Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[CH2:25][N:26]1[CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:29]3[CH:30]4[CH:35]([CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]([CH2:25][C:24]([F:36])([F:37])[F:23])[CH2:27][CH2:28]3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: FC(F)(F)CN1CCNC2CCCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCN(CC(F)(F)F)C2CCCCC21
Reaction time: 24 h
Yield: 12.2 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.080 g, 0.41 mmol) was suspended in acetonitrile (2 mL) then DIPEA (0.158 mL, 0.90 mmol) and 1-(2,2,2-trifluoro-ethyl)-decahydro-quinoxaline (0.119 g, 0.54 mmol) were added followed by HATU (0.192 g, 0.50 mmol). The resulting mixture was stirred for about 24 hours and then further amounts of DIPEA (79 μL) and HATU (0.192 g) were added and stirring continued over the weekend. The mixture was evaporated and the residue was taken up in sodium hydroxide (1 N) and stirred for 30 minutes. HCl (1 N, 2.5 mL) was added and the solution extracted with ethyl acetate (×3). The organics were dried over sodium sulfate, filtered and evaporated. The material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) and the fractions containing the desired product were combined and freeze-dried to give the title compound as a white solid (0.020 g). LCMS m/z 399.17 [M+H]+ R.T.=10.05 min (Analytical Method 2).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][C@@H:2]1[N:7]([C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Reaction time: 3 h
Yield: 83 %

Procedure:
3-Methyl-(3S)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (250 mg), benzeneacetic acid (210 mg) and Hunigs base (450 □l) were dissolved in DMF (10 ml) and HATU (720 mg) added portionwise over 2 min. The reaction mixture was stirred for 3 h, diluted with EtOAc, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica with 25% EtOAc/isohexane as eluent to give the sub-title compound (330 mg)
Reaction SMILES: [I-:1].[CH:2]1[C:15]2[C:6](=[S+:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24].[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(Cl)(Cl)Cl.CO>[I-:1].[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:4]1[CH:3]=[CH:2][C:15]2[C:6]([CH:5]=1)=[S+:7][C:8]1[C:13](=[CH:12][CH:11]=[C:10]([N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)[CH:9]=1)[N:14]=2
Reactant: c1ccc2[s+]c3ccccc3nc2c1
Reactant: COCCNCCOC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCCN(CCOC)c1ccc2nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenothiazin-5-ium iodide (400 mg, 0.567 mmol) was dissolved in CHCl3 (20 mL) and bis(2-methoxyethyl)amine (0.17 mL, 1.13 mmol) was added dropwise. The mixture was stirred at RT overnight. The solvent was removed and the material was used without purification. The salt (200 mg, 0.281 mol) was dissolved in MeOH (20 mL) and a solution of N-Boc piperazine (105 mg, 0.562 mmol) was added. The mixture was stirred for 24 hrs and the solvent was removed by evaporation. The crude material was purified by flash silica gel chromatography to give a dark blue solid of the desired product.
Reaction SMILES: [N-]1C=CN=C1.[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:35])=[C:16]([N:20]4[CH2:24][CH:23]=[C:22]([CH2:25][N:26](C(OC(C)(C)C)=O)[CH3:27])[CH2:21]4)[C:17]=3[Cl:19])[C:12](=[O:36])[C:11]([C:37](O)=[O:38])=[CH:10]2)[CH2:8][CH2:7]1.[C:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])#[N:41]>>[ClH:19].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:35])=[C:16]([N:20]4[CH2:24][CH:23]=[C:22]([CH2:25][NH:26][CH3:27])[CH2:21]4)[C:17]=3[Cl:19])[C:12](=[O:36])[C:11]([C:37](=[O:38])[CH:42]([C:40]#[N:41])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:10]2)[CH2:8][CH2:7]1
Reactant: CN(CC1=CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC#N
Agent: c1c[n-]cn1
Product: CCOC(=O)C(C#N)C(=O)c1cn(C2CC2)c2c(Cl)c(N3CC=C(CNC)C3)c(F)cc2c1=O
Product: Cl
Yield: 103.1 %

Procedure:
5.8 g of 1-cyclopropyl-6-fluoro-8-chloro-7-(3-(N-methyl-t-butoxycarbonylamino)methyl-2,5-dihydropyrrol-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid imidazolide and 5.66 g of ethyl cyanoacetate as starting materials were subjected to the same process as described in Example 39 to obtain 2.80 g of the object compound
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2ccccc2-c2ccccc2)n1
Yield: 65 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 2-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (238 mg). Yield: 65%. 1H NMR (250 MHz, DMSO-d6) δ 7.31-7.61 (m, 9H, Harom), 8.43 (s, 1H, HPz 5), 8.46 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(Br)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Br)cc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 53 %

Procedure:
N-(1-ethoxy-ethylidene)-4-bromo-benzamide 565 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-bromo-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (437 mg, yield: 53%) was obtained as a solid phase.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[O:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C>[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:41][N:40]=2)=[O:43])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: Fc1ccc(F)c(OC2CCNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)C1)c1cc(-c2ccccc2)on1
Reaction time: 0.03 h
Yield: 35.4 %

