Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=O)(=[O:12])=[O:11])([O-])=O.B>O1CCCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][CH:23]1[CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])(=[O:12])=[O:11]
Reactant: O=C(NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C1CCc2ccccc2C1
Agent: B
Solvent: C1CCOC1
Product: Nc1ccccc1S(=O)(=O)NCCCCCCNCC1CCc2ccccc2C1
Yield: 76 %

Procedure:
To a solution of 1, 2, 3, 4-tetrahydro-2-naphthalencarboxylic acid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide (0.090 g, 0.19 mmol) in tetrahydrofuran (5 mL) cooled to 0° C. was added 2 mL 1M solution of borane:THF complex and the reaction mixture was refluxed for 12 h. The reaction mixture was cooled in an ice bath and quenched with 2 mL of 1N HCl. The reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (3×25 mL). The organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford an oil which was purified by preparative TLC to afford the titled compound (0.06 g,70%); hydrochloride salt mp (162-163° C.).
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]4[C:18]5([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)[C:17](=[O:31])[NH:16][C:13]4=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([C:47]([F:50])([F:49])[F:48])[C:43]([NH2:46])=[N:44][CH:45]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]2([C:12]3[C:13](=[CH:14][CH:15]=[C:10]([C:7]4[S:6][C:5]5=[N:4][CH:3]=[C:2]([C:40]6[CH:41]=[C:42]([C:47]([F:50])([F:49])[F:48])[C:43]([NH2:46])=[N:44][CH:45]=6)[N:9]5[N:8]=4)[CH:11]=3)[NH:16][C:17]2=[O:31])[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccc(-c3nn4c(I)cnc4s3)cc12
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccc(-c3nn4c(-c5cnc(N)c(C(F)(F)F)c5)cnc4s3)cc12
Temperature: 120 °C
Yield: 40.6 %

Procedure:
A mixture of 5-Iodo-2-(1′-(tert-butoxycarbonyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-yl)-imidazo[2,1-b][1,3,4]thiadiazole (46 mg, 0.082 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (31 mg, 0.106 mmol), PdCl2(dppf) (13 mg, 0.016 mmol) and sat Na2CO3 (0.41 mL) in DME (0.82 mL) was heated under microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with DCM and washed with H2O. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (Isolute/Flash, Sill, 0% to 5% MeOH in DCM) to give the desired product (19.5 mg, 41%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.77 min, [M+H]+ m/z 586.2; 1H NMR (300 MHz, DMSO) δ 10.90 (s, 1H), 8.87 (d, J=1.8 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.83 (dd, J=8.1, 1.7 Hz, 1H), 7.77 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.72 (s, 2H), 3.71 (s, 4H), 1.77 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].[OH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:27]([C:24]2[N:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)=[O:28])[CH2:16][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)c2ccc(O)cn2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 52.1 %

Procedure:
A mixture of 1-(2-tert-butyl-4-chlorophenyl)piperazine dihydrochloride (Reference Example 20, 0.50 g, 1.54 mmol), 5-hydroxypyridine-2-carboxylic acid (0.26 g, 1.84 mmol), triethylamine (644 μL, 4.62 mmol), EDCI (0.29 g, 1.84 mmol) and HOBt (0.28 g, 1.84 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 days. The reaction mixture was added to saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100) to give the title compound (0.30 g, 52%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[N+:23]([O-])=O>C(O)C.[Pt]=O>[CH3:1][N:2]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(c1ccccc1)c1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CN(c1ccccc1)c1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A suspension of N-methyl-5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.5 g, 1.2 mmol), and platinum oxide (25 mg, 5%) in 20 ml ethanol was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered with the aid of celite. (4-(3-(N-methyl-N-phenylamino)-4-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.42 g, 90%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.98 (d, br, 4H), 3.24 (s, 3H), 3.58 (s, br, 2H), 3.63 (s, br, 2H), 3.94 (s, br, 2H), 6.68 (d, J=7.9 Hz, 2H), 6.73 (d, J=2.2 Hz, 1H), 6.82 (m, 3H), 7.23 (m, 2H), 7.45 (s, 5H). 13C NMR (125 MHz, CDCl3): δ (ppm) 39.1, 51.8, 113.9, 117.4, 117.8, 118.1, 118.2, 129.0, 129.6, 127.6, 130.2, 135.3, 136.2, 138.8, 145.2, 149.2, 170.8.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2F)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2F)c1OC
