Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+]>[C:8]1([S:14]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCNS(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
7 G of gamma-aminobutyric acid was dissolved in 120 mL of 1N sodium hydroxide solution, and 15 g of benzenesulfonyl chloride was dropwise added thereto under ice-cooling. 2N sodium hydroxide solution was added to the mixture to adjust the pH to 9.2 and stirred for 4 hours. The stirred mixture was washed with 50 mL of ethyl acetate, and hydrochloric acid was added thereto to adjust the pH to 2 or less. After extracting with 500 mL of ethyl acetate, this was dried with magnesium sulfate and filtered. After a concentration under reduced pressure, the obtained residue was recrystallized with ethanol solution to give 13 g of the desired product.
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.[CH3:25]C1N=CC([C@@H](N)C)=CC=1>>[CH3:25][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: Cc1ccc([C@H](C)N)cn1
Product: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 1 using IM46 and commercially available (S)-1-(6-methyl-pyridin-3-yl)-ethylamine (Supplier Netchem Inc., Catalog No 519526). Yield=0.27 g (21%). 1H NMR (600 MHz, DMSO) δ 8.61 (d, 1H), 8.37 (s, 1H), 7.57 (d, 1H), 7.26 (m, 2H), 7.16 (m, 2H), 7.09 (d, 2H), 4.92 (m, 1H), 2.41 (s, 3H), 2.19 (m, 1H), 1.91 (m, 1H), 1.36 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 281.2 (MH+), tR=0.86 min (method A).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[C:3]#[CH:4].C([Li])CCC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[C:4]#[C:3][C:2]([CH3:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH3:1])[CH3:23]
Reactant: C#CC(C)(C)OC1CCCCO1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)(C)OC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of 2-(1,1-dimethyl-prop-2-ynyloxy)-tetrahydropyran (10.0 g, 59.4 mmol) in THF (100 mL), cooled to −78° C. was added n-butyl lithium (26 mL, 65 mmol) as a solution in hexanes. The mixture was stirred at −78° C. for 1 h then a solution of ethyl chloroformate (7.0 mL, 108.5 mmol) in THF (100 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h then quenched by addition of a saturated aqueous solution of ammonium chloride. This mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated to provide 7.5 g (53%) of 4-methyl-4-(tetrahydro-pyran-2-yloxy)-pent-2-ynoic acid ethyl ester as a clear oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12]
Reactant: ClCCCCBr
Reactant: CCC1C(=O)Nc2ccccc21
Product: CCC1(CCCCCl)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:7]1(C1C=CC(C)=CC=1)C1C=CC(C)=CC=1)([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C(OCC)C>[CH:1]([NH:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCN1c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C(CNC(C)C)C1(c1ccc(C)cc1)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(-c2nc3c(CNC(C)C)cn(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 7-(7-((isopropylamino)methyl)-2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Example 4.1) (53 mg, 0.101 mmol) in EtOH (1 ml) was treated with 2M NaOH (0.151 ml, 0.302 mmol) and stirred at RT for 16 hours. The solvent was removed under reduced pressure and the crude product was dissolved in water and the pH was adjusted to pH 1 using 2M HCl. The mixture was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure to afford an orange solid. The solid was suspended in diethyl ether, sonicated and then filtered, rinsing the filter-cake with diethyl ether (×3). The resultant solid was dried under atmosphere to afford the titled compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:9]=1.Cl.C(=O)([O-])[OH:32].[Na+].