Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21])[CH:2]=[CH2:3].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:3][CH:2]1[CH2:1][C:4]2[C:5]([N:11]3[C:15](=[O:16])[C:14]4[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=4[C:12]3=[O:21])=[CH:6][CH:7]=[CH:8][C:9]=2[O:10]1
Reactant: C=CCc1c(O)cccc1N1C(=O)C2=C(CCCC2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC1Cc2c(cccc2N2C(=O)C3=C(CCCC3)C2=O)O1

Procedure:
Example 2 was prepared, as a yellow oil, by treating 0.48 g of 1D with PTSA in xylene according to the procedures described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40][CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-:53].[Ca+2].[OH-:55]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40]([CH3:41])(=[O:55])=[O:53])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CSc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(S(C)(=O)=O)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (193 mg, 0.32 mmol) was dissolved in chloroform (5 mL). After the solution had been cooled to 0° C., 3-chloroperoxybenzoic acid (mCPBA) (259 mg, 0.87 mmol, 58% purity) was added in portions. After 30 minutes, the reaction was warmed to room temperature and calcium hydroxide (80 mg, 1.1 mmol) was added. After 5 minutes, the reaction was filtered and the filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography (˜20 g silica, 10% EtOAc/CH2Cl2 through 100% EtOAc) to give the desired product (146 mg, 0.23 mmol, 73%) as a white solid.
Reaction SMILES: C([N:8]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]3[OH:36])=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:45])[CH:19]=1)[CH2:9][CH2:10][C:11](=[O:13])[NH2:12])C1C=CC=CC=1>CO.[C].[Pd]>[C:11]([CH2:10][CH2:9][NH:8][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]3[OH:36])=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:45])[CH:19]=1)(=[O:13])[NH2:12]
Reactant: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(OCCCNCCC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.9 %

Procedure:
4-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]-propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.5 g) was dissolved in methanol (8 mL). To the solution was added 10% palladium-carbon powder (0.1 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. A part (0.1 g) of the residue was dissolved in a mixed solvent of methanol (1 mL) and ethyl acetate (1.5 mL). To the solution was added a seed crystal, and the mixture was stirred at room temperature for 3 days. The precipitated crystals were collected by filtration. The crystals were washed with a mixed solvent of methanol and ethyl acetate (2/3), and dried under reduced pressure to give the title compound (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[C:17]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:25]1[CH2:24][CH2:23][N:22]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][CH2:26]1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C=C2C(=O)Nc3cc(OC)c(OC)cc32)CC1

Procedure:
4.0 g. of 5,6-dimethoxy-3-hydroxymethylene oxindole was reacted with N-carbethoxy piperazine as described in Example 2, except that 0.10 g. toluene sulfone acid was added as a catalyst. Yield, 3.05 g. of product, m.p. 172°-174° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2ocnc2c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 61 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 1.0 mmol), iodobenzene (612 mg, 3.0 mmol), t-BuOK (224 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 119 mg (61%) of 2-phenylbenzoxazole is obtained. Table I, entry 3.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:36][CH2:35][C:34]5[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cc1
Temperature: 112 °C
Yield: 77.3 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (1.23 g, 3.0 mmol), 4-Methoxy-benzylamine (493 mg, 3.6 mmol), Pd2(dba)3 (210 mg, 0.3 mmol), Xphos (142 mg, 0.3 mmol), t-BuONa (576 mg, 6 mmol) and dioxane (6 mL) was added in a 10 mL of sealed tube, and the reaction mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution. Then water was added into the solution and extracted by DCM (50 mL×3). The combined organic layer was dried by Na2SO4, concentrated in vacuo, separated by TLC (DCM: EtOAc=4:1) to give {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(4-methoxy-benzyl)-amine (1.2 g, yield: 77%). 1H NMR (DMSO-d6, 400 MHz): δ 8.36 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.29 (s, 2H), 7.14 (s, 1H), 6.97-6.90 (m, 3H), 6.46 (d, J=8.8 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H), 4.20 (s, 2H), 3.77 (s, 3H), 3.12 (s, 2H). LC-MS (ESI): m/z=518 [M+H]+
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[C:19]2[N:20]=[CH:21][S:22][C:18]=2[CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[S:7]([O:12][CH2:13][CH:14]1[C:19]2[N:20]=[CH:21][S:22][C:18]=2[CH2:17][CH2:16][CH2:15]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCC1CCCc2scnc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCc3scnc32)cc1
Temperature: 10 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
9.95 g (52 mmoles) p-toluenesulfonyl chloride are added portionwise to a mixture of 8 g (47 mmoles) of the above derivative (IV) and 15 g anhydrous pyridine, while maintaining the temperature at 10° C. After stirring for 24 hrs at room temperature, the mixture is hydrolyzed and is then extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated. The residual oil crystallizes slowly. The product is recristallyzed from boiling isopropyl oxide, on cooling. Yield: 72%. M.p.=64°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[F:36][C:37]([F:42])([F:41])[C:38](O)=O>>[CH3:18][N:15]1[C:14]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:38]1[C:37]([F:42])([F:41])[F:36])=[N:10][C:11]=2[N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C(F)(F)F)nc4ccccc43)nc21