Yield: 85 %

Procedure:
Sodium hydride (50%, 1 g), ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetate (7 g) and methyl iodide (4.14 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionate (6.2 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc2nc(Br)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(Br)cnc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
2-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine (0.300 g, 1.41 mmol) was dissolved in DMF (5 mL) and cooled down to 0° C. NaH (60%, 68 mg, 1.70 mmol) was added slowly. After the addition was complete stirring was continued for 30 minutes at 0° C. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.30 mL, 1.70 mmol) was added and the reaction mixture was allowed to warm up overnight. The reaction was quenched with H2O. The aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (40 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 340 mg of 2-bromo-6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a yellow liquid (70% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[N:11]=[C:10]2[O:24][CH3:25])=[C:4]([F:26])[CH:3]=1.[CH3:27][O:28][CH2:29]Cl.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:27][O:28][CH3:29])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:22])([F:23])[C:18]([F:19])([F:21])[F:20])[N:11]=[C:10]2[O:24][CH3:25])=[C:4]([F:26])[CH:3]=1
Reactant: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and chlorodimethyl ether with sodium hydride in dimethylformamide there is obtained 1-(4-chloro-2-fluoro-5 -methoxymethoxy-phenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR CDCl3, 400 MHz): 7.34 ppm (d,1H), 7.13 ppm (d,1H), 5.22 ppm (q,2H), 3.98 ppm (s,3H), 3.52 ppm (s,3H);
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH:20]=1)=O)(C)(C)C.[ClH:36].CCOCC>CO>[ClH:36].[O:29]([CH2:28][CH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:19]2[CH:18]=[N:17][CH:16]=[C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:20]=2)[CH2:22][CH2:23]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOc3ccccc3)CC2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc(OCCC2CCN(c3cncc(OC[C@@H]4CCCN4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-(2-phenoxyethyl)-1-piperidinyl]pyridine (150 mg, 0.31 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2 mL) under Ar at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water. The aqueous solution was washed twice with EtOAc, then filtered over a cotton plug. The water was removed under reduced pressure at 35° C., and the residue was purified by HPLC (ACE AQ 150×21.2 mm; UV detection at 254 and 280 nm; flow 10.0 mL/min; gradient of 0 to 50% CH3CN in water [both containing 0.05 vol % CF3COOH] in 25 min, to 100% in another 5 min; tR 13.6-19.7 min) to obtain, after evaporation, the trifluoroacetate (131 mg). This salt was treated with PL-HCO3 MP anion exchange resin (Polymer Laboratories) in MeOH. to afford the free amine. The solution was evaporated, and the residue was dissolved in MeOH (0.5 mL) and treated again with 2N anhydrous HCl/ether (2 mL) under Ar protection at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water. The solution was filtered over a cotton plug, and the water was removed under reduced pressure at 35° C. After lyophilization from water, the hydrochloride (117 mg) was obtained as a colorless solid. [α]20D+2.6 (c 6.9 g/L, MeOH). 1H NMR (D2O, 400 MHz) δ 7.59 (s, 1H), 7.13 (s, 1H), 6.92 (m, 2H), 6.57 (m, 3H), 4.22 (m, 1H), 4.08 (m, 1H), 3.88 (m, 1H), 3.60 (m, 2H), 3.41 (m, 2H), 3.18 (m, 2H, J=6.8 Hz), 2.52 (m, 2H), 2.04-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.78-1.62 (m, 1H), 1.43 (m, 2H), 1.31 (m, 3H), 0.93 (m, 2H). 13C NMR (D2O, 100 MHz) δ 157.9, 156.4, 148.5, 129.1, 121.2, 120.4, 117.2, 114.0, 67.3, 65.2, 58.0, 47.0, 45.5, 34.4, 31.1, 30.1, 25.4, 23.0. HRMS (ESI) calcd for C23H32N3O2 (M+H+) m/z 382.2495, found 382.2484. Anal. Calcd. for C23H31N3O2.2.2HCl.0.7H2O: C, 58.24; H, 7.35; N, 8.86; Cl, 16.44. Found: C, 58.36; H, 7.33; N, 8.80; Cl, 16.