[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH3:23])=[N:21][N:22]=[C:11]1[CH:10]([NH:9][C:40](=[O:41])[C:39]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:37]([Cl:36])[CH:38]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:32]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC1N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)c(Cl)c1)c1nnc(C)n1-c1sc(CC)cc1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)acetate (1.0 g) synthesized by a known method such as WO94/06802 was added to 2M hydrochloric acid (24 ml), and the mixture was stirred at 60° C. for 0.5 hour. The reaction mixture was cooled to 0° C. A saturated aqueous sodium hydrogencarbonate solution, chloroform and 3,4-dichlorobenzoyl chloride (0.53 g) were added and the mixture was stirred for 1 hour. The organic layer was taken out and dried over magnesium sulfate. The residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-hexane) and crystallized from diisopropyl ether to give 0.06 g of ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl)-3-(3,4-dichlorobenzoylamino)propionate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[N:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:14]3[N:15]=[C:16]([NH2:20])[N:17]=[CH:18][C:19]=3[C:11]=2[CH:10]=[CH:9][N:8]=1)(=O)=O.[CH2:28]1COCC1.C[Mg]Br>CN1CCCC1=O>[CH:21]1([N:13]2[C:14]3[N:15]=[C:16]([NH2:20])[N:17]=[CH:18][C:19]=3[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:28])[C:12]2=3)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1ncc2c3ccnc(OS(=O)(=O)C(F)(F)F)c3n(C3CCCC3)c2n1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CN1CCCC1=O
Product: Cc1nccc2c3cnc(N)nc3n(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A flame-dried two-necked flask was charged under argon with compound 86 (0.100 g, 0.25 mmol), ferric acetylacetonate (0.0044, 0.012 mmol), THF (2 ml) and N-methylpyrrolidone (0.1 ml). Methylmagnesium bromide (0.27 g, 2.2 mmol, 3M in ether) was added via syringe to the resulting red solution. A yellow precipitate formed immediately. The reaction was stirred at room temperature for 30 min and quenched with 5% NaHCO3, then extracted into DCM The resulting organic solution was washed with brine, dried and concentrated. Purification by flash chromatography (10% methanol/DCM/1% NH4OH) gave compound 87 as a light yellow solid (0.036 g, 54%). LCMS-ESI (POS), M/Z, M+1: Found 268.1, calculated 268.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]2[C:6]3[CH:15](O)[O:14][C:13](=O)[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.O.[NH2:20][NH2:21]>CS(C)=O>[Cl:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]2[C:6]3[CH:15]=[N:21][NH:20][C:13](=[O:14])[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1OC(O)c2c1c(O)nc1cc(Cl)c(Cl)cc21
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]ncc2c1c(O)nc1cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
1.76 g (0.0062 mol) of (RS)-7,8-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 18 ml of dimethyl sulphoxide while gassing with argon. 0.31 g (0.0062 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 42 hrs. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 0.32 g (18%) of 8,9-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>O.O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Oc2cccc(Cl)c2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc(Oc2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.16 mL of 2.0 mol/L aqueous sodium hydroxide was added to a mixed solution of 1.0 mL of methanol and 1.0 mL of tetrahydrofuran containing 0.10 g of methyl 2-(benzamido)-4-(3-chlorophenoxy)benzoate while ice-cooled and stirred at room temperature for 5 hours. The reaction mixture was added to water and 1.0 mol/L hydrochloric acid while ice-cooled, and a solid substance was separated by filtration to obtain 92 mg of 2-(benzamido)-4-(3-chlorophenoxy)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([CH:14]([CH3:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>O1CCOCC1>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([O:13][C:5]2[N:4]([CH:14]([CH3:23])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:3]=[C:2]([CH3:1])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c(=O)c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2ccc(Cl)c(Cl)c2)c(OC(=O)c2ccc(F)cc2)c1-c1ccccc1

