Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:21]([O:23]CC)=[O:22])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CCN(C)CC2)c2nc(C3CC3)cc(C(=O)O)c12
Temperature: 70 °C

Procedure:
To an EtOH solution (10 mL) of ethyl 6-cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (620 mg, 1.811 mmol) was added sodium hydroxide (5.43 mL, 5.43 mmol) and the mixture heated at 70° C. for 1 hour. The solvent was removed in vacuo and the residue was dissolved in 20 mL of water. The contents were acidifed with acetic acid, and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to afford a minor amount of product. The aqueous phase was concentrated in vacuo and the crude residue purified by reverse phase HPLC purification (eluent: 0% ACN/H2O, 0.1% TFA to 45% ACN/H2O, 0.1% TFA). The isolated solid product was concentrated from toluene to afford the final product as 510 mg (90%). LCMS E-S (M+H)=315.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=6.57 Hz, 4 H), 2.10 (d, J=13.14 Hz, 2 H), 2.30-2.42 (m, 3 H), 2.55 (s, 3 H), 2.77-2.92 (m, 3 H), 3.30 (br. s., 2 H), 3.57 (d, J=12.13 Hz, 2 H), 4.98 (m, J=11.78, 11.78, 3.85, 3.66 Hz, 1 H), 7.46 (s, 1 H), 9.87 (br. s., 1 H).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](C2CO2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CS(C)=O.C(OCC)(=O)C>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:7]([OH:10])[CH2:8][O:9][CH2:1][CH2:2][OH:4])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: OCCO
Reactant: c1ccc(COc2ccc(C3CO3)cc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCOCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
9.5 g of potassium tert-butoxide was added to 92 ml of ethylene glycol. The mixture was heated to 80° C. Thereto was dropwise added, in 3 hours, a solution of 34.7 g of 2-(4-benzyloxyphenyl)oxirane dissolved in 220 ml of dimethyl sulfoxide. The resulting mixture was stirred for 30 minutes at the same temperature. The reaction mixture was cooled and added to a mixture of 1 liter of ice water and 600 ml of ethyl acetate. The resulting mixture was adjusted to pH 7 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 200 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1) to obtain 25 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([C:22]#[N:23])=[C:9]([S:20][CH3:21])[S:10][C:11]=2[C:12](=O)[C:13]([CH3:18])=[CH:14]N(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(OC)OC)C.[N+:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]([NH2:44])=[NH:43])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>C1(C)C=CC=CC=1.CCOC(C)=O.CN(C=O)C>[N+:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]2[N:44]=[C:12]([C:11]3[S:10][C:9]([S:20][CH3:21])=[C:8]([C:22]#[N:23])[C:7]=3[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]([CH3:18])=[CH:14][N:43]=2)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: CSc1sc(C(=O)C(C)=CN(C)C)c(C2CCCCC2)c1C#N
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1sc(-c2nc(Nc3cccc([N+](=O)[O-])c3)ncc2C)c(C2CCCCC2)c1C#N
Temperature: 90 °C
Yield: 42 %

