Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:48][C:49]6([CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)OCC[O:50]6)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:41][CH2:42][N:43]([CH2:46][C:47]5[CH2:48][C:49](=[O:50])[CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)[CH2:44][CH2:45]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(C3)OCCO4)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1

Procedure:
A mixture of EXAMPLE 249E (20 mg) and pyridinium p-toluenesulfonate (16.8 mg) in acetone/H2O (1:1, 3 mL) was heated in a microwave to 135° C. for 8 minutes. The mixture was diluted with dichloromethane (100 mL), washed with water and brine, and dried over Na2SO4. Filtration and evaporation of solvent gave the product.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[CH:3]2[CH2:7][CH:8]=[CH:9][CH2:10][CH:2]12.[K].S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:25][CH2:26][N:27]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][N:29]=[C:28]1[CH3:35]>>[CH3:35][C:28]1[N:27]([CH2:26][CH2:25][N:5]2[C:1](=[O:11])[CH:2]3[CH2:10][CH:9]=[CH:8][CH2:7][CH:3]3[C:4]2=[O:6])[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][N:29]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C1NC(=O)C2CC=CCC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K]
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)C2CC=CCC2C1=O

Procedure:
1,2,3,6-Tetrahydrophthalimide is converted to the potassium salt and reacted with 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate according to the procedure described in Example 13. The crude reaction mixture obtained is concentrated and the concentrate distributed between water and toluene. The toluene layer is separated and the solvent is evaporated to leave a residue which is recrystallized from 2-propanol, affording N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-1,2,3,6-tetrahydrophthalimide melting at about 118°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][C:20](=[O:21])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH3:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(C)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred mixture of p-methoxyphenethyl amine (3.28 g, 21.7 mmol), p-fluorophenyl propionic acid (3.31 g, 19.7 mmol), and 150 ml anhydrous dichloromethane was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.16 g, 21.7 mmol). The mixture was stirred at ambient temperature for 40 hours and then washed with 1N sodium hydroxide, 1N hydrochloric acid, and saturated sodium chloride, dried, filtered and evaporated to a green solid (5.41 g, 91%). 1H NMR (CDCl3) δ 7.18 (m, 2H); 6.98 (m, 4 H); 6.81 (d, 2 H); 5.32 (br s, 1 H); 3.79 (s, 3 H); 3.44 (q, 2 H); 2.90 (t, 2 H); 2.68 (t, 2 H); 2.39 (t, 2 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].C(O)(=O)CC.N(OS(=O)(=O)O)=O.[CH:25]([O:27][C:28](=[O:40])[CH2:29][CH2:30][N:31]([CH2:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:26].S(=O)(=O)(O)[NH2:42]>CO.C(O)(=O)C>[CH:25]([O:27][C:28](=[O:40])[CH2:29][CH2:30][N:31]([C:32]1[CH:37]=[CH:36][C:35]([N:42]=[N:1][C:2]2[S:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]=2[N+:7]([O-:9])=[O:8])=[CH:34][CH:33]=1)[CH2:38][CH3:39])=[CH2:26]
Reactant: Nc1sc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C=COC(=O)CCN(CC)c1ccccc1
Reactant: NS(=O)(=O)O
Agent: O=NOS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CO
Solvent: CCC(=O)O
Product: C=COC(=O)CCN(CC)c1ccc(N=Nc2sc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 2 °C
Reaction time: 2 h

