Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14]1([CH:17]=O)[CH2:16][CH2:15]1>>[NH3:1].[CH:14]1([CH2:17][NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=CC1CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NCC2CC2)C1
Product: N

Procedure:
tert-butyl (3S)-3-(cyclopropylmethylamino)pyrrolidine-1-carboxylate was prepared by a method similar to that described in preparation 1 using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and cyclopropane carboxaldehyde except that the crude product was purified by chromatography on silica gel eluting with a solvent gradient of dichloromethane changing to dichloromethane:methanol:0.88 ammonia (90:10:1 by volume) to yield the title compound, 5.2 g (81%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]([CH3:20])=[CH:13][N:12]=2)[C:3]=1[NH2:21].[N:22]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:21]=[N:22][N:9]([CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]([CH3:20])=[CH:13][N:12]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(CNc2nc(N)nc(Cl)c2N)c1C
Reactant: O=N[O-]
Agent: [Na+]
Product: COc1c(C)cnc(Cn2nnc3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 6-chloro-N4-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 3.597 min. 1HNMR (CDCl3): δ 8.22 (s, 1H), 7.12 (broad t, 1H), 4.61 (s, 2H), 4.56–4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:12]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(OOS([O-])(=O)=O)([O-])(=O)=[O:19].[K+].[K+]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[OH:19][C:9]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:1])[C:12]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CCOC(=O)c1cccc(OS(C)(=O)=O)c1C
Agent: Cl[Ru]Cl
Agent: [K+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1c(O)ccc(OS(C)(=O)=O)c1C
Temperature: 90 °C
Reaction time: 22 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 2-methyl-3-[(methylsulfonyl)oxy]benzoate (116b, 3.0 g, 12 mmol) in trifluoroacetic acid (35 mL) and trifluoroacetic anhydride (15 mL) was added potassium persulfate (3.5 g, 13 mmol) and dichloro(p-cymene)ruthenium(II) dimer (0.36 g, 0.59 mmol). The resulting mixture was stirred at 90° C. in a sealed tube for 22 hours. The reaction mixture was concentrated under vacuum then diluted with water (50 mL) and extracted with dichloromethane (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (40% EtOAc/Heptane) to give ethyl 6-hydroxy-2-methyl-3-[(methylsulfonyl)oxy]benzoate (116c, 1.3 g, 41% yield) as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].[H-].[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3](=[O:4])[CH2:20][C:19]#[N:21])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2cc(OC)ccc2c1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(=O)CC#N)ccc2c1
Temperature: 90 °C

Procedure:
To a solution of 6-methoxy-naphthalene-2-carboxylic acid methyl ester (1.0 g, 4.7 mmol) in dry toluene (8 mL), NaH (0.55 mg, 9.4 mmol) were added and the mixture was heated at 90° C. To the hot solution, acetonitrile (1.2 mL) was added dropwise. The reaction was then heated for 18 hours and the product precipitated from the reaction mixture as its sodium salt.
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:12][CH3:13].C>O>[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH:7]=[CH:6][C:4](=[O:5])[C:3]([OH:9])=[C:2]1[CH3:1])[CH2:11][CH2:12][CH3:13]
Reactant: Cc1occc(=O)c1O
Reactant: CCCCOCCCN
Solvent: O
Product: CCCCOCCCn1ccc(=O)c(O)c1C
Reaction time: 0.5 h

Procedure:
1-(3-Butoxypropyl)-3-hydroxy-2-methylpyrid-4-one was prepared by dissolving 10.0 g maltol and 3 equivalents of 3-butoxypropylamine in 200 ml of water. The mixture was refluxed for 72 hours, decolorizing charcoal was added and the mixture was stirred for an additional 0.5 hours. The mixture was filtered through a coarse frit containing 0.5 inches of Celite, and the filtrate was concentrated in vacuo to remove the water and excess amine. The remaining oil was crystallized from ether, yielding crystals of pure product.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:3]1.C(N(CC)CC)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37]>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:3][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:5][CH2:6][N:7]1[C:36]([C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)=[O:37]
Reactant: O=C(Cl)c1cccs1
Reactant: CC1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1C(=O)c1cccs1
Reaction time: 2 h