Procedure:
To a solution of 4-cyclohexyl-5-(3-dimethylamino-2-methyl-acryloyl)-2-methylsulfanyl-thiophene-3-carbonitrile (0.5 g, 1.7 mmol) in toluene (3 ml) was added DMF-DMA and the reaction was heated at 90° C. overnight resulting in conversion to product as determined by TLC (40% EtOAc:hexanes). The crude product was combined with DMF (10 ml) and 3-nitrophenylguanidine (0.5 g, 2.78 mmol) in a sealed tube and heated at 120° C. overnight resulting in conversion to product as determined by TLC (40% EtOAc:hexanes). The reaction was partitioned between EtOAc and water, the organics were dried over sodium sulfate then concentrated in vacuo. The crude product was purified by chromatography (silica gel, 10% EtOAC:hexanes) to afford 0.334 g (3.05 umol) of V-7 in 42% yield for 2 steps. 1H NMR (CDCl3) δ 1.0–2.0 (m, 10H), 2.1 (s, 3H), 2.6 (s, 3H), 7.4 (m, 1H), 7.7 (d, 1H), 7.8 (d, 1H), 8.3 (s, 1H), 8.7 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](O)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].S(Cl)([Cl:32])=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14]([Cl:32])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: COCCOCC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 800 mg. of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetate was added (all at once) at 0° under N2 atmosphere, thionyl cloride (3 ml.) and the mixture was stirred at room temperature under N2 for 1 hour. The excess of thionyl chloride was removed in vacuo and the residue dissolved in dry benzene (10 ml.) and evaporated to dryness. There was obtained the title product (791 mg.) as a yellowish oil. nmr (CDCl3): δppm 2.9-3.9 (2H, m, H-3), 4.10 (3H, s, -OCH3), 3.5-3.9 (4H, m, -OCH2CH2O-), 4.24 (2H, s, O=C-CH2O-), 5.35-5.45 (2H, m, -CH2 -Ar), 5.70 (1H, m, H-4), 6.12 (1H, s, -CHCl), 7.52, 7.67, 8.21, 5.39 (4H, A2 ' B2 ', aromatic -H); ir (neat): 1780 cm-1 (broad, νc=o, β-lactam and ester), 1695 (νc=o, thioester), 1525 (νNO2).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1cccc(N)c1
Solvent: CC(C)=O
Product: C=CC(=O)Nc1cccc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Propenoyl chloride from Aldrich Chemical Company Ltd. (2.2 gm, 24.3 mMole) was added dropwise to an ice-cold solution of 3-aminobenzamide (5.0 gm, 36.8 mMole) in 30 ml of acetone. The mixture was stirred on ice for 30 minutes, and then the white precipitate was filtered off and washed with cold acetone and then with cold water to give 4.2 gm of white product. The product was crystallized from 25% aqueous dimethyl sulphoxide and the crystallized product had a melting point of 229° C. to 230° C. The overall yield was 44%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:28](=O)([O:37][CH2:38][CH:39]1[CH2:43][CH2:42][O:41][CH2:40]1)[O:29]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][N:20]([C:28]([O:37][CH2:38][C@H:39]5[CH2:43][CH2:42][O:41][CH2:40]5)=[O:29])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(OCC1CCOC1)ON1C(=O)CCC1=O
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: O=C(OC[C@H]1CCOC1)N1CCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 10 %

Procedure:
According to the procedure for compound 398 using 2,5-dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl)methyl carbonate (0.023 g, 0.096 mmol) afforded 5.7 mg (10% yield) of 484, as a trifluoroacetic acid salt after preparatory HPLC purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>ClCCl>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([F:16])[CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Solvent: ClCCl
Product: Cc1cn(-c2ccc(Nc3nc(C)cc(Cc4ccccc4)n3)cc2F)cn1
Yield: 86.2 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) and 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (88 mg, 0.57 mmol) using in analogous manner the procedure described in example 43b). Column chromatography (15 g silica, dichloromethane+3.7% methanol v/v) afforded the title compound (148 mg, 86%) as a white solid. MS ISP (m/e): 374.4 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.98 (dd, 1H), 7.65 (s, 1H), 7.26 (m, 8H), 6.92 (s, 1H), 6.53 (s, 1H), 3.98 (s, 2H), 2.38 8s, 3H), 2.31 (s, 3H). Mp 155-158° C.
Reaction SMILES: [NH+]12CC[NH+](CC1)C[CH2:2]2.OO.[N:11]12[CH2:18][CH2:17][N+:14]([O-:19])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.IC.[F:22][B-:23]([F:26])([F:25])[F:24].[Na+]>C1COCC1.C(#N)C>[F:22][B-:23]([F:26])([F:25])[F:24].[CH3:2][O:19][N+:14]12[CH2:17][CH2:18][N:11]([CH2:16][CH2:15]1)[CH2:12][CH2:13]2
Reactant: [O-][N+]12CCN(CC1)CC2
Reactant: C1C[NH+]2CC[NH+]1CC2
Agent: F[B-](F)(F)F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CI
Product: CO[N+]12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-fluoro-4-methoxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazoniabicyclo[2.2.2]octane N-oxide is prepared by the reaction of 1,4-Diazoniabicyclo[2.2.2]octane with hydrogen peroxide as described by Farkas in J. Chem. Eng. Data (1968) 13, 278. 1,4-Diazabicyclo[2.2.2]octane N-oxide (12.8 g, 10 mmol) in THF (100 mL) is reacted with iodomethane (14.1 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The filtrate is evaporated to afford 1-methoxy-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: [C:1]([C:3]([CH3:9])([CH3:8])[C:4]([NH:6][NH2:7])=O)#[N:2].CCN(CC)CC.Cl.[C:18](=[NH:27])(OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:8][C:3]([C:4]1[NH:6][N:7]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:27]=1)([CH3:9])[C:1]#[N:2]
Reactant: COC(=N)c1ccccc1
Reactant: CC(C)(C#N)C(=O)NN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1nc(-c2ccccc2)n[nH]1
Yield: 65 %