Procedure:
Following the procedures for 157, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and trifluoroacetic acid were reacted to give 186. LCMS m/z: 559.3 (MH+)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1>CN(C=O)C>[CH2:7]([O:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
DMF (12 mL), K2CO3(1.19 g, 8.55 mmol) and benzyl bromide (0.75 mL, 6.27 mmol) was added to 4-bromo-2-fluorophenol (1.1 g, 5.7 mmol), and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated and the residue was diluted with 20 mL water. The mixture was extracted with EtOAc. The organic layer was separated and dried with MgSO4 to obtain the title compound (1.62 g, 100%).
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[CH:12]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(OP([CH2:23][C:24]1[CH:25]=[C:26]([C:34]([O:36][CH3:37])=[O:35])[C:27](=[CH:32][CH:33]=1)[C:28]([O:30][CH3:31])=[O:29])(OCC)=O)C.CC(C)([O-])C.[K+]>>[CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11](/[CH:13]=[CH:23]/[C:24]3[CH:25]=[C:26]([C:34]([O:36][CH3:37])=[O:35])[C:27](=[CH:32][CH:33]=3)[C:28]([O:30][CH3:31])=[O:29])[CH:12]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(C(=O)OC)c1)OCC
Reactant: CCC1(c2cc(C=O)cs2)OCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCC1(c2cc(/C=C/c3ccc(C(=O)OC)c(C(=O)OC)c3)cs2)OCCO1

Procedure:
In a manner similar to that of Example 8(a), by reaction of 4.6 g (21.6 mmol) of 2-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-4-carbaldehyde with 8.9 g (26 mmol) of dimethyl 4-(diethoxyphosphorylmethyl)-phthalate and 2.9 g (26 mmol) of potassium tert-butoxide, the desired product is obtained in the form of a yellow oil (m=7 g; Y=87%).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=S)[C:4]=2[CH:3]=1.[C:17]1([S:23][CH2:24][CH2:25][C@H:26]2[CH2:31][NH:30][CH2:29][CH2:28][NH:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([S:23][CH2:24][CH2:25][C@@H:26]2[NH:27][CH2:28][CH2:29][N:30]([C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[S:11][C:10]=4[NH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[N:6]=3)[CH2:31]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(SCC[C@H]2CNCCN2)cc1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Solvent: c1ccncc1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCSc2ccccc2)C1
Yield: 15.7 %