Procedure:
To a solution of 1-(3-methylpiperazin-1-yl)-4-phenylphthalazine BSL-2 (200 mg, 0.58 mmol) in 10 mL dichloromethane was added triethylamine (0.23 mL, 1.6 mmol, 3 eq) and thiophene-2-carbonyl chloride (0.095 mL, 0.88 mmol, 1.5 eq). After 2 h, the reaction was diluted with ethyl acetate and washed with sat. NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (2-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl)(thiophen-2-yl)methanone, 1. MS (M+H)+=415.1.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23]>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]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:22]([NH:21][CH3:20])=[O:23])=[CH:25][CH:26]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CNC(=O)c1ccc(-c2cccn3nc(Nc4ccccc4OC)nc23)cc1

Procedure:
4-[2-(2-Methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-N-methyl-benzamide was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 4-(N-methylaminocarbonyl)phenylboronic acid (31.0 mg, 0.173 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c and was isolated as a pale yellow solid (0.023 g, 39%). MP=275-278° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48-8.45 (m, 1H), 8.41-8.37 (m, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.64-7.59 (m, 2H), 7.08-7.02 (m, 1H), 7.00-6.88 (m, 3H), 6.17 (br s, 1H), 3.92 (s, 3H), 3.07 (d, J=4.7 Hz, 3H). MS=374 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12](=[O:13])[NH:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:7]2)[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)NC(=O)C1CCC(Oc2cccc(N)c2C#N)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCC(C(=O)NC(C)C)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 4-(3-amino-2-cyanophenoxy)-N-isopropylcyclohexanecarboxamide (Example 45b) and ethyl 3-oxobutanoate as a yellow solid (56%). MS 414 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2.[C:17](O[Na])([CH3:19])=[O:18].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[O:12][C:17](=[O:18])[CH3:19])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2
Reactant: C=CCc1c(O)c(C)cc2ccc(=O)oc12
Reactant: CC(=O)O[Na]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=CCc1c(OC(C)=O)c(C)cc2ccc(=O)oc12
Yield: 129.2 %

Procedure:
In such a manner a mixture of 6-methyl-7-hydroxy-8-allylcoumarin (VII) (6.3 g), anhydrous AcONa (1.5 g) and acetic anhydride (40 ml) was refluxed for 1 h. The reaction mixture was gently diluted with water (40 ml), refluxed for 10 min and then poured into H2O (300 ml) yielding a precipitate, which was collected by filtration and washed several times with H2O. The dried product was crystallized from MeOH yielding 6-methyl-7-acetoxy-8-allylcoumarin (X) (6.1 g; m.p. 110°-11° C.). ##STR15##
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>ClCCl>[ClH:23].[F:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[CH:14]/[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Fc1ccc(/C=C/C2=CCN(Cc3ccccc3)CC2)cc1
Solvent: ClCCl
Product: Cl
Product: Fc1ccc(/C=C/C2=CCNCC2)cc1
Temperature: 0 °C
Yield: 69 %

Procedure:
To a solution of (E)-1-benzyl-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (11.6 g, 37.5 mmol) in dichloromethane (500 ml) at 0° C. was added 1-chloroethyl chloroformate (4.85 ml, 45 mmol). The reaction was stirred initially at 0° C., and allowing it to warm to room temperature over 2 hours. The solvent was evaporated and methanol (500 ml) added. The mixture was heated at reflux for 1 hour, cooled to room temperature, and the solvent evaporated to a slurry. Diethyl ether was added and the resultant precipitate filtered and dried to yield (E)-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine hydrochloride (6.2 g, 69%) as a white solid. δH (DMSO-d6) 2.49-2.53 (2H, m, tetrahydropyridinyl CH2), 3.23 (2H, t, J 6.1 Hz, tetrahydropyridinyl CH2), 3.69 (2H, br s, tetrahydropyridinyl CH2), 5.90 (1H, br s, tetrahydropyridinyl 5-CH), 6.61 (1H, d, J 16.3 Hz, ArCHCHC), 6.92 (1H, d, J 16.3 Hz, ArCHCHC), 7.15-7.20 (2H, m, ArH), 7.55-7.59 (7H, m, ArH) and 9.45 (1H, br s, NH).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:20][C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[S:22])[CH:17]([CH3:19])[CH3:18]>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:22][C:21](=[N:20][CH2:16][CH:17]([CH3:18])[CH3:19])[N:23]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CC(C)CNC(=S)NCC(C)C
Product: CC(C)CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CC(C)C
Product: Cl