Procedure:
5.7 parts of 2-amino-3,5-dinitrothiophene, 20 parts of propionic acid and 30 parts of acetic acid were charged and cooled to 2° C. 11.4 parts of 40% (w/w) nitrosyl sulfuric acid were added, whilst the temperature was held below 4° C. The diazotization mixture was stirred for a further 2 hrs at 2-4° C. To a separate vessel were charged 6.5 parts of 3-(ethyl-phenyl-amino)-propionic acid vinyl ester, 100 parts of methanol, 1 part sulfamic acid and 100 parts of ice. With stirring, the diazotization mixture was slowly added followed by a further 300 parts of ice. The reaction mixture was stirred over night and the product was isolated by filtration, washed subsequently with water, methanol and again water, then dried to yield 7.4 parts of 3-{[4-(3,5-dinitro-thiophen-2-ylazo)-phenyl]-ethyl-amino}-propionic acid vinyl ester. λmax=626 nm (acetone).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Temperature: 80 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of intermediate 47, 2-azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (660 mg, 2.6 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added triphenylphosphine (740 mg, 2.8 mmol), and the mixture stirred under nitrogen for 1 hr. The tetrahydrofuran was evaporated in vacuo and a mixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated at 80° C. for 20 hrs. This was washed with CH2Cl2, and the aqueous phase basified with dilute NH4OH and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and concentrated to provide 210 mg (0.91 mmol, Yield 35%) of the title compound; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.10 (2H, s) 7.23–7.29 (1H, m) 7.53–7.60 (2H, m); LC/MS m/z 233 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:15][C:16]1[N:21]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (389 mg, 1.933 mmol) and 2,4-dichloropyrimidine (240 mg, 1.611 mmol) in N,N-dimethylformamide (6.4 mL) was added cesium carbonate (1050 mg, 3.22 mmol) and the mixture was heated at 80° C. for 1 hour and then to 70° C. overnight. The reaction was then cooled to ambient temperature, diluted with ethyl acetate, and washed with water (3×) and brine (1×). The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate/hexanes) to provide 410 mg (1.3 mmol, 81%) of tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as white solid. MS APCI: [M+H]+ m/z 314.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([C:24](O)=[O:25])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.O[NH:41][C:42](=[NH:44])[CH3:43].CCN(CC)CC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([C:24]4[O:25][N:44]=[C:42]([CH3:43])[N:41]=4)=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:34])[CH3:35])=[CH:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)NO
Reactant: CC(C)c1ccc(-c2nc3c(c(C(=O)O)nn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2nn(-c3ccccc3)c3nc(-c4ccc(C(C)C)cc4)n(-c4ccc(Cl)cc4)c(=O)c23)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (15 mg, 0.031 mmol) is treated with SOCl2 (0.5 mL) at 80° C. for 1 h. and cooled down to room temperature. SOCl2 is removed under vacuum and the residue is dissolved in anhydrous dichloromethane (0.5 mL). N-hydroxy-acetamidine (9 mg, 0.12 mmol) is added followed by Et3N (0.02 mL). The mixture is stirred at room temperature for 1 h and then poured into water (5 mL). The mixture is extracted with EtOAc(3×3 mL). After the combined extracts is concentrated and dried under vacuum for 5 h., the residue is dissolved in anhydrous dioxane (0.5 mL) followed by the addition of NaOAc (15 mg). The mixture is stirred at 80° C. for 24 h to complete the conversion. After cooling down to room temperature, the mixture is treated with water and extracted with EtOAc. The combined extracts is concentrated and the residue is purified by preparative LC/MS to provide the title compound 5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CDCl3) δ (ppm) 8.21(d, 2H), 7.54(t, 2H), 7.42(t, 1H), 7.32 (d, 2H), 7.29(d, 2H), 7.12(m, 4H), 2.87(m, 1H), 2.55(s, 3H), 1.20(d, 6H). HPLC-MS calculated C29H23ClN6O2 (M+1+): 523.2. Found: 523.2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccoc1C(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccoc1C(=O)Cl

