Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].C(N(CC)CC)C.[CH2:14]([S:21][C:22]1[N:26]([CH3:27])[N:25]=[C:24]([Cl:28])[C:23]=1[C:29](Cl)=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([S:21][C:22]1[N:26]([CH3:27])[N:25]=[C:24]([Cl:28])[C:23]=1[C:29]([NH:6][O:5][CH2:2][CH:3]=[CH2:4])=[O:30])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCON
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1SCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CCONC(=O)c1c(Cl)nn(C)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
In a suspension of allyloxyamine hydrochloride (2.3 g, 21 mmol) in tetrahydrofuran (20 ml), 2.9 g (29 mmol) of triethylamine was added at 0° C., stirred at room temperature for 5 minutes and then a solution of 5-benzylthio-3-chloro-1-methylpyrazole-4-carboxylic acid chloride (2.1 g, 7.0 mmol) in tetrahydrofuran (10 ml) was added dropwise. After stirring at room temperature for 1 hour, water (100 ml) was added and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and the solvent was distilled off to obtain the desired product (2.4 g). Oily substance. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.45 (s, 3H), 4.11 (s, 2H), 4.53 (d, J=6.3 Hz, 2H), 5.34-5.45 (m, 2H), 6.00-6.13 (m, 1H), 7.03-7.06 (m, 2H), 7.24-7.28 (m, 3H), 9.14 (brs, 1H).
Reaction SMILES: N[C@H]([C:8]([OH:10])=[O:9])CCCCN.NN.[CH:13]1[C:18](N=C=S)=[CH:17][C:16]2[C:22]([O:24][C:25]3([C:35]4[CH:36]=[CH:37][C:38]([OH:40])=[CH:39][C:34]=4[O:33][C:27]4[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]3=4)[C:15]=2[CH:14]=1)=[O:23].C(N(C(C)C)CC)(C)C.C1C=CC(C(O)=O)=C(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)C=1>CN(C=O)C>[CH:13]1[C:18]([C:8]([OH:10])=[O:9])=[CH:17][C:16]2[C:22]([O:24][C:25]3([C:35]4[CH:36]=[CH:37][C:38]([OH:40])=[CH:39][C:34]=4[O:33][C:27]4[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]3=4)[C:15]=2[CH:14]=1)=[O:23]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: NN
Agent: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reaction time: 12 h

Procedure:
Peptide-resin obtained via from Method 5, containing an ivDde protecting group on the epsilon nitrogen of lysine, was mixed with a solution of hydrazine in DMF (10% hydrazine/DMF, 2×10 mL, 10 min) to remove the ivDde group. The epsilon nitrogen of the lysine was labeled with fluorescein-5-isothiocyanate (0.12 mmol) and diisopropylethylamine (0.12 mmol) in DMF. The mixture was agitated for 12 h (fluorescein-containing compounds were protected from light). The resin was then washed with DMF (3×10 mL) and twice with CH2Cl2 (10 mL) and dried under nitrogen for 1 h. The peptide was cleaved from the resin using Reagent B for 4 h and the solution collected by filtration. The volatiles were removed under reduced pressure and the residue was dried under vacuum. The peptide was precipitated with ether, collected and the precipitate was dried under a stream of nitrogen. The precipitate was added to water (1 mg/mL) and the pH of the mixture was adjusted to 8 with 10% aqueous meglumine. Cyclization of the peptide was carried out for 48 h and the solution was freeze-dried. The crude cyclic peptide was dissolved in water and purified by RP-HPLC on a C18 column with linear gradient of acetonitrile into water (both phases contained 0.1% TFA). Fractions containing the pure product were collected and freeze dried. The peptides were characterized by ES-MS and the purity was determined by RP-HPLC (linear gradient of acetonitrile into water/0.1% TFA).
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:15][CH:14]=[CH2:13]
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
2 g (9.48 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 9.5 ml (9.5 mmol) of 1M allylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After filtration and evaporation the oil obtained was distilled to give 1.45 g of 2-(1 (RS)-chloro-3-butenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; b.p. 53° C./0.4 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](C)[C:3]=1N1CCCC2C(=O)N(C)NC1=2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][C:31]3[C:35](=[O:39])[N:36]([CH3:38])[NH:37][C:30]2=3)=[C:25]([CH3:40])[CH:24]=1>>[ClH:1].[CH3:40][C:25]1[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[CH:27][C:26]=1[N:29]1[CH2:34][CH2:33][CH2:32][C:31]2=[C:35]([O:39][CH:2]([CH2:7][CH2:6][CH3:8])[CH2:3][CH2:4][CH3:5])[N:36]([CH3:38])[N:37]=[C:30]12
Reactant: COc1ccc(N2CCCc3c2[nH]n(C)c3=O)c(C)c1
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1ccc(OC)cc1C)CCC2
Product: Cl