Procedure:
5.3 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 3.8 g of 1,3-diisobutylthiourea were reacted according to the prescription made in Example 16 and worked up as described in Example 25.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16].C1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl.O>[Cl:17][C:15]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:16]
Reactant: O=C(Cl)Cl
Reactant: CC(C)[C@H](Nc1ccccc1)C(=O)O
Agent: CN(C)c1ccccn1
Solvent: c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](C(=O)O)N(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the m-phenoxybenzyl ester of N-phenyl valine (1.2 mmole) is added 12.5% phosgene in benzene (2.3 mmole), cooled in an ice bath, and then dimethylaminopyridine (1.22 mmole). The reaction mixture is stirred at RT for 3 days. Then one ml of benzene, 0.15 g of dimethylaminopyridine and 2 ml of phosgene are added and the reaction stirred overnight at RT. The reaction is worked up using chloroform/water. The chloroform layer is washed with dilute sulfuric acid, water and brine, dried over sodium sulfate and filtered. The solvent is removed by rotoevaporation to yield the m-phenoxybenzyl ester of N-chloroformyl,N-phenyl valine.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[NH2:4].[CH3:22][CH2:23]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([NH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]2[N:4]=[C:22]([CH3:23])[O:1][N:2]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CC(=O)Nc2sccc2C(N)=NO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2sccc2-c2noc(C)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg, 0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resulting solution was stirred at 60° C. for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide. Retention time (min)=6.733, method [7], MS(ESI) 330.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]3[C:26]([CH3:25])=[CH:30][C:29]([CH3:31])=[N:28]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCCOc3ccccc3C)o2)n1
Temperature: 125 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 3,5-dimethylpyrazole (1.00 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(3,5-dimethyl-1-pyrazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (187 mg, 16%). Melting point 103-104° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CCCNCC1
Reactant: CCCCBr
Product: CCCCN1CCCCCC1

Procedure:
The first N-substitution of azepane was carried out using butyl bromide as an N-alkylating agent to form 1-butylazepane. An equimolar amount of butyl bromide was added dropwise to a solution of azepane in methanol keeping the temperature at 20° C. by an ice-water bath. The mixture was hydrolyzed with potassium carbonate, extracted with ether, and dried over Na2SO4. The solution was fractionally distilled at reduced pressure and the fraction with bp 195° C. was collected. 1H-NMR (300 MHz, CDCl3) δ 0.90 (t, 3H), 1.28 (sextet, 2H), 1.42 (m, 2H), 1.60 (broad m, 8H), 2.42 (m, 2H), 2.60 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.CN(CCCN=C=NCC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:12][N:13]([O:14][CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a mixture of 4-fluorobenzoic acid (5.0 grams (hereinafter “g”), 36 millimoles (hereinafter “mmol”)) and N,O-dimethylhydroxylamine hydrochloride (3.8 g, 39 mmol) in 200 mL of CH2Cl2 at 0° C. was added triethylamine (5.0 milliliters (hereinafter “mL”), 36 mmol). The solution was warmed to room temperature and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide (6.8 g, 36 mmol) were added. The resulting solution was stirred for 16 hours (hereinafter “h”). Next, the solution was diluted with 200 mL of ethyl acetate and washed with 100 mL of saturated NaHCO3, 50 mL of H2O, twice with 50 mL of 1N HCl, and 50 mL of H2O. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a light yellow oil. The oil was purified by chromatography through a plug of silica gel with 50% ethyl acetate/hexane to give title compound as a light yellow oil (5.5 g, 85%). ES(+)MS m/e=184 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]1([CH:19]2[O:21][CH:20]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C.[H-].[Na+]>CO.ClCCl.ClCCl>[OH:21][CH:20]([CH:19]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C1OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C(O)C(Oc1ccc(OC)cc1[N+](=O)[O-])c1ccccc1