Procedure:
2-Cyano-2-methylpropanehydrazide (100 mg, 0.78 mmol) and Et3N (0.1 mL, 0.86 mmol) were added to a solution of methyl benzimidate hydrochloride (100 mg, 0.58 mmol) in dry MeOH (10 mL), and the mixture was heated to reflux for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluant 15% EtOAc in petroleum ether) to get 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile (80 mg, yield 51%). 1H NMR (300 MHz, MeOD) δ 7.98-7.95 (m, 2H), 7.52-7.50 (m, 3H), 1.82 (s, 6H). MS (ESI) m/z: Calculated for C12H12N4: 212.11. found: 213.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31](O)=[O:32])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:35]([N:38]([CH2:42][CH3:43])[CH:39]([CH3:41])[CH3:40])([CH3:37])C.[CH3:44][N:45](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:46].F[P-](F)(F)(F)(F)F>O1CCCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31]([N:45]3[CH2:46][CH2:40][CH:39]([N:38]4[CH2:35][CH2:37][CH2:43][CH2:42]4)[CH2:41][CH2:44]3)=[O:32])[CH:12]=2)[CH2:2][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)O)c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)N3CCC(N4CCCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of step iii) (0.1 g), 4-(N-pyrrolidin-1-yl)piperidine (0.037 g) and N,N-diisopropylethylamine (0.25 mL) in tetrahydrofuran (10 mL) was added HATU (0.17 g) and then stirred at room temperature for 3 hours. The reaction mixture was then concentrated to dryness and the crude product purified by HPLC to afford the title compound as a solid (0.07 g).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][OH:19])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C.CN(C)[CH:59]=[O:60]>O.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([O:60][CH3:59])=[O:19])=[O:9])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1CCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccccc1N(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-nitro-N-methyl-N-[2-(2-hydroxyethyl)phenyl]benzamide (686 mg) in N,N-dimethylformamide (12 ml) was added pyridinium dichromate (4.3 g) and the mixture was stirred at ambient temperature for 2 days. The mixture was diluted with water (80 ml) and the aqueous solution was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Filtering and removal of solvents afforded a brown oil. To a solution of the brown oil in methanol (3 ml) and benzene (11 ml) was added trimethylsilyl diazomethane (1.7 ml) and the resulting solution was stirred at ambient temperature for 30 minutes. The mixture was evaporated in vacuo to give 4-nitro-N-methyl-N-(2-methoxycarbonylmethylphenyl)benzamide (517 mg) as a dark-green oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=O)[CH2:15]Br)=[CH:4][CH:3]=1.C(O)(=O)C.[CH:22]([NH2:24])=[NH:23].O>C(N)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:23]=[CH:22][NH:24][CH:15]=2)=[CH:4][CH:3]=1
Reactant: N=CN
Reactant: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Solvent: NC=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2-c2c[nH]cn2)cc1
Yield: 24.6 %

Procedure:
A vigorously stirred solution of 1.0 g (3.5 mmol) of 4-methyl-2'-bromoacetyl-1,1'-biphenyl and 1.86 g of formamidine acetate in 10 mL of formamide was heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into 100 mL of water and the resultant mixture extracted several times with ether. The combined extracts were washed with water (3×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography over silica gel, eluting with hexane/ethyl acetate (1:1) to yield 200 mg (0.86 mmol, 24%) of the product. FAB-MS (Li spike): calculated for C16H14N2 234; found 241 (M+Li). 1H NMR (200 MHz, CDCl3); 2.34 (s, 3H), 6.61 (s, 1H), 7.10 (m, 4H), 7.30 (m, 3H), 7.48 (s, 1H), 7.68 (dd, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9]>O>[O-:10][C:8]([C:7]([F:12])([F:11])[F:6])=[O:9].[NH+:1]1[NH:2][CH:3]=[N:4][CH:5]=1
Reactant: c1nc[nH]n1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: O=C([O-])C(F)(F)F
Product: c1nc[nH+][nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2,4-Triazole (2.0 g, 28.96 mmol) was dissolved in 5 ml of distilled water. Trifluoroacetic acid (2.15 ml, 3.30 g, 28.96 mmol) was added via syringe at room temperature and the reaction was stirred at room temperature for 1 hour. The water was removed in vacuo with heating to approximately 90° C. for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[NH2:14][NH2:15]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:14][NH2:15].[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:14][NH2:15]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1cc(C(F)(F)F)ccc1Cl
Product: NNc1ccc(C(F)(F)F)cc1Cl
Temperature: 150 °C