Procedure:
Example 12c was prepared according to the procedure described in Example 12a, except that 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one was replaced by 7-(4-methoxy-2-methyl-phenyl)-2-methyl-1,2,4,5,6,7-hexahydro-pyrazolo[3,4-b]pyridin-3-one.
Reaction SMILES: [CH:1]1([C:7]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[Na]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:11][CH2:10][CH:9]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:30]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Agent: [Na]
Product: O=C(C1CCCCC1)C(CCN1CCN(c2ccccn2)CC1)c1ccccc1
Yield: 78.3 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.55 mmol) and 1-(2-pyridyl)piperazine (1.55 mmol) with sodium triacetoxyboranehydride (2.0 mmol) gave pure product 1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (475 mg) in 78% yield. The oxalate salt was prepared as described above.
Reaction SMILES: [NH2:1][CH:2]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CCOC(C)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][CH:2]([CH:7]([C:8]([F:11])([F:10])[F:9])[C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH3:6])=[O:4])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)cc1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A solution of methyl 2-amino-3-(trifluoromethyl)-4,4,4-trifluorobutanoate (2.12 g, 8.87 mmol) in CH2Cl2 (10 mL) was stirred under nitrogen at 25° C. Pyridine (10 mL, 126 mmol) was added dropwise followed by 4-chloro-benzenesulfonyl chloride (2.81 g, 13.3 mmol) in one portion, and the resulting solution stirred for 18 hours at 25° C. After this time period, the reaction was complete by TLC (20:80 EtOAc:PE). After quenching with H2O, the mixture was diluted with Et2O (200 mL). The organic layer was washed with 1 N aq. HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL), and then dried (MgSO4). After concentration, the crude product was purified by Biotage Flash™ 40 chromatography, eluent: 5:95 to 20:80 EtOAc:PE, to obtain methyl 2-[(4-chloro-phenyl)sulfonylamino]-3-trifluoromethyl-4,4,4-trifluorobutanoate as a solid (1.53 g, 42%). Mass Spectrum
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[CH2:6][CH2:5]2.C([O:18][C:19](=[O:30])[C:20](=[CH:26]OCC)[C:21](OCC)=[O:22])C>>[F:1][C:2]1[CH:11]=[C:10]2[C:9]3[N:8]([CH:26]=[C:20]([C:19]([OH:30])=[O:18])[C:21]2=[O:22])[CH:7]([C:12]([F:13])([F:15])[F:14])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: Fc1ccc2c(c1)CCC(C(F)(F)F)N2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: O=C(O)c1cn2c3c(cc(F)cc3c1=O)CCC2C(F)(F)F

Procedure:
6-Fluoro-2-trifluoromethyltetrahydroquinoline is condensed with an equimolar amount of diethylethoxymethylenemalonate according to the method of Example 1. The ester intermediate of Formula III is hydrolyzed according to Example 1, and the solid product is recrystallized from N,N-dimethyl formamide to provide crystal of 6,7-dihydro-9-fluoro-1-oxo-5-trifluoromethyl-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 295°-297° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)nc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)nc1

Procedure:
To a mixture of the amidine of step 1 (10 mmol and sodium bicarbonate (20 mmol) in isopropanol (150 ml), 3-bromo-1,1,1-trifluoroacetone (15 mmol) is added. After heating at 80°-85° C. for 24 hours, the reaction mixture is cooled and filtered. The residue is washed with methylene chloride and the combined organic fractions are dried over sodium sulfate, filtered and concentrated. The crude mixture is chromatographed on silica gel using mixtures of ethyl acetate, isopropanol and ammonium hydroxide as eluants to give the desired 4,5-dihydro-imidazole
Reaction SMILES: C(OC([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:7]1)=O)C.[CH2:34]([OH:36])C.[OH-:37].[Na+].Cl>>[C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH2:6][C@@H:7]2[C:34]([OH:36])=[O:37])[CH:22]=[CH:21]3)[CH2:25][CH2:26]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: [OH-]
Reactant: CCO
Reactant: CCOC(=O)[C@@H]1CCCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CCCC[C@@H]4C(=O)O)ccc3c2)CC1
Reaction time: 18 h