Procedure:
To a stirred mixture of 4-methoxy-2-nitrophenol (11.87 g, 70 mmol), ethyl 3-phenyloxirane-2-carboxylate (10.39 g, 54 mmol) and ethanol (175 mL) was added portionwise 60% sodium hydride (0.65 g, 16 mmol) and the red mixture stirred at reflux for 9 days. The solvent was removed in vacuo, the residue dissolved in ethyl acetate and extracted three times with 10% aqueous potassium carbonate. The organic layer was washed with water and brine, dried (MgSO4), filtered and the solvent stripped in-vacuo to yield an oil. Column chromatography (dichloromethane then 5% methanol/dichloromethane) afforded (9.5 g, 49%) of slightly impure title compound that was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ1.21 (t, 3H) 3.25 (d, 1H, J=7.5 Hz) 3.77 (s, 3H), 4.20 (q, 2H) 4.67 (q, 1H, J=3.5, 7.5 Hz), 5.51 (d, 1H, J=3.5 Hz), 6.82 (d, 1H, J=9.2 Hz), 6.92 (dd, 1H, J=9.2, 3.0 Hz), 7.3-7.4 (m, 6H). HPLC (Method A): 3.24 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:24])([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:26]([O:28]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:26](=[O:28])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:17]2([CH3:24])[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(C)(c1ncnn1C)C(c1ccc(F)cc1)N2
Solvent: CO
Solvent: O
Product: Cn1ncnc1C1(C)c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Yield: 54 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.19 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (1 mL) was stirred under reflux overnight. The resulting solution was cooled and filtered, washed the cake by methanol (2 mL) to obtain a white solid, dried in vacuum at 55° C. to obtain the title compound (40 mg, yield 54%). LC-MS (ESI) m/z: 377 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.83 (s, 3H), 2.86 (s, 3H), 4.61 (s, 1H), 6.88-6.92 (m, 2H), 7.11-7.169 (t, J=8.8 Hz, 2H), 7.19-7.22 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.47-7.49 (m, 1H), 7.60-7.64 (t, J=8.0 Hz, 1H), 7.72 (s, 1H), 12.40 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[C:11](=[CH:14]N(C)C)[CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl.[CH3:20][N:21]([CH3:25])[C:22]([NH2:24])=[NH:23]>C(O)C>[CH3:20][N:21]([CH3:25])[C:22]1[N:24]=[CH:14][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:23]=1
Reactant: CN(C)C(=N)N
Reactant: CCCN1CCC[C@@H]2CC(=O)C(=CN(C)C)C[C@H]21
Agent: Cl
Solvent: CCO
Product: CCCN1CCC[C@H]2Cc3nc(N(C)C)ncc3C[C@@H]21

Procedure:
A reaction mixture was prepared from 4.7 g. of trans-(±)-1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline and 2.5 g. of 1,1-dimethylguanidinehydrochloride in 50 ml. of anhydrous ethanol. The reaction mixture was heated overnight under a nitrogen atmosphere, and was then cooled and the volatile constituents removed in vacuo. The resulting residue was dissolved in ethyl acetate and the ethyl acetate solution contacted with an excess of 10% aqueous sodium hydroxide. Trans-(±)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline formed in the above reaction, being insoluble in the basic layer, remained in the ethyl acetate layer. The aqueous layer was separated and the ethyl acetate layer extracted once with water and once with saturated aqueous sodium chloride. The ethyl acetate layer was dried and the ethyl acetate removed in vacuo to leave 0.75 g. of an orange oil. The oily residue was chromatographed over florisil using hexane containing increasing amounts (1-50%) of ethyl acetate as the eluant. Fractions shown by TLC to contain the desired trans-(±)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were combined and the solvent removed from the combined fractions in vacuo. The resulting residue was dissolved in ethanol and gaseous hydrogen chloride passed into the solution thus forming the corresponding dihydrochloride salt. The ethanol was removed therefrom in vacuo and the dihydrochloride salt crystallized from a methanol ethyl acetate solvent mixture to yield 0.170 g. of a white solid having a molecular ion at 274.
Reaction SMILES: [N+]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[Cl:15]Cl>>[Cl:15][C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: ClCl
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Product: O=C(O)c1cc(F)c(F)cc1Cl

Procedure:
2-chloro-4,5-difluorobenzoic acid may be prepared by decarboxylating 4,5-difluorophthalic anhydride or 4,5-difluorophthalic acid to form 3,4-difluorobenzoic acid in N-methyl-2-pyrrolidone, quinoline, or dimethyl acetamide optionally using copper, copper oxide, copper salts, or halides and salts of Zn, Cd, Ag and Ni as a catalyst, treating said 3,4-difluorobenzoic acid with a mixture of nitric and sulfuric acids, to produce 2-nitro-4,5-difluorobenzoic acid, and treating said 2-nitro-4,5-difluorobenzoic acid with elemental chlorine to form 2-chloro-4,5-difluorobenzoic acid.