Procedure:
0.1 mol (34.7 g) of 3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone was dissolved in 300 ml of absolute dioxane. After adding 15 ml of triethylamine, 0.11 mol (17 g) of p-fluorobenzoyl chloride in dioxane was added dropwise. After heating for several hours under reflux, the reaction batch was worked up as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:28]([NH2:35])[CH2:27]1>>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:28]([NH:35][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[N:9]=2)[CH2:27]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1COc2ccccc21
Product: O=S(=O)(Nc1cccc2nc(NC3COc4ccccc43)ccc12)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=436.1 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonyl chloride and rac-2,3-dihydro-benzofuran-3-ylamine (CAS 109926-35-4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.CC(=C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:10]([CH3:20])([CH3:15])[CH3:11])[C:3]=1[OH:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(O)c(C)c1
Agent: C=C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(O)c(C(C)(C)C)c1
Yield: 2443.9 %

Procedure:
To a 1 liter flask equipped with a condenser, over-head stirrer, and gas inlet tube was added 2,4-dimethylphenol (200 g, 1.64 m.), toluene (400 ml), and p-toluenesulfonic acid (10 g). After heating this solution to reflux, isobutylene was added continuously for 14 hrs. Upon cooling, the solution was washed twice with water (400 ml), dried (MgSO4), and the solvent evaporated to afford a dark brown liquid. GC confirmed that this liquid was about 72% product. Distillation afforded 253 g (86.6%) of clear product which was shown to be 97% pure by GC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: Clc1ccc(Nc2nc(-c3ccccc3)cs2)cc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
To (3,4-Dichloro-phenyl)-thiourea (2 g, 9.04 mmol) in ethanol (35 mL) was added 2-Bromo-1-phenyl-ethanone and the solution was refluxed overnight. The reaction mixture was allowed to cool to room temperature and the resulting solid was filtered and washed with cold ethyl acetate to yield 2.45 g (85%) of an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J=1.8 Hz, 1H), 7.87 (d, J=7.5 Hz, 2 H), 7.61-7.29 (m, 6H); LCMS m/z 319 [M−1]
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:12][C:13]([F:17])=[N:14][C:15]=1F.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)(C)C>[Cl:9][C:10]1[C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][C:13]([F:17])=[N:12][C:11]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1nc(F)c(Cl)c(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1nc(Nc2ccc(Cl)cc2)c(Cl)c(N2CCOCC2)n1
Temperature: 110 °C

Procedure:
4-Chloroaniline (1.44 g) was added to a solution of the product from step (i) (0.88 g) and N,N-diisopropylethylamine (0.484 g) in 1,4-dioxane (15 ml) and isopropylalcohol (15 ml) and the mixture heated at 110° C. for 6 days. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4), and evaporated under reduced pressure. The solid was triturated with ethyl acetate, filtered and the filtrate purified by chromatography on silica eluting with 3% ethyl acetate in toluene. Yield 0.28 g
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#N)[C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)[OH:30].O.[OH-].[Na+]>C1COCC1>[OH:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]2[C:21]3[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[O:20][C:17]2([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)C(c1ccccc1C#N)n1cncc1CCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCO

Procedure:
2-(1-{5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-imidazol-1-yl}-2-hydroxy-2-methyl-propyl)-benzonitrile (1.5 g, 3.75 mmol) is dissolved in THF (15 mL). Concentrated sulfuric acid (0.80 mL, 15.03 mmol) and water (0.80 mL) are added and the mixture is stirred at reflux for 24 h. After cooling down, the mixture is basified to pH 10 using 10% aqueous sodium hydroxide and is then extracted with ethyl acetate twice. The combined organic phase is dried over Na2SO4 and concentration in vacuo. The residue obtained is purified by silica gel chromatography (dichloromethane-methanol, 9:1) to give 4-[5-(2-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 287.1403; [(M+H)+ Calcd for C16H19N2O3: 287.1396]; 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.56 (s, 3 H), 3.06 (br. s, 2 H), 3.75-4.18 (m, 2 H), 5.74 (br. s, 1 H), 6.92 (br. s, 1 H), 7.15 (d, J=1.3 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.67 (t, J=7.3 Hz, 1 H), 7.78 (t, J=7.3 Hz, 1 H), 8.24 (d, J=7.3 Hz, 1 H)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:1][CH2:2][CH:3]2[CH2:6][CH2:5][O:4]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine was added p-toluenesulfonyl chloride (6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 243 (M+H)+, 260 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24])[NH:8][C:7](=[O:25])[C:6]([C:26]([F:29])([F:28])[F:27])=[CH:5]2.Br[CH2:31][C:32]#[CH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:33]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=2)[CH:5]=[C:6]([C:26]([F:29])([F:27])[F:28])[C:7]1=[O:25])[C:32]#[CH:31]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)c(C(F)(F)F)cc3cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c(C(F)(F)F)cc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 86.7 %