Procedure:
3-Methyl-2-furancarbonyl chloride was prepared by refluxing 3-methyl-2-furancarboxylic acid (20.0 g) with thionyl chloride (25 ml) in toluene (75 ml) for 3 hours. After removal of the solvent, the acid chloride was distilled (b.p. 74°-76° C. at ca. 12 mm).
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:16][C:10]=3[C:9]([N+:21]([O-:23])=[O:22])=[CH:8][C:7]=2[N:6]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:5]1.O.Cl>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[Cl:2][CH2:3][CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([S:17]([NH2:1])(=[O:19])=[O:18])=[CH:16][C:10]=3[C:9]([N+:21]([O-:23])=[O:22])=[CH:8][C:7]=2[N:6]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:5]1
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: N
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Conc. aqueous NH3 (0, 32 mL, 4.7 mmol) was added to a solution of 116 (215 mg, 0.47 mmol) in THF (10 mL) at −78° C. After 10 min water (10 mL), aqueous HCl (2 N, 5 mL, 9.4 mmol), and EtOAc (20 mL) were added and the mixture was allowed to warm to room temperature. Brine was added and the mixture was extracted with EtOAc (×2). The combined extracts were washed with brine and dried, and the EtOAc solution was evaporated onto silica. Chromatography eluting with EtOAc/petroleum ether (1:10 then 1:3 then 2:1) gave 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-7-sulfonamide (123) (158 mg, 77%) as a pale yellow solid: mp (EtOAc) 274-278° C. (dec.); 1H NMR [(CD3)2SO] δ 9.11 (s, 1H), 8.89 (d, J=1.6 Hz, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.11 (dd, J=8.9, 1.7 Hz, 1H), 7.66 (s, 1H), 4.73-4.64 (m, 2H), 4.57-4.49 (m, 1H), 4.24-4.11 (m, 2H). Anal. (C15H11ClF3N3O5S) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[Br:9][CH2:10][CH2:11][OH:12]>>[BrH:9].[NH:8]=[C:4]1[N:3]([CH2:10][CH2:11][OH:12])[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]1
Reactant: Cc1nc(N)sc1C
Reactant: OCCBr
Product: Br
Product: Cc1sc(=N)n(CCO)c1C
Yield: 46.6 %

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (1.0 g, 7.8 mmol) and 2-bromoethanol (0.68 mL, 9.4 mmol) were processed as described in Example 8A to provide 0.92 g (47%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 2.19 (s, 6H), 3.61-3.68 (m, 2H), 4.03 (t, J=4.9 Hz, 2H), 5.14 (br s, 1H), 9.27 (s, 1H); MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A solution of methyl hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-propanoate (0.1 g, 0.27 mmol) in methanol (2 mL) was treated with aqueous sodium hydroxide (2M, 1 mL). After 2 hours at ambient temperature, the reaction was diluted with water, neutralized with 1 N hydrochloric acid, and extracted with n-butanol. The combined extracts were dried and concentrated to give 0.1 g of hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-propanoic acid; 1H NMR (300 MHz, CD3OD) δ 7.41 (d, 2H), 7.36 (dd, 2H), 7.34 (d, 2H), 7.29 (dd, 1H), 6.98 (d, 2H), 5.05 (s, 2H), 3.81 (s, 2H), 3.25 (m, 2H), 3.23 (m, 2H), 3.20 (t, 2H), 3.00 (m, 2H), 2.91 (m, 2H), 2.56 (t, 2H), 2.02 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Cc1nnc(S)s1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(C)s3)C(=O)O)cc2)cc1

Procedure:
Example 31 is prepared from 5-methyl-1,3,4-thiadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.O1CCCC1>[Pd](Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(C)(C)CC2=O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)OC(C)(C)C=C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
A mixture of 2.1 g (10 millimoles) of 7-methoxy-2,2-dimethyl-4-chromanone, 50 ml of tetrahydrofuran, 20 ml of water, 2.66 g (15 millimoles) of palladium chloride and 4.2 g (0,11 mole) of sodium tetrahydro borate is stirred at 0° C. for 20 minutes and thereafter at 5° C. for a further 4 hours. The reaction mixture is filtered, the filtrate extracted twice with 50 ml of chloroform each. The solvent is distilled off, the residue taken up in 50 ml of toluene and distilled in the presence of anhydrous potassium hydrogen sulfate for 20 minutes. The reaction having been completed the organic phase is washed twice with 20 ml of water each and the solvent is removed. The crude product is purified by column chromatography. Thus 1.75 g of the desired compound are obtained in the form of a colorless oil, yield 85%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 76 %

Procedure:
Following the procedure for Example 517 starting with (R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (0.148 g, 76%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (s, 1H), 7.95 (s, 1H), 7.43-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.57 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([C:14]([OH:16])=[O:15])=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[S:4][CH:3]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:6]2=[N:7][C:8]3[C:14](=[O:15])[O:16][C:11](=[O:13])[C:9]=3[CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: O=C(O)c1cc2scc(Cl)c2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3c(Cl)csc3cc21
Yield: 89 %