Procedure:
A mixture of 3,4-dichlorobenzotrifluoride (48 g), hydrazine hydrate (65 g) and pyridine (240 g) was stirred and heated at 150° C. for 6 hours in an autoclave at a pressure of 4 bar. The cooled mixture was quenched with sodium hydroxide solution and the organic layer evaporated in vacuo. The residue was dissolved in diethyl ether, washed (water) and the ether evaporated to give 2-chloro-4-trifluoromethylphenylhydrazine and 2-chloro-5-trifluoromethylphenylhydrazine as a 95/5 mixture (36 g),
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C1OCCCO1>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH:20]([CH3:22])[CH3:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:1][C:2]1[N:3]=[C:4]([NH:27][CH:24]2[CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)N
Reactant: NC1CC1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Agent: C1COCOC1
Product: CC(C)Nc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Product: Fc1ccc(-c2ccc3nc(Cl)nc(NC4CC4)c3n2)cc1
Reaction time: 1 h

Procedure:
The procedure used in the first step was as follows: a mixture of 2,4-dichloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine (2.0 g), isopropylamine (2 ml) or cyclopropylamine (2 ml) in 2,6-dioxane (20 mL) was stirred for 1 hour. Solvents were concentrated in vacuo and the residue was dissolved in DCM (20 ml). The solid was filtered to provide 2-chloro-6-(4-fluorophenyl)-N-isopropylpyrido[3,2-d]pyrimidin-4-amine and 2-chloro-6-(4-fluorophenyl)-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine respectively, which were characterized by their mass spectra as follows: MS (m/z) 317 [M+H]+ and MS (m/z) 315 [M+H]+, respectively.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O])[C:7]([CH3:15])([CH3:14])[CH2:6]1)=[O:3].[C:16]([O:20]O)(C)([CH3:18])[CH3:17].[CH2:22]1[CH2:27]CCC[CH2:23]1>[Mo](=O)(=O)=O>[C:2]([NH:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:20][CH:16]2[CH2:18][CH2:27][CH2:22][CH2:23][CH2:17]2)[C:7]([CH3:15])([CH3:14])[CH2:6]1)(=[O:3])[CH3:1]
Reactant: C1CCCCC1
Reactant: CC(=O)NC1CC(C)(C)N([O])C(C)(C)C1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Product: CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
A stirred mixture of 10.0 g of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl, 16 ml of 70% aqueous tert-butylhydroperoxide and 0.67 g of molybdenum trioxide in 75 ml of cyclohexane is heated under reflux in a flask fitted with a Dean-Stark apparatus. After 6 ml of water is collected, the reaction mixture is transferred to a Fisher Porter apparatus and heated at 140° C. and 30 psi for 4 hours. The decolorized reaction mixture is filtered and the filtrate is washed with water, aqueous sodium sulfite, brine, dried (MgSO4) and concentrated to give 13.61 g of a white solid. Recrystallization from heptane affords 10.39 g of the title compound as a white crystalline solid, m.p. 140°-44° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Cl)=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1.O1CCOC[CH2:21]1>>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:15]2[CH2:19][CH2:21][CH2:17][CH2:16]2)=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)C)cnc1Cl
Reactant: C1COCCO1
Reactant: C1CCOC1
Product: Cc1cc(C(=O)OC(C)C)cnc1C1CCCC1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
Under argon, Pd(dppf) (11 mg, 14 μmol) is added to a solution of 6-chloro-5-methyl-nicotinic acid isopropyl ester (300 mg, 1.40 mmol) in dioxane (60 mL). To this mixture, a 0.5 M solution of cyclopentyl zink chloride in THF (452 mg, 2.11 mmol, 4.2 mL) is added dropwise. The mixture is stirred at 75° C. for 18 h before it is cooled to rt and quenched with water. The mixture is further diluted with water and extracted twice with EA (100 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give 6-cyclopentyl-5-methyl-nicotinic acid isopropyl ester (138 mg) as a pale yellow oil; LC-MS: tR=0.91 min; [M+1]+=248.53.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[OH-].[Na+].O>CCOCC>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][NH:15][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCC(C)Oc1ccc(SCCN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)NCCSc1ccc(OC(C)CC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(1-methylpropoxy)phenylthio]ethylamine (2.21 g, 8.65 mmol) in 25 ml of ether, at 0° and under N2, is added ethyl chloroformate (0.52 g, 4.76 mmol) by syringe, followed by addition of 10% aqueous sodium hydroxide (3.5 ml) and additional ethyl chloroformate (0.51 g, 4.76 mmol). After 15 min., the reaction is worked up by addition of water and extraction with ether. The combined organic phases are washed with 1N sulfuric acid, with water and with brine, dried and filtered, the filtrate is concentrated in vacuo and the product is purified by prep. TLC to give ethyl N-{2-[4-(1-methylpropoxy)phenylthio]ethyl}carbamate (compound 76, Table A).