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH:38]=[O:39])[CH2:34][CH2:33]2)[C:26]=1[CH3:40])=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][N:32]2[CH2:33][CH2:34][N:35]([CH:38]=[O:39])[CH2:36][CH2:37]2)[C:26]=1[CH3:40])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(C=O)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(C=O)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (178 mg) was condensed with 4-(5-formyl-2,4-dimethyl-1H-pyrrol-3-ylmethyl)-piperazine-1-carbaldehyde (125 mg) using piperidine (cat. amount) in ethanol at 80° C. for 4 hours to give the titled compound.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.[NH2:21][C@@H:22]([C:26]([OH:28])=[O:27])[C@@H:23]([CH3:25])[OH:24].[OH-].[Na+]>C1(C)C=CC=CC=1.C(#N)C.C1COCC1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([NH:21][C@@H:22]([C:26]([OH:28])=[O:27])[C@@H:23]([CH3:25])[OH:24])=[O:14])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](C(=O)N[C@@H](C(=O)O)[C@@H](C)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-4-pentylcyclohexane carboxylic acid (198 mg, 1.0 mmol) in dry toluene (1 mL) is treated with oxalyl chloride (760 mg, 5.9 mmol) at 0° C. and the mixture is stirred for 2 h at the same temperature and 1 h at room temperature. Excess reagent is removed in vacuo. A solution of the crude acid chloride in dry acetonitrile (2 mL) is added to a mixture of D-allo-Thr (100 mg, 0.85 mmol), 2N aq. NaOH (600 μl, 1.20 meq) and TEA (85 mg, 0.85 mmol) in THF (1.5 mL), following the procedure described in Example 1. The crude product 2c-6 is purified by chromatography (1.5×18 cm column, 5% CH3OH and 0.4% HOAc in CH2Cl2): NMR δ 0.88 (t, J≃7, 3 H), 4.15 (m, 1 H), 4.54 (m, 1 H), 6.49 (d, 1H); MS (CI, CH4) m/z 300 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Reactant: Clc1cccc(Cl)n1
Product: Cc1nn(C)c(Oc2cccc(Cl)n2)c1Sc1ccccc1Cl
Yield: 27.3 %

Procedure:
A mixture of 1.1 g (4 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole and 5.0 g (34 mmol) of 2,6-dichloropyridine was refluxed with heating for 20 hours. After completing the reaction, the reaction mixture was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (2:1 v/v)) to give 0.40 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(6-chloropyridine-2-yloxy)pyrazole.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH:4]1[C:9]2[C:10]3[C:21](=O)[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[O:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11](=[O:12])[C:10]=2[C:9]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:13]1=[O:14])[CH3:2]
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: CCN
Solvent: ClC(Cl)Cl
Product: CCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Ethylamine (0.2 mL, 3 mmol) was added to a stirred solution of benz[d]indeno[1,2-b]pyran-5, 11-dione (2) (0.49 g, 2 mmol) in CHCl3 (10 mL). The bright orange mixture stirred overnight. To the reaction mixture CHCl3 (100 mL) was added and the mixture washed with H2O (3×25 mL) and brine (1×25 mL), dried (MgSO4), and concentrated under reduced pressure to give an orange-red solid (0.43 g, 75%): mp 188-189° C.; IR (thin film) 2986, 1690, 1656, 1611, 1549, 1503, 1430, 1320, 1197, 991 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ8.66 (d, 1H, J=8.3 Hz), 8.32 (d, 1H, J=7.9 Hz), 7.69 (dt, 1H, J=8.4, 1.4 Hz), 7.60 (dd, 1H, J=8.0, 1.4 Hz), 7.52 (d, 1H, J=6.9 Hz), 7.40 (m, 3H), 4.56 (q, 2H, J=7.2 Hz), 1.53 (t, 3H, J=7.2 Hz); CIMS, m/z (relative intensity) 276 (MH+, 100). Anal. Calcd for C18H13NO2: C, H, N.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].[CH3:26][S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CC(O)(C)C.O>[CH3:25][C@@H:3]1[C@H:2]([O:1][CH2:31][CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4]1
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCS(C)(=O)=O
Temperature: 22 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