Procedure:
These compounds were prepared in a manner analogous to that of Step I of Example 1, using 1.0 gram (0.002 mole) of 3-(6-fluoro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil, 0.7 gram (0.005 mole) of 80% 3-bromopropyne, and 0.7 gram (0.005 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide. The crude reaction product was subjected to column chromatography on silica gel. Elution was accomplished using 1:4 ethyl acetate-hexane and 1:1 ethyl acetatehexane. The appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-[1-(2-propyn-1-yl)-3-trifluoromethyl-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil (Compound 42), mp 248°-250° C. Other product-containing fractions were combined and concentrated under reduced pressure, yielding 0.1 gram of the O-alkylated product, 3-[2-(2-propyn-1-yloxy)-3-trifluoromethyl-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil (Compound 26A). The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])[CH:8]=[CH:9][C:2]=12.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:20])[CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])[CH:8]=[CH:9][C:2]=12
Reactant: CNc1ccc(-c2ccc3nonc3c2)c(OC)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N(C)C)ccc1-c1ccc2nonc2c1
Temperature: 25 °C

Procedure:
200 mg (0.8 mmol) of (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-methyl-amine are stirred at 0 to 5° C. in 5 mL of DMF, then over 1 minute treated with 1 mL NaHMDS-solution (1.0 M, 1.25 eq.) and stirred another minute. Then, 0.5 mL (7.8 mmol, 10 eq.) of methyliodide is added and stirred 2 minutes under warming to rt. Then, the mixture is extracted with ethyl acetate/aqueous NaHCO3, the combined organic layers dried with sodium sulfate and concentrated. This yields the desired product as a reddish-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([NH:48][C:14](=[O:16])[C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])=[CH:9][CH:10]=[N:11][CH:12]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (600 mg, 2.38 mmol) (as prepared in Ex. 2, Part A) in DMF (6 mL) cooled to 0° C. was added EDC (457 mg, 2.38 mmol) and HOBT (365 mg, 2.38 mmol) and the mixture was stirred for 5 min. To the resultant solution was added DIPEA (0.416 mL, 2.384 mmol) followed by benzyl amine (307 mg, 2.86 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was treated with ice and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford N-benzyl-4-(4-chloro-2-fluorophenyl)nicotinamide (680 mg, 2.00 mmol, 84% yield). LC/MS (ESI) m/e 341.0 [(M+H)+, calcd for C19H15ClFN2O 341.1]; LC/MS retention time (method A): tR=1.73 min.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1[CH:7]=[CH:6]N=C1)=[O:2].[ClH:13].Cl.[NH:15]1[CH:19]=[C:18]([CH2:20][N:21]2[C:27]3[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=3[CH2:25][N:24]([C:33]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)=[O:34])[CH2:23][CH2:22]2)[N:17]=[CH:16]1.[CH2:45](N(CC)CC)[CH3:46].N1CCCCC1>C(Cl)Cl.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>[ClH:13].[ClH:13].[NH:15]1[CH:19]=[C:18]([CH2:20][N:21]2[C:27]3[CH:28]=[C:29]([NH:32][C:1]([N:8]4[CH2:9][CH2:46][CH2:45][CH2:11][CH2:12]4)=[O:2])[CH:30]=[CH:31][C:26]=3[CH2:25][N:24]([C:33]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)=[O:34])[CH2:23][CH2:22]2)[N:17]=[CH:16]1.[ClH:13].[CH3:6][CH2:7][O:34][CH2:33][CH3:35]
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Reactant: CCN(CC)CC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOCC
Product: O=C(Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2)N1CCCCC1
Reaction time: 2 h

Procedure:
Carbonyidiimidazole (0.045 g, 0.137 mmol), was added to a solution of Example 26 (0.050 g, 0.125 mmol), and triethylamine (0.038 mL, 0.275 mmol) in dry methylene chloride (1 mL) at rt under argon. After stirring for 2 hr, piperidine (0.013 mL, 0.13 mmol) was added. After stirring for 15 hr, the reaction was diluted with NaHCO3 and CHCl3. The organic layer was washed with NaHCO3, water, and brine (1×3 mL each), dried over MgSO4, filtered and concentrated. The product was purified by reverse phase HPLC with a gradient of 40-90% aquous methanol with 0.1% TFA and the HCl salt was formed by treatment with 1M HCl/ether to afford Example 247 (0.006 g, 10%).