Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[S:50][C:16]2[N:17]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:38][CH:37]=3)[C:18](=[O:34])[N:19]([CH:22]([CH3:33])[CH:23]([OH:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[S:50][C:16]2[N:17]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:42]4[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:40][CH:41]=3)[C:18](=[O:34])[N:19]([CH:22]([CH3:33])[C:23]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)=[O:32])[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12]
Reactant: CCc1cc2c(=O)n(C(C)C(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(C(C)C(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a mixture of oxalylchloride (0.12 mL) and methylene chloride (10 mL) were added a solution (5 mL) of dimethyl sulfoxide (0.096 mL) in methylene chloride and a solution (5 mL) of 4′-{[6-ethyl-3-[2-hydroxy-2-(4-methoxyphenyl)-1-methylethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.68 g) in methylene chloride at −78° C., and the mixture was stirred at the same temperature for 15 min. Triethylamine (0.86 mL) was added, and the mixture was allowed to warm to room temperature. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.27 g, 40%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][C:29]2[CH:30]=[N:31][C:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:27][CH:28]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCOCC3)nc2)=C(c2ccccc2)S1(=O)=O
Yield: 17.2 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol), 6-morpholin-4-ylpyridin-3-amine (0.108 g, 0.60 mmol) and TEA (0.06 mL, 0.60 mmol) in MeCN (2 mL) was heated at 140° C. for 1 h in a microwave reactor. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 3:1 mixture of EtOAc and petroleum ether as eluant, to give the title compound (0.038 g, 17%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.81 (d, 1H), 7.24-7.1.5 (m, 1H), 7.14-7.10 (m, 4H), 6.94 (s, 1H), 6.72 (dd, 1H), 6.12 (d, 1H), 3.75 (t, 4H), 3.33 (t, 4H), 1.77 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.9, 157.5, 142.9, 131.6, 131.9, 130.0, 129.1, 128.3, 124.7, 124.2, 110.2, 105.9, 66.7, 62.1, 46.1, 27.9; Mass Spectrum: M+H+ 443.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:28](OCCC(C)C)=[O:29]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:15])([CH3:16])/[C:10](=[N:28]/[OH:29])/[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)C1
Reactant: CC(C)CCON=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)/C1=N\O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
To a solution of 1-benzyl-4,4-dimethylpiperidine-2,6-dione (1.00 g, 4.32 mmol) in THF (20 mL) at −78° C. was slowly added LiHMDS (1.0M in THF, 4.8 mL, 4.8 mmol). The resulting thick white slurry was stirred at −78° C. for 20 min then isopentyl nitrite (0.70 mL, 5.20 mmol) was added dropwise which caused a bright orange color to appear. The reaction mixture was stirred at −78° C. for 30 min then gradually warmed to room temperature over 1 h and quenched with saturated aqueous NH4Cl. The biphasic mixture was stirred vigorously for 5 min then diluted with H2O and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (20% to 50% EtOAc/hexanes) to isolate first 340 mg (30%) of (Z)-1-benzyl-4,4-dimethylpiperidine-2,3,6-trione 3-oxime as a white solid followed by 280 mg (25%) of (E)-1-benzyl-4,4-dimethylpiperidine-2,3,6-trione 3-oxime as a white solid.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]=[C:16]([C:18](=[NH:22])[NH:19][C:20]#[N:21])[CH:15]=[CH:14][N:13]=1.[CH2:23](Cl)[Cl:24]>C(#N)C>[Cl:24][C:23]1[N:22]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[N:17]=2)[N:19]=[CH:20][N:21]=1
Reactant: N#CNC(=N)c1ccnc(Cl)n1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc(-c2ncnc(Cl)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of N,N-dimethylformamide (8.5 mL, 110 mmol) in methylene chloride (100 mL) was added phosphorus oxychloride (8.0 mL, 87 mmol) dropwise, and the mixture was stirred for 0.5 h. The resulting mixture was poured into a cold (0° C.) suspension of 2-chloro-N-cyano-4-pyrimidinecarboximidamide (i.e., the product of Step A) (13 g, 73 mmol) in acetonitrile (200 mL). The resulting mixture was stirred overnight in an ice bath. The mixture was passed through a short silica gel pad, eluted with 30% ethyl acetate in hexanes, and concentrated under reduced pressure to give 7 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]([C:7](=[O:9])[C:4]3[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=3)[C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(Cl)cs1
Reactant: NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2ccc(Cl)cc21
