Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:36][C:37](=[O:54])[CH2:38][CH:39]([NH:43][C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:40][CH:41]=[CH2:42])[C:14](=[O:35])[N:15]([CH2:27][CH:28](OCC)OCC)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[O:25][CH3:26])=[CH:8][CH:7]=1)(C)(C)C.[CH:55]([OH:57])=O>>[CH2:47]([NH:46][C:44]([N:43]1[CH:39]([CH2:40][CH:41]=[CH2:42])[CH2:38][C:37](=[O:54])[N:36]2[CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:55]([OH:57])=[CH:11][CH:10]=3)[C:14](=[O:35])[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=3[O:25][CH3:26])[CH2:27][CH:28]12)=[O:45])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=CO
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc(OC)c1OC)CC(OCC)OCC)NC(=O)NCc1ccccc1
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc(OC)c3OC)CC2N1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid {2-(4-tert-butoxy-phenyl)-1-[(2,2-diethoxy-ethyl)-(2,3-dimethoxy-benzyl)-carbamoyl]-ethyl}-amide (3.7 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 2-Allyl-8-(2,3-dimethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic benzylamide (1.3 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H) 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.82 (s, 3H), 3.66 (s, 3H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 599.32 (M+H), 621.38 (M+Na), 637.19 (M+K)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[C:25]1([CH:31]([CH2:36][C:37](Cl)=[O:38])[CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([N:1]2[C:37](=[O:38])[CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][C:33]2=[O:34])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CC(CC(=O)Cl)c1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N2C(=O)CC(c3ccccc3)CC2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a stirred solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.50 g, 2.0 mmol) in chloroform (15 mL) with triethylamine (1.8 mL, 10.0 mmol) was added 3-phenylpentanedioyl dichloride (0.45 g, 1.84 mmol). The mixture was stirred at ambient temperature for 2 h, washed with 20% hydrochloric acid solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from ethyl acetate/hexane to afford a solid, which was washed with cold methanol and dried in air to afford the title compound (0.46 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.50-7.20 (m, 10H), 6.07 (br s, 1H), 4.60 (d, J=5.6 Hz, 2H), 3.60-3.50 (m, 1H), 3.13 (dd, J=17.1, 4.2 Hz, 2H), 2.95 (dd, J=17.1, 12.0 Hz, 2H), 2.68 (s, 3H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:20]=[C:21]([C@@H:26]([NH2:28])[CH3:27])[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C@@H:26]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:27])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(F)c(F)c1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)c(F)c1
Yield: 54 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(3,4-difluoro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 54% of theory; LC (method 5): tR=1.00 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10](=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1
Reactant: O=c1[nH]c(-c2ccccc2)no1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1nc(-c2ccccc2)no1
Temperature: 100 °C
Reaction time: 6 h
Yield: 52.7 %

Procedure:
To a mixed solution of 3-phenyl-1,2,4-oxadiazol-5(4H)-one (2.00 g, 12.3 mmol) in phosphorus oxychloride (36 g) was added pyridine (1.93 ml, 23.9 mmol), and the mixture was stirred at 100° C. for 6 hours. The solvent was distilled off under reduced pressure. The residue was poured to ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.17 g (52.4%) of the desired product as a solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:13].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(Cl)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1
Yield: 111.3 %

Procedure:
N-benzyloxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (10 g) and 3,4-dihydoxyphenethylamine hydrochloride (4.2 g) were added to a mixture of n-butyl alcohol (100 ml) and water (14 ml) and then the mixture was refluxed for 4 hours. The above-mentioned acetal (1 g) was added to the mixture and the resultant mixture was refluxed for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ethyl acetate and collected by filtration. The crystals were recrystallized from a mixture of methanol and ether to give 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.0 g), mp 210° to 212° C. (dec).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Br:5][C:6]1[C:7]([O:16][CH:2]([CH3:4])[CH3:3])=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Reactant: CC(C)Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: CC(C)Oc1ncc(C(F)(F)F)cc1Br
Temperature: 50 °C
Reaction time: 14 h
Yield: 71.3 %