Procedure:
DIPEA (153.5 mg, 1.2 mmol) followed by HOBt (44.1 mg, 0.32 mmol) and EDCI (113.8 mg, 0.59 mmol) were added to a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (73.4 mg, 0.29 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(2,5-difluoro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (70 mg, 0.29 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 50% EtOAc in hexane) afforded 45 mg (35.4% Yield) of 5-phenyl-isoxazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 428, 91.77%. 1H NMR (300 MHz, DMSO-d6): δ 8.8-8.68 (m, 1H), 8.0-7.9 (m, 2H), 7.6-7.5 (m, 3H), 7.4 (s, 1H), 7.34-7.2 (m, 2H), 6.9-6.75 (m, 1H), 5.3-5.0 (m, 2H), 4.2-4.0 (m, 2H), 3.9 (m, 1H), 3.8-3.7 (m, 1H), 3.7-3.5 (m, 2H), 2.3-2.2 (m, 1H), 2.1 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[CH3:33][C:34]1[CH:35]=[CH:36][C:37](B(O)O)=[C:38]2[C:43]=1[N:42]=[CH:41][CH:40]=[CH:39]2.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:37]2[CH:36]=[CH:35][C:34]([CH3:33])=[C:43]3[C:38]=2[CH:39]=[CH:40][CH:41]=[N:42]3)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Reactant: Cc1ccc(B(O)O)c2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2csc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)c2cccnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (7), (8-methyl-5-quinolyl)boronic acid (48), Tetrakis(triphenylphosphine)palladium(0), and sodium carbonate, were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70° C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, triturated in methanol, centrifuged, decanted and the resulting solid was dried under vacuum and treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 49A as a white powder (18.1 mg, 31%). 1H NMR (500 MHz, DMSO d6) δ=12.93 (br, 1H), 12.60 (s, 1H), 8.94 (m, 1H), 8.01 (d, 1H), 7.89 (s, 1H), 7.87 (d, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.57 (t, 1H), 7.54 (dd, 1H), 7.44-7.41 (m, 3H), 7.11 (s, 1H), 2.76 (s, 3H) ppm. ESI MS [M+H] 429.22.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:42])[CH:38]=[CH:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:42])/[CH:38]=[CH:39]/[CH2:40][CH3:41]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCC=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C=C/C(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 100 mg (1 mmole) of n-pentenoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 95 mg (Yield: 23%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][CH3:10])(=O)=O.[F:15][C:16]([F:26])([F:25])[CH2:17][CH2:18][S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:14][C:11]([F:12])([F:13])[CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][CH:22]([S:19]([CH2:18][CH2:17][C:16]([F:26])([F:15])[F:25])(=[O:21])=[O:20])[C:23]#[N:24]
Reactant: CCC(CCOS(C)(=O)=O)C(F)(F)F
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCC(C#N)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a solution of 3.0 g of 3-(trifluoromethyl)pentyl methanesulfonate and 2.6 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 50 ml of dimethyl sulfoxide was added 1.8 g of potassium carbonate at room temperature, heated to 60° C. and then stirred at the same temperature for 3 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 3.00 g of 5-(trifluoromethyl)-2-(3,3,3-trifluoropropylsulfonyl)heptanenitrile (hereinafter referred to as the present compound (14)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:14](=[O:16])[O:13][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[NH:15][C:14](=[O:16])[O:13][C:8]4([CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCC2)O1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C2(CCCC2)O1

Procedure:
Prepared from 6-bromo-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2-(1H)-one and 3-chlorophenyl boronic acid according to Procedure A. Off-white solid: mp 140-145° C. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.75 (t, 1H, J=1.8 Hz), 7.53-7.63 (m, 3H), 7.44 (t, 1H, J=7.9 Hz), 7.36 (m, 1H), 6.95 (d, 1H, J=8.6 Hz), 2.09-2.15 (m, 4H), 1.81-1.89 (m, 4H). MS (ESI) m/z 314 [M+H]+. Anal. Calc. For C18H16ClNO2: C, 68.90; H, 5.14; N, 4.46. Found: C, 60.94; H, 4.94; N, 3.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([CH3:17])=[N:10]2)=[CH:5][CH:4]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CS(C)=O>[CH:18]1([NH:24][C:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(-n2nc(C)cc2C(=O)O)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(-n2nc(C)cc2C(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2-(4-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (752 mg, 3.24 mmol) was suspended in methylene chloride (25 mL) and DMSO (3 drops) was added. After the reaction was stirred at room temperature for 1 hour, it was concentrated in vacuo. The residue was diluted twice with methylene chloride (60 mL) and concentrated to dryness. The residue was diluted again with methylene chloride (45 mL), cyclohexylamine (650 μL, 5.68 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted further with methylene chloride, washed with NaOH (10%) and 1 N HCl, then dried over Na2SO4. Concentration gave 630 mg of the title compound, which was used in the next reaction without further purification. LC-MS (C18H23N3O2 calculated 313) m/z 314 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18](=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccc([N+](=O)[O-])c2)c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
The reaction of hydroxylamine 82 (0.71 g, 2 mmol) with 3-nitrobenzaldehyde (57) (0.302 g, 2 mmol) afforded, after workup, a light yellow solid. The crude product was recrystallized from ethyl acetate/petroleum ether to obtain 0.71 g (1.44 mmol. 72%) of 83 as a light yellow crystalline solid: mp 149°-151° C.; IR (CH2Cl2) 3440, 2980, 1700, 1622, 1552, 1535, 1475, 1355, 1300, 1215, 1100, 1018, 810 cm-1 ; 1H NMR (CDCl3) δ 1.14 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.2 Hz, 3H), 2.30 (s, 6H), 3.64 (s, 3H), 4.97 (septet, J=6.2 Hz, 1H), 5.08 (s, 1H), 6.37 (s, 1H), 7.32-9.29 (m, 9H); 13C NMR (CDCl3) δ 19.78, 22.47, 22.70, 40.51, 51.58, 67.81, 103.27, 103.99, 119.82, 121.99, 123.79, 125.43, 129.16, 130.24, 131.05, 132.75, 132.94, 134.75, 145.57, 146.11, 148.91, 149.20, 150.56, 167.59, 168.60. Anal. Calcd for C26H27N3O7 : C, 63.28; H, 5.47. Found: C, 63.49; H, 5.47.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: Fc1ccccn1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccccn2)CC1