Yield: 53 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 463 mg (2.85 mmole) portion of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem., 13, 393 (1976)) was transformed into the acyl imidazole by reaction with 500 mg (3.09 mmole) of 1,1′-carbonyldiimidazole. The intermediate 4-chloro-2-thiophene-(1-imidazo)carboxamide coupled directly with 500 mg (2.37 mmole) of 6-chloro-2-oxindole-1-carboxamide in the presence of 783 mg (6.41 mmole) of 4-(N,N-dimethylamino)pyridine to give 665 mg of crude greenish-yellow solid. Recrystallization gave 450 mg (1.27 mmole, 53% yield) of pure title compound as a yellow solid, m.p. 231-3° C. (acetic acid).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:23]
Reactant: CCOC(=O)CCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Yield: 55.4 %

Procedure:
A mixture of 2.91 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of ethyl 4-bromobutyrate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 12 hours. The solvent was removed in vacuo, the residue was treated with water and the product was extracted with ethyl acetate. The dried (over magnesium sulfate) extract was concentrated in vacuo and the crude product was purified by chromatography on 200 g of silica gel. Elution with 5% ethyl acetate-toluene gave 2.55 g (54% yield) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, the titled compound, as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:9][CH:8]=[C:7]([Br:20])[CH:6]=2.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Br:20][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:21]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CCCCC(=O)Cl
Reactant: CS(=O)(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]methanesulfonamide (46.4 g, 0.129 mol) in 1000 mL pyridine was slowly added valeryl chloride (1.1 equivalents). After 1.5 hours the mixture was yellow and turbid. The reaction mixture was then heated at reflux for 12 hours, allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was mostly dissolved in 10% HCl to adjust to pH 1. The resulting suspension was adjusted to pH 12 with the addtion of 50% aqueous sodium hydroxide and stirred overnight. A precipitate formed and was isolated by filtration and air-dried to provide 45 g of N-[2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as a pale gray/green solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:26])=[N:19][C:20]=2[C:21]=1[O:22][CH3:23])(C)(C)C.C(#N)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=3)=[N:19][C:20]=2[C:21]=1[O:22][CH3:23]
Reactant: COc1c(OCCCNC(=O)OC(C)(C)C)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(OCCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
tert-Butyl[3-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)propyl]carbamate (Step 1, 1.2 g, 2.3 mmol) was diluted in a mixture of trifluoroacetic acid (6 mL) and dichloromethane (24 mL). The mixture was stirred at rt overnight, then was concentrated in vacuo to afford a viscous yellow oil. Acetonitrile was added to the mixture, and the desired was isolated by vacuum filtration as a white solid (0.55 g, 60%). 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.13 (2H, m), 3.02 (2H, m), 4.01 (3H, s), 4.25 (2H, m), 4.35 (2H, t), 4.57 (2H, m), 7.45 (1H, d), 7.73 (1H, m), 7.92 (2H, br m), 8.06 (1H, d), 8.69 (1H, m), 8.87 (1H, m), 9.43 (1H, m).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[C:19]([NH2:23])(C)(C)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:23][CH2:19][CH3:20])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CC(C)(C)N
Agent: CCN
Solvent: CC(=O)CC(C)=O
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 66.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 2.3 g (31 mmol) of t-butylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 3.6 g of theanine (yield: 66.7%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN(C(C)C)C(C)C.[NH2:23][CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]1[OH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:13])[NH:23][CH:24]1[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]1[OH:33])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC1Cc2ccccc2C1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1Cc2ccccc2C1O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
5-Chloro-1H-indole-2-carboxylic acid (116 mg, 0.67 mmol) was dissolved in DCM (10 ml) containing DIPEA (0.21 ml, 1.19 mmol) and 2-aminoindan-1-ol (Method 1; 101 mg, 0.67mmol) and HATU (247 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for approximately 18 hours. The resulting solution was washed with water (20 ml) and the aqueous layer extracted with DCM (2×20 ml). The organic extracts were combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (195 mg, 100%) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1>[C:17]([CH2:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1)([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Cc1ccncc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1ccncc1C(=O)O