Procedure:
2-Bromopropane (0.78 ml, 8.3 mmol) was added to a stirred suspension of 3-bromo-5-trifluoromethyl-2(1H)-pyridone (2.0 g, 8.3 mmol) and silver carbonate (1.16 g, 4.2 mmol) in hexane (40 ml) and the mixture stirred at 50° C. for 14 h, then at reflux for 3 h. More 2-bromopropane (0.78 ml) was added and reflux resumed for a further 3 h. On cooling, the mixture was filtered, the filtrate diluted with hexane (100 ml) and washed with water (50 ml). The organic layer was dried (Na2SO4), evaporated, and the residual oil subjected to column chromatography over silica gel, eluting with ethyl acetate/hexane (5:95) to leave the product as a colourless oil (1.68 g).
Reaction SMILES: C[N:2](C)[C:3]([C@@H:5]1[C@@H:10]2[CH2:11][CH2:12][N:7]([CH:8]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH:33][C@@H:9]1[C@H:8]([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]2[CH2:12][CH2:11][C@H:10]1[C@@H:5]([C:3]([NH2:2])=[O:4])[CH2:6]2
Reactant: COc1ccc(OC)c(CN)c1
Reactant: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(CN[C@H]2[C@H]3CCN(C[C@@H]3C(N)=O)[C@H]2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
A mixture of 48 (1.2 g, 3 mmol), 2,5-dimethoxybenzyl amine (0.6 g, 3.3 mmol) camphor sulfonic acid (45 mg) in toluene (15 ml) was heated at reflux with removal of water for 3 hours and then the solvent was removed. The residue was dissolved in small amount of THF (3 ml) and this solution was added to a solution of sodium triacetoxyborohydride (1.7 g, 8 mmol) in acetic acid (40 ml) at room temperature. The mixture was stirred at room temperature for 3 hours and the solvent was removed. Water was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated. Recrystallization from MeOH/acetone to give by-product. The mother liquor was concentrated and the residue was purified by recrystallization from MeOH/EtOAc to give 50 (0.27 g, 0.56 mmol, 19%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.[OH-].[Li+].Cl>C(O)(C)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(C)c(-c2ccc(C(=O)O)cc2)c(C)c1

Procedure:
The compound from Example 9 part (a) (1.3 g) was dissolved in a mixture of isopropanol (15 mL) and water (8 mL). Lithium hydroxide (1.3 g) was added and the reaction mixture was refluxed. After 2 hours the solution was poured into 2N HCl and the product was extracted into ether. After drying the organic phase with MgSO4 and evaporation a white solid was obtained (1.15 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([C:29]3[CH:33]=[C:32]([C:34]([NH:36]C(OC(C)(C)C)=O)=[NH:35])[S:31][C:30]=3[S:44][CH3:45])(=[O:28])=[O:27])[CH:21]=2)=[C:16]([CH3:46])[CH:15]=1)=[O:12])[CH3:2].[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([C:29]3[CH:33]=[C:32]([C:34](=[NH:35])[NH2:36])[S:31][C:30]=3[S:44][CH3:45])(=[O:27])=[O:28])[CH:21]=2)=[C:16]([CH3:46])[CH:15]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCCNC(=O)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)c(C)c1