Procedure:
Combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (0.455 g, 1.85 mmol), (S)-2-(2-phenylsulfanyl-ethyl)-piperazine (0.411, 1.85 mmol) and pyridine (5 mL) and reflux for 36 hours. Evaporate the mixture and apply the material to 10 g of SCX, then elute with methanol followed by 5% 2N ammonia-methanol in dichloromethane and then 2N ammonia-methanol. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 7% 2N ammonia-methanol in dichloromethane gives (S)-10-[3-(2-phenylsulfanyl-ethyl)-piperazin-1-yl]-2-methyl 4H-3-thia-4,9-diazabenzo[f]azulene (0.126 g, 0.290 mmol, 16%). Mass spectrum (APCI): m/z=435.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[N:31]=3)=[C:13]2[C:24]([OH:26])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:43]1([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:45][CH2:44]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:38])[CH3:37])[N:31]=3)=[C:13]2[C:24](=[O:26])[N:46]([CH:43]2[CH2:44][CH2:45]2)[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)cs3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Reactant: Clc1cccc(CNC2CC2)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h
Yield: 34.4 %

Procedure:
A mixture of compound D2 (2.87 g, 4.60 mmol), cyclopropyl-(2,3-dichlorobenzyl)amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 2.49 g, 11.5 mmol), DIPEA (3.15 mL, 18.4 mmol), DMAP (140 mg, 1.15 mmol), HOBt (932 mg, 6.90 mmol) and EDC.HCl (2.65 g, 13.8 mmol) in CH2Cl2 (50 mL) was stirred at rt for 6 days. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→1:3→1:2→1:1→3:2) yielded the title compound (1.30 g, 34%). LC-MS: tR=1.33 min, ES+: 821.54.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[C:29]#[C:30][CH2:31][OH:32])=[CH:4][CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][OH:32])=[CH:33][CH:34]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(C#CCO)n2Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(CCCO)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
A solution of 7-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.247 mmol) in methanol (15 mL) was degassed and refilled with nitrogen for 3 times; then 10% Pd/C (30 mg) was added. The mixture was degassed and refilled with hydrogen 3 times and stirred under 45 psi of hydrogen at room temperature for 20 min. The mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated to give 7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 82.6% yield) as a grey solid. LCMS retention time 1.447 min; LCMS MH+ 491.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][N:11]1[CH2:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:12]1=[O:24])C1C=CC=CC=1.[NH3:26]>CO>[CH2:17]([O:16][C:14]1[CH2:15][N:11]([CH2:10][C:9]([NH2:26])=[O:8])[C:12](=[O:24])[CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CN1CC(OCc2ccccc2)=CC1=O)OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)CN1CC(OCc2ccccc2)=CC1=O

Procedure:
25.0 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester was dissolved in 500 ml of methanol and stirred at 40° C with passing of gaseous NH3 for 5 hours. Then the reaction solution was evaporated and the residue was mixed with 50 ml of acetone. The precipitated crystals were filtered by suction and dried. 15.2 g of TLC pure product with a melting point of 174.5 to 175.5° C. was obtained. For the product:
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8](OS(C)(=O)=O)[CH2:9][CH:3]1[CH2:4][CH2:5]2.C([O:17][C:18]([S-:20])=[S:19])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C@@H:3]2[CH2:9][CH:8]([S:19][C:18]([SH:20])=[O:17])[CH2:7][C@H:6]1[CH2:5][CH2:4]2
Reactant: CCOC(=S)[S-]
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC[C@H]1CC(SC(=O)S)C2
Reaction time: 2 h

Procedure:
Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[CH2:19]>>[C:1]([O:5][C:6](=[O:17])[CH:7]([CH2:19][CH2:18][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[CH2:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Product: CC(C)(C)OC(=O)C(CCS(=O)(=O)c1ccccc1)CC1(C(=O)O)CCCC1