Temperature: 25 °C

Procedure:
To a rapidly stirred suspension of 4-methylnicotinic acid HCl (952 mg, 5.48 mmol) in THF (25 ml) at −78° was added n-butyl lithium (17.0 mmol) over 20 min, maintaining the temperature below −50°. The reaction was maintained at −78° for 1.5 h, the temperature raised to −30° and after 40 min CO2 gas bubbled through the solution for 10 min maintaining the temperature between −30 to −20°. The reaction was then allowed to warm to ambient temperature, poured into water (30 ml) and to this was added 1M HCl (30 ml). The solution was washed with DCM (2×20 ml) and the aqueous layer concentrated in vacuo at a temperature below 50° to give crude 4-(carboxymethyl)nicotinic acid as a brown oil. m/z (ES+, 70V) 182 (MH+). The brown oil was dissolved in trifluoroacetic anhydride (15 ml) and after 10 min heated at 100° in a sealed tube for 4 days. The solvent was removed under vacuum and the resulting crude 3-(trifluoromethyl)-1H-pyrano[3,4-C]pyridin-1-one, m/z (ES+, 70V) 216 (MH+) dissolved in concentrated NH4OH (10 ml) and heated at 100° for 1 h, additional concentrated NH4OH (10 ml) added after 20 and 40 minutes. The reaction was allowed to cool to ambient temperature, and the pale brown aqueous solution separated. The organic layer was separated and concentrated in vacuo to yield a brown/orange oily solid purified by column chromatography (SiO2:EtOAc) to give the title compound (957 mg, 82%) as a pale yellow solid. δH (DMSO-d6) 9.24 (1H, s), 8.71 (1H, d, J 5.4 Hz), 7.65 (1H, d J 5.4 Hz), 7.11 91H, s), 3.19 (1H, br s). m/z (ES+, 70V), 215 (MH+).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([NH:14][C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:4]=1[C:5]([OH:7])=[O:6])(=[O:17])[CH3:16]
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(F)c(F)c(F)c(F)c1C(=O)O

Procedure:
The general pathway to the compounds of formula IV is illustrated with 2-nitro-3,4,5,6-tetrafluorobenzoyl chloride. This starting material is treated with n-butyl lithium and malonic half acid ester to form 2-nitro-3,4,5,6-tetrafluoro-β-oxo-benzene propanoic acid ethyl ester. This product can be converted to 5-nitro-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester by a three step reaction. The starting material is first treated with triethylorthoformate and subsequently with cyclopropyl amine in t-butyl alcohol. The product is ring closed with potassium t-butoxide to form 5-nitro-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester. This product is hydrogenated to form the corresponding 5-amino compound. This is then hydrolyzed to form 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid. Alternatively compounds of the formula IV may be prepared by a series of reactions illustrated with 3,4,5,6-tetrafluoroanthranilic acid. The acid is reacted with acetic anhydride and acetic acid to form 2-acetylamino-3,4,5,6-tetrafluorobenzoic acid. This compound is reacted with oxalyl chloride and dichloromethane in the presence of N,N-dimethylformamide catalyst to form 2-acetylamino-3,4,5,6-tetrafluorobenzoyl chloride. This product is treated with n-butyl lithium and malonic half acid ester to form 2-acetylamino-3,4,5,6-tetrafluoro-β-oxobenzenepropanoic acid ethyl ester.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3=[N:28][N:29]=[C:30]([C:31]4[CH:35]=[C:34]([CH3:36])[O:33][N:32]=4)[N:20]3[N:19]=2)=[N:14][CH:15]=1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[CH3:36][C:34]1[O:33][N:32]=[C:31]([C:30]2[N:20]3[N:19]=[C:18]([O:17][CH2:16][C:13]4[N:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=4)[C:27]4[C:22]([C:21]3=[N:28][N:29]=2)=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:35]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO[Si](C)(C)C(C)(C)C)cn4)nn23)no1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)cn4)nn23)no1

Procedure:
A solution of 6-[5(tert-butyldimethylsilyloxymethyl)pyridin-2-ylmethyloxy]-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.4 g, 2.78 mmol) in AcOH/THF/H2O [3:1:1, 50 ml] was stirred at room temperature for 36 h. The mixture was concentrated under reduced pressure and then azeotroped with toluene (2×50 ml). The material was used without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[N:6]=1)(=O)=O.C([Li])CCC.[CH:35]1([CH2:41][OH:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:41][O:42][C:5]2[N:6]=[C:7]([S:26]([CH3:29])(=[O:27])=[O:28])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: OCC1CCCCC1