Procedure:
Following the procedure in Example 1: step d, 6-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester ((Example 311: step a) 12 mg) was treated with 1:1 TFA/DCM. Purification by HPLC yielded the product (8.3 mg) as a white solid. 1H-NMR (CD3OD): δ 8.31 (s, 1H), 7.97 (m, 1H), 7.94 (m, 1H), 7.65 (m, 2H), 7.29 (m, 2H), 7.09 (m, 1H), 4.10 (q, 2H, 7.2 Hz), 3.20 (t, 2H, 7.0 Hz), 2.71 (s, 3H), 2.33 (t, 2H, J=7.3 Hz), 2.19 (s, 3H), 1.65 (m, 2H), 1.55 (m, 2H), 1.40 (m, 2H), 1.23 (t, 3H, J=7.2 Hz). ESI-MS (m/z): Calcd. for C28H34N4O5S3 (M+H): 603.2; found: 603.2.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:19][N:20]([CH3:25])[S:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([O:5][CH2:6][C:7]#[N:8])[CH:3]=1)(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#CCOc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-aminophenoxy)-acetonitrile (1.5 g, from Example 1), triethylamine (3.22 mL) in THF (35 mL) was added dimethylsulfamoyl chloride (4.2 mL) dropwise over 10 min. After stirring at room temperature for 1 hr, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with 5% HCl solution and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate:dichloromethane (10:90) to give N,N-dimethyl-N'-(3-cyanomethoxyphenyl)-sulfamide (1.11 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.ClN1C(=O)CCC1=O.[CH:17]1([CH2:20][N:21]2[C:29]3[N:28]=[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[CH:33][CH:32]=4)[NH:26][C:25]=3[C:24](=[O:39])[N:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:22]2=[O:48])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH:17]1([CH2:20][N:21]2[C:29]3[N:28]=[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N:37]([CH3:38])[C:6]([C:4]5[N:3]=[N:2][S:1][CH:5]=5)=[O:8])=[CH:35][CH:36]=4)[NH:26][C:25]=3[C:24](=[O:39])[N:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:22]2=[O:48])[CH2:19][CH2:18]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: O=C(O)c1csnn1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1csnn1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A mixture of [1,2,3]thiadiazole-4-carboxylic acid (29 mg, 0.30 mmol) in dichloromethane (6 mL) at 25° C. was treated with triphenylphosphine-polystyrene 100–200 mesh (372 mg, 0.46 mmol). This mixture was cooled to 0° C. and then treated with N-chlorosuccinimide (49 mg, 0.37 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (55 mg, 0.12mmol) and triethylamine (96 μL, 0.69 mmol). The reaction was then stirred at 25° C. for 3 days. At this time, the reaction was filtered to remove solids and rinsed with dichloromethane. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:99 methanol/dichloromethane) afforded [1,2,3]thiadiazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (17 mg, 24.7%): LR-MS for C27H24FN7O3S (M+H)+ at m/z=546.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([C:12]#[N:13])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.CC(C)=O>[C:12]([C:9](=[N:6]/[C:3](=[C:2](\[NH2:1])/[C:7]#[N:8])/[C:4]#[N:5])[CH3:10])#[N:13]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CC(=O)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C#N)=N/C(C#N)=C(\N)C#N
Yield: 41 %