Procedure:
A stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.15 g, 0.61 mmol, Example 30B) and 2-fluoropyridine (0.3 mL, 3.5 mmol) was heated to 175° C. under microwave conditions for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 20% to 35% ethyl acetate in hexane) to provide (4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 326(M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.06 (dd 1H), 7.52 (m, 1H), 7.37-7.26 (m, 5H), 6.80 (d, 1H), 6.62 (t, 1H), 5.04 (s, 2H), 4.84 (s, 1H), 3.78 (m, 2H), 3.25-3.16 (m, 2H), 2.08 (m, 2H), 1.64-1.55 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH:16]=[O:17])[CH2:15][CH:6]2[CH2:7][N:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH2:9][CH:5]2[CH2:4]1)[CH3:2].O.O.P([O-])(O)(O)=[O:21].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:1]([C:3]1([C:16]([OH:21])=[O:17])[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:11])[N:12]([CH3:13])[CH3:14])[CH2:9][CH:5]2[CH2:4]1)[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCC1(C=O)CC2CN(C(=O)N(C)C)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(C(=O)O)CC2CN(C(=O)N(C)C)CC2C1
Yield: 99.7 %

Procedure:
5-Ethyl-5-formyl-N,N-dimethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19b (0.4 g, 1.68 mmol) was dissolved in the solvent mixture of 18 mL of tetrahydrofuran and 9 mL of water, followed by addition of sodium dihydrogenphosphate dihydrate (787 mg, 5.04 mmol), sodium chlorite (0.454 g, 5.04 mmol) and 2-methyl-2-butene (354 mg, 5.06 mmol) at 0° C. The reaction mixture was reacted at 0° C. for 2 hours under nitrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.426 g, yield 100%) as a yellow solid which was directly used in the next step.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][SH:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:12][CH2:11][CH2:10][N:9]([CH3:13])[CH3:8])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CN(C)CCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 18.7 %

Procedure:
To sodium hydride (600 mg, 15 mmol 60% in mineral oil) were added DMF (10 ml), 2-dimethylaminoethanethiol (1.3 g, 9.2 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred at 100° C. for 10 hours. After addition of saturated brine the reaction mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (10% methanol/chloroform) to give the subject compound (24 mg, yield 21%).
Reaction SMILES: FC1C=C(C=CC=1)[O:5]C1N=C(CO)C=CC=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18].C(N(CC)CC)C>CCOCC>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:20]([CH:17]([CH3:19])[CH3:18])[C:21]([OH:5])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: OCc1cccc(Oc2cccc(F)c2)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.8 grams (0.0078 mole) of cyano(6-(3-fluorophenoxy)-2-pyridine methanol and 2.4 grams (0.0098 mole) of 2-isopropyl-2-(4-chlorophenyl)acetic acid chloride in 50 milliliters of anhydrous ether was added 3 milliliters of triethylamine. A white precipitate separated out immediately. The reaction mixture was stirred at room temperature for one-half (1/2) hour. The mixture was successively washed with water, dilute hydrochloric acid, dilute sodium hydroxide, dilute sodium bicarbonate, dilute hydrochloric acid and water and thereafter dried over anhydrous magnesium sulfate and concentrated under vacuo to give 3.6 grams of 4-chloro-α-(1-methylethyl)benzeneacetic acid:cyano(6-(3-fluorophenoxy)-2-pyridinyl)methyl ester product as a viscous yellow oil having a refractive index of n(25/D)=1.5560. The structure of the product was confirmed by its nuclear magnetic resonance spectrum (NMR). In addition, upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 65.52, 4.74 and 6.18 percent, respectively, as compared with theoretical contents of 65.66, 4.59 and 6.38 percent, respectively, as calculated for the above-named compound (Compound No. 3).