Agent: [Li]CCCC
Product: CS(=O)(=O)c1nc(OCC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2,4-bis(Methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 5) (98 mg, 0.2 mmol) was reacted with 1 equivalent each of n-butyl lithium and cyclohexyl methanol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel eluted with 85/15 hexanes/ethyl acetate afforded 2-(cyclohexylmethoxy)-4-(methyl-sulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (HRf product): 1H-NMR 500 MHz (CDCl3): δ 0.9-1.1 (m, 1H), 1.10-1.2 (m, 2H), 1.2-1.4 (m, 3H); 1.67-1.88 (m, 3H), 1.9-2.0 (m, 2H), 3.38 (s, 3H), 4.29 (d, J=6 Hz, 2H), 7.0 (d, J=7 Hz, 1H), 7.18-7.22 (m, 3H), 7.24-7.28 (m, 2H), 7.36 (d, J=2 Hz, 1H) and 28 mg of 2-(methylsulfonyl)-4-(cyclohexylmethyloxy)-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine (LRf product): 1H-NMR 500 MHz (CDCl3): δ 0.87-0.9 (m, 1H), 0.95-1.07 (m, 2H), 1.1-1.3 (m, 2H), 1.33 (m, 2H), 1.7-1.82 (m, 4H), 3.40 (s, 3H), 4.37 (d, J=6 Hz, 2H), 7.08-7.12 (m, 2H), 7.22-7.30 (m, 4H), 7.36 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-:16])([OH:15])=[O:14]>C(Cl)CCl>[N+:13]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([O-:15])=[O:14].[N+:13]([C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12])([O-:16])=[O:14]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Product: COc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 55.3 %
Yield: 72.5 %

Procedure:
A solution of 8.2 g (50 mmole) of 4-tertbutylanisole in 15 ml of ethylene dichloride was placed in a 40 ml two necked round-bottomed flask equipped with a thermometer, a dropping funnel and magnetic stirring bar. The flask was placed in an ice-water bath and the contents were stirred and cooled. When the temperature reached +4° C., 4.72 g (3.32 ml, 52.4 mmol) of 70% nitric acid was added at such a rate that the temperature of the reaction mixture remained below 10° C. The completion of the acid addition took 15 minutes. Then the reaction mixture was stirred for 15 minutes while the flask was still immersed in the ice-water bath. After this time the reaction mixture was allowed to warm-up to 23° C. and left for 3 more hours with stirring to complete the nitration. The stirring was then stopped and the lower (organic) layer was collected. From this solution ethylene dichloride is removed by rotary evaporation at 40° C. under 20 mmHg and an oily residue was subjected to vacuum distillation. A 6" Vigreux column and a pressure of 1 mmHg was applied. These conditions afforded separation of the 4-nitroanisole bp 86° C. from 2-nitro-4-tertbutylanisole bp 102°-105° C. It resulted in the collection of 7.576 g of 99.1% pure 2-nitro-4-tertbutylanisole and 2.116 g of 96.4% pure 4-nitroanisole, mp 54° C. wth a total yield of 72.5% of 2-nitro-4-tertbutylanisole.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][S:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:33]([C:32]3[CH:34]=[CH:35][C:29]([S:28][CH3:27])=[CH:30][CH:31]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CSc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CSc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 451.09 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-(methylmercapto)-aniline.
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10](/[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[CH2:24])[N:22]=1)=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:25].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[OH:25][CH2:24][CH2:23][C:21]1[N:22]=[C:18](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]=1
Reactant: C=Cc1coc(/C=C/c2ccccc2)n1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
9-Borabicyclo[3.3.1]nonane (0.5N tetrahydrofuran solution, 158 ml) was added to a solution of 2-(trans-styryl)-4-vinyloxazole (13.0 g) in tetrahydrofuran (500 ml) at 0° C., and the mixture was stirred at room temperature for 15 hours. Water (10 ml), a 3N aqueous solution (80 ml) of sodium hydroxide and aqueous hydrogen peroxide (80 ml) were successively added dropwise to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 6 hours. After water (600 ml) and ethyl acetate (200 ml) were added to the resultant reaction mixture to separate an organic layer, the water layer was extracted with ethyl acetate (200 ml). After the organic layers were collected, washed with saturated saline (200 ml) and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→ethyl acetate alone) to obtain the title compound (14.1 g) as a colorless solid.