Procedure:
3-Chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid (1.45 g) is heated at 85° to 90° C. for 30 minutes then 90° to 102° C. for 30 minutes in acetic anhydride (7 mL). The reaction is cooled, the solids filtered off and washed with ether to give 1.2 g of 3-chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid anhydride. The proton magnetic resonance spectrum is consistant with the structure.
Reaction SMILES: [OH-].[K+].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH3:26]>CS(C)=O>[CH2:23]([N:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:13]=[C:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCn1cc(-c2ccc(OC)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Potassium hydroxide (4.36, 76 mmol, 1.3 eq.) is suspended in 40 ml of anhydrous DMSO, to the suspension is added a solution 2-phenyl-4-(4-methoxyphenyl)imidazole (15.02, 60 mmol) and bromobutane (8.63 g, 63 mmol, 1.05 eq.) in 80 ml of DMSO at room temperature over 2 h, the resulting mixture is stirred over 24 h, and then poured into 400 ml of ice-water, extracted with ethyl acetate (100 ml×4), washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified through flash chromatography to give 16.73 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole. MS (+VE) m/z 307 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([OH:20])=O)=[CH:15][C:14]=2[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:41]2>C1COCC1.C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:41]4)=[O:20])=[CH:15][C:14]=2[CH:21]=1
Reactant: O=C(O)c1cc2cc(CSSc3ccccn3)ccc2o1
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2cc(NC(=O)c3cc4cc(CSSc5ccccn5)ccc4o3)ccc2[nH]1
Reaction time: 8 h

Procedure:
A stirred solution of 15 (247 mg, 0.78 mmol) in 30 mL dry THF at room temperature under argon, was treated sequentially with solutions of dicyclohexylcarbodiimide (177 mg, 0.86 mmol) in 5 mL methylene chloride, 4-(dimethylamino)pyridine (29 mg, 0.23 mmol) in 2 mL methylene chloride, and 10 (200 mg, 0.86 mmol) in 5 mL methylene chloride. The reaction mixture was stirred overnight. Dicyclohexylurea was filtered from the reaction mixture, and the filtrate was washed with water, cold 0.1M HCl, saturated aqueous sodium bicarbonate, and water. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a dark oil. The crude product was further purified by chromatography on a silica gel column, eluting with ethyl acetate:hexanes to give 16 as an off-white solid: NMR (acetone-d6) δ 1.6 (s, 9H), δ 4.3 (s, 2H), δ 7.0-8.6 (m, 12H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:31])[C@@H:17]([NH2:30])[CH2:18][O:19][P:20]([O:23][CH2:24][CH2:25][N+:26]([CH3:29])([CH3:28])[CH3:27])([O-:22])=[O:21].[C:32]([N:36]=[C:37]=[S:38])(C)(C)[CH3:33].C(=O)(O)[O-].[Na+]>CO.O.ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:31])[C@@H:17]([NH2:30])[CH2:18][O:19][P:20]([O:23][CH2:24][CH2:25][N+:26]([CH3:27])([CH3:29])[CH3:28])([O-:22])=[O:21].[CH2:32]([NH:36][C:37]([NH2:26])=[S:38])[CH3:33]
Reactant: CC(C)(C)N=C=S
Agent: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)COP(=O)([O-])OCC[N+](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCNC(N)=S
Reaction time: 0.17 h

Procedure:
100 mg of sphingosylphosphorylcholine were dissolved in 10 ml methanol:water, 2:1, in a 25 ml Erlenmeyer flask. To the stirred solution were added 100 mg of tertiary butyl isothiocyanate. The solution was stirred for 10 min, then 2.5 ml of 1N sodium bicarbonate were added. The solution was left to stir for 48 hours, transferred to a separatory funnel and 80 ml dichloromethane, 30 ml methanol and 40 ml water were added. The organic phase was washed with 40 ml of water, then dried over MgSO4, filtered and evaporated to dryness. The compound was purified by preparative TLC using dichloromethane:methanol:water, 65:35:5 for development. The silica spot containing the product was viewed by an ultraviolet lamp, scraped and eluted with dichloromethane: methanol:water, 1:2:1, in a small column. Yield: 80 mg; M.S. Na+=574.