Procedure:
3-(1-Carboxycyclopentyl)-2-[2-(phenylsulphonyl)ethyl]propanoic acid t-butyl ester was prepared following the procedure of Example 38, using as starting materials the propanoic ester of Example 35 and phenyl vinyl sulphone. The product was isolated as an oil (15%). Found: C,60.25; H,7.24. C21H30O6S. 0.13 CH2Cl2 requires C,60.24; H,7.24%. The above glutaric acid derivative was coupled with cis-3-amino-cyclohexanecarboxylic acid ethyl ester using the general procedure of Example 81 to yield 3-{1-[cis-3-ethoxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}-2-[2-(phenylsulphonyl)ethyl]propanoic acid t-butyl ester as a foam (71%). Found: C,63.53; H,8.02; N,2.38. C30H45NO7S requires C,63.91; H,8.05; N,2.48%. The above diester was treated with trifluoroacetic acid using the procedure of Example 242 to give 3-{1-[(cis-3-ethoxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}-2-[2-(phenylsulphonyl)ethyl]propanoic acid as a foam (96%). Found: C,61.90; H,7.54; N,2.86. C26H37NO7S requires C,61.51; H,7.35; N,2.76%. The above monoester was hydrolysed using the general procedure of Example 323 to give the title diacid as a foam (95%). Found: C,59.00; H,6.83; N,2.51. C24H33NO7S. 0.5 H2O. 0.1 CH3CO2C2H5 requires C,58.92; H,7.04; N,2.81%.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[CH:18][CH:19]=1>O1CCCC1.[NH4+].[Cl-]>[F:13][C:14]1[CH:19]=[C:18]([C:10]2([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2cccc(F)c2)C1
Temperature: 0 °C
Yield: 105.8 %

Procedure:
1-Boc-3-azetidinone (500 mg, 2.77 mmol, available from Aldrich #696315) was dissolved in dry tetrahydrofuran (20 ml) under N2 atmosphere. The solution obtained was cooled at 0° C. and 3-Fluorophenylmagnesiumbromide (1M in THF) (3.33 ml, 3.33 mmol) was added dropwise under stirring. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was diluted with NH4Cl sat. sol. (50 ml) and the organics were extracted with ethylacetate (3×50 ml). Collected organics after solvent evaporation afforded the title compound (D28) (783 mg)
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][CH2:21]S)[CH2:18][C@@H:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:16]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH2:15][C:14]=2[CH:36]=1)#[N:9]>C1COCC1.C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][CH2:21][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C@@H:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:16]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32])[CH2:15][C:14]=2[CH:36]=1)#[N:9]
Reactant: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCS)C[C@H]1Cc1ccccc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCNS(C)(=O)=O)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonamide (23.8 mg, 0.25 mmol) was added to a suspension of sodium hydride (10 mg, 0.25 mmol, 60% in oil, washed with hexanes) in THF (1.5 mL). The mixture was stirred at rt for 30 min. and Compound B of Example 27 (47.6 mg, 0.1 mmol) was added. The resulting mixture was stirred at reflux temperature for 16 hours. The reaction mixture was cooled to rt, diluted with DCM (10 mL) and washed with water. The DCM solution was dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC (Column: YMC S-5 ODS 100×20 mm; UV: 220 nm; Flow rate: 20 mL/min; solvent: gradient from 50-90% MeOH in water containing 0.1% TFA in 10 min.). The fractions containing the desired products were pooled and concentrated to afford the title compound as a colorless foam, 5.2 mg (10.6%) MS m/e 491 (M+H)+; 489(M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[OH:11][CH2:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[C:21]([C@@H:19]([C@H:17]([C@@H:15]([C@@H:13]([CH2:12][OH:11])[OH:14])[OH:16])[OH:18])[OH:20])[OH:22]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: Cc1ccc(C=O)cc1C
Product: Cc1ccc(C=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1C

Procedure:
The ionic fluids prepared are used for carrying out the dehydration reaction at room temperature, for example 3,4 dimethyl benzaldehyde is reacted with sorbitol to form 3,4-dimethylbenzylidene sorbitol.