93 %

Procedure:
According to the method described for the synthesis of 207d, 206e (18.2 g, 63.8 mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH2Cl2 (300 mL) to give 207e (22.0 g, 93%) as an oil, which was used without further purification. 1H NMR (CDCl3): δ 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m, 1H). 13C NMR (CDCl3): δ 142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MH+): 369.1429, found: 369.1451.