A mixture of (+/−)-Tert-butyl (1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.), methylsulfonylethene (30.0 equiv.) and CESIUM CARBONATE (1.2 equiv.) in t-BuOH (0.22 M) was stirred at 22° C. for 5 hrs. The reaction was cooled to room temperature, followed by the addition of NaHCO3(aq.) and water. The mixture was extracted with EtOAc and the combined organics were dried over MgSO4, filtered, and concentrated. The sample was purified by ISCO chromatography to yield (+/−)-tert-butyl (1R,5S,6S)-5-methyl-6-(2-(methylsulfonyl)ethoxy)-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate in 84% yield. LC/MS (m/z)=456.2 (MH+), Rt=0.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.60 Hz, 3H), 1.47 (s, 9H), 1.92-2.16 (m, 2H), 2.17-2.32 (m, 1H), 2.93-3.00 (m, 1H), 3.09 (s, 3H), 3.18 (d, J=14.87 Hz, 1H), 3.38-3.52 (m, 1H), 3.63 (d, J=2.40 Hz, 1H), 3.95-4.06 (m, 1H), 4.21 (td, J=9.84, 2.42 Hz, 1H), 4.56 (d, J=7.58 Hz, 1H), 5.58 (br. s., 1H), 5.66 (d, J=9.44 Hz, 1H), 7.20 (d, J=4.99 Hz, 1H), 8.73 (d, J=4.99 Hz, 1H), 9.05 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:19]I>CN(C)C=O>[CH:3]1([N:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)[CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1ccc(NC2CCCCC2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CCCCC1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.38 g, 9.48 mmol) was washed 3× with hexanes then a solution of 2-cyclohexylamino-5-nitropyridine (1.88 g, 8.5 mmol) dissolved in dimethylformamide (20 mL) was added. After stirring for 30 minutes at 22° C., the reaction mixture was cooled to 0° C. and methyl iodide (0.55 mL, 8.9 mmol) was added. The solution was stirred for 1.5 hours at 0° C. followed by quenching with saturated aqueous NH4Cl. The reaction mixture was diluted with ethyl acetate and extracted 5× with water (200 mL), saturated NaCl, dried over Na2SO4 and concentrated in vacuo oil was chromatographed on SiO2 using 2:1 hexanes/ethyl acetate as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:22]([CH:26]=1)[C:23]([NH2:25])=[O:24]>>[C:23]([C:22]1[CH:26]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:27]1[CH2:28][CH2:29][CH:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:32]1)(=[O:24])[NH2:25]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: NC(=O)c1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C(N)=O)c2)cnn1-c1ccc(Cl)cc1
Yield: 21.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzamide (2.5 g), the title compound (0.94 g) was obtained, melting point: 270° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+]>O>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: Nc1ccccc1SCc1ncon1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccccc1SCc1ncon1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
A mixture of 3-(2-aminophenylthiomethyl)1,2,4-oxadiazole (4.14 g), 4-chlorobenzoyl chloride (3.68 g), sodium hydroxide (0.8 g) and water (15 ml) was stirred at 25° for 4 hours. Crude product was recovered by filtration and crystallised from ethanol to give 3-[2-(4-chlorobenzamido)phenylthiomethyl]-1,2,4-oxadiazole, m.p. 103°.
Reaction SMILES: CCN[C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:5].C1([C@@]2(N3C4N=CN=C(N)C=4N=C3)O[C@H](CO)[C@@H](O)[C@H]2O)CCCCC1.[Mg+2].[Cl-].[Cl-]>>[C@@H:9]1([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:4][OH:5])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: Nc1ncnc2c1ncn2[C@]1(C2CCCCC2)O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cl-]
Agent: [Mg+2]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Incubation tubes, in triplicate, receive 100 μl of [3H]NECA (94 nM in the assay), 100 μl l of 1 μM cyclohexyladenosine (CHA), 100 μl of 100 mM MgCl2, 100 μl of 1 IU/ml
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:19]C(=O)C)([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[CH2:7][CH2:8][CH3:9])(=O)C.[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[ClH:32].NC(CCC1C=CC=CC=1OCCCCCCC)(CCC)CO>>[ClH:32].[NH2:19][C:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=1)([CH2:7][CH2:8][CH3:9])[CH2:5][OH:4]
Reactant: CCCC(CCc1cccc(O)c1)(COC(C)=O)NC(C)=O
Reactant: CCCCCCCCBr
Agent: CCCCCCCOc1ccccc1CCC(N)(CO)CCC
Agent: Cl
Product: CCCCCCCCOc1cccc(CCC(N)(CO)CCC)c1

Procedure:
2-Acetamido-2-[2-(3-hydroxyphenyl)ethyl]pentyl acetate and octyl bromide were used in the same manner as working example 52 (9) and (10) to give the subject compound as a yellowish oily substance.