Procedure:
10.8 g of diaminomaleonitrile and 10.0 g of acetyl cyanide were added successively to a solution of 1.9 g of p-toluenesulfonic acid in 100 ml of dry diethyl ether. The resulting yellow powder was collected by filtration and dried. The crude product thus obtained was dissolved in 600 ml of acetone and any insoluble insoluble solids were removed by filtration. 900 ml of water was added to the filtrate to obtain α-cyanoethylidenediaminomaleonitrile in 41% yield.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:5][C:6]([CH2:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].O1CCCC1.P(OCC)(OCC)([S-])=[S:25]>O>[C:1]([C:3]1[C:4]([CH:15]2[CH2:16][CH2:17][CH2:18]2)=[CH:5][C:6]([CH2:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:25])[NH2:2]
Reactant: CCc1cc(C2CCC2)c(C#N)cc1C(=O)OC
Reactant: CCOP(=S)([S-])OCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C2CCC2)c(C(N)=S)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.1 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate (compound 181.5, 3.00 g, 12.3 mmol, 1.00 equiv) in a solvent mixture of tetrahydrofuran and H2O (80 mL/40 mL). To this was added O,O′-diethyl dithiophosphate (6.69 g, 35.9 mmol, 3.00 equiv) dropwise with stirring. The resulting solution was stiffed at 85° C. for 48 h (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was then concentrated in vacuo. The crude product was purified by re-crystallization from petroleum ether to furnish 1.30 g (38%) of methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate as a light yellow solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][O:15][C@H:6]1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.[OH-].[Li+]>CO>[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@@H:6]1[O:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CCCCCCCS[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCS[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In 10 ml. of methanol was dissolved 2.45 g. of the compound (18), and 10 mg. of lithium hydroxide was added to the solution. The mixture was stirred at room temperature for one hour to yield the desired n-heptyl 1-thio-β-D-xylopyranoside which was a compound of the present invention. The yield was 95%.
Reaction SMILES: Br.[C:2]([NH:5][CH2:6][CH2:7][N:8]=[CH:9][NH:10][CH2:11][NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH3:3].[ClH:22].[C:23]([C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH2:36][C:37](=[O:39])[NH2:38])=[C:31](O)[CH:30]=[CH:29]2)(=[NH:25])[NH2:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:22].[ClH:22].[C:2]([NH:5][CH2:6][CH2:7][N:8]=[CH:9][NH:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23](=[NH:24])[NH2:25])[CH:27]=3)[C:32]=2[CH2:36][C:37](=[O:39])[NH2:38])=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)NCCN=CNCNc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCCN=CNCNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 1.4 g of 4-[(2-acetylaminoethyl)iminomethylaminomethylamino]benzoic acid.hydrobromide, 1.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 884 mg of DCC and 43.6 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 4 days at room temperature. The precipitate was filtered and the filtrate was added dropwise to 250 ml of a mixed liquid of ether and acetone (1:10) and this was stirred for 24 hours under cooling with ice. Then, the precipitate was collected by filtration. To this collected precipitate was added 7 ml of DMF to dissolve the precipitate with heating, and 1.46 ml of concentrated hydrochloric acid was added under cooling with ice and stirring. This solution was added dropwise to 400 ml of ether.acetone (1:20), followed by stirring for 1 hour under cooling with ice and then 24 hours under cooling with water. After the supernatant was decanted, 20 ml of DMF was again added to the residue to dissolve the residue with heating, and further 1.5 ml of concentrated hydrochloric acid was added under cooling with water and stirring. This solution was added dropwise to 400 ml of acetone, followed by stirring for 1 hour under cooling with ice and then 24 hours under cooling with water. Thereafter, the precipitate was collected by filtration to obtain a crude product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:19]([O-])=O)=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)=[O:2].[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][C:7]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: COC(=O)C1CCN(c2cc(C=O)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2cc(C=O)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
To methyl 1-(5-formyl-2-nitrophenyl)piperidine-4-carboxylate 64 (0.881 g, 3.0 mmol) was added EtOAc (20 mL) and palladium (0.482 mg, 0.45 mmol). The nitrogen atmosphere was replaced by hydrogen from a double balloon and the reaction mixture was stirred at room temperature for 3 h, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave methyl 1-(2-amino-5-formylphenyl)piperidine-4-carboxylate 65 (0.043 g, 5.4% yield) as a yellow oil. Mass spectrum: calculated for C14H18N2O3 262.1. found 263.2 (M++1). In addition, methyl 1-(2-amino-5-(hydroxymethyl)phenyl)piperidine-4-carboxylate 66 (0.534 g, 67% yield) was isolated as a yellow solid. Mass spectrum: calculated for C14H20N2O3 264.2. found 265.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>C1COCC1.CO.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:13][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1ncc(Br)c(OC)n1
Temperature: 0 °C
Reaction time: 66 h

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (Frontier Scientific, Logan, USA, 0.895 mmol) in THF (2.5 ml) cooled with an ice-bath was added a 2 M solution of ethylamine in MeOH (Aldrich, Buchs, Switzerland, 0.492 ml). The RM was stirred at 0° C. for 1 h and at rt for 66 h then the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/iPrOH 0% to 6%) to give after evaporation of the fractions containing the title compound an off-white solid. (HPLC: tR 2.16min (Method A); M+H=232, 234 MS-ES)