Procedure:
(R)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-3-carboxylic acid ethyl ester (3633.4 mg, 0.08046 mmol) was dissolved in ethanol (5 mL, 80 mmol) then treated with 1 M aqueous sodium hydroxide (5 ml, 5 mmol). The mixture was stirred vigorously for 18 hours. pH was adjusted to 3-4 with 3 N HCl and reaction was then extracted three times with ethyl acetate. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Ethyl ether was then added and a white precipitate formed which was removed via filtration to give a white solid that 86% pure by HPLC. The process was repeated two additional times to give the title compound as a white solid (156 mg, 44%). EDI-MS: 424.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ=7.82 (s, 1H), 7.74-7.62 (m, 2H), 7.42 (d, J=2.3, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.08 (d, J=2.5, 1H), 4.43-4.34 (m, 1H), 4.33-4.22 (m, 2H), 2.71 (br. s., 1H), 2.16 (d, J=2.0 Hz, 2H), 1.88-167 (m, 4H), 1.40-1.25 (m, 3H), 1.24-1.11 (m, 4H), 1.10-0.95 (m, 5H), 0.79 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1.C(Cl)(Cl)Cl.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and in an anhydrous medium, 340 mg (1.23 mmol) of the compound obtained in Step H are suspended in 7 ml of isopropanol and 21 ml of chloroform in the presence of 810 mg of 230-400 mesh silica; 234 mg (6.18 mmol) of sodium borohydride are added slowly. After 2 hours' stirring at room temperature, acetic acid is added and the reaction mixture is filtered through a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered, concentrated and purified by flash chromatography over silica gel (eluant:ethyl acetate/petroleum ether, 6:4) to yield the title compound in the form of a yellow solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15]>>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C#CC(=O)OC
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
The process may involve reacting 2-(azidomethyl)-1,3-difluorobenzene of formula III with methyl propiolate, to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV, and converting the methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV to rufinamide.
Reaction SMILES: C([Li])CCC.[Li].C(Br)CCC.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[CH2:21]1[O:23][CH2:22]1>CCOCC.O>[CH:12]1([CH2:21][CH2:22][OH:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: C1CO1
Reactant: C1=Cc2ccccc2C1
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCBr
Product: OCCC1C=Cc2ccccc21
Reaction time: 1 h

Procedure:
The above compound is prepared as described by Howell & Taylor, J.C.S., 1957, 3013. To butyl-lithium, prepared from lithium (20.0 g) and butyl bromide (234 g) in ether, indene (116 g., 1.0 M) is added with stirring under nitrogen at -10°. After 1 hour at -10°, ethylene oxide (88 g) in ether (300 ml) is added in 1/2 hour. After warming to 10°, 500 ml water is added cautiously and stirring is continued until there is no lithium remaining. The layers are separated and the organic layer is washed once with dilute HCl and three times with water. After drying the ether is removed and the product distilled - collecting 76 g (48%) at 125-135/0.2 mm. N.M.R. establishes the position of the double bond as 2,3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[F:13][CH:14]1[C:19](=O)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1.N>C(O)(=O)C.OP(O)(O)=O>[F:13][CH:14]1[C:19]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:18][CH2:17][NH:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: N
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3F)c2c1
Reaction time: 16 h
Yield: 46.6 %

Procedure:
A solution of 5-nitroindole (38) (1.0 g, 6.167 mmol) in glacial acetic acid (10 mL) at 90° C. was treated with compound 130 (1.33 g, 6.167 mmol) in glacial AcOH (5 mL), 1 M H3PO4 in glacial AcOH (5 mL) and the resulting solution was stirred at same temperature for 16 h. The reaction was brought to room temperature, poured into 15% cold aqueous ammonia solution (100 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:99 to 5:95) to obtain compound 131 (0.75 g, 47%) as a yellow solid. mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.35 (brs, 1H), 2.86-3.06 (m, 1H), 3.19-3.26 (m, 1H), 3.35-3.58 (m, 2H), 5.28 (d, 1H, J=49.5 Hz), 6.53-6.56 (m, 1H), 7.58 (d, 1H, J=8.7 Hz), 7.74 (s, 1H), 8.02 (dd, 1H, J=2.4, 9.0 Hz), 8.68 (d, 1H, J=2.4 Hz), 11.94 (s, 1H); ESI-MS m/z (%): 262 (MH+, 100), 233 (50).
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:4]([C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([F:14])[C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:38][O:39][CH2:40]Cl.O>ClCCl>[F:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:4]([C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[C:11]([F:14])[C:12]=1[O:13][CH2:38][O:39][CH3:40])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COCCl
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c1OC1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(OCOC)c(F)c1OC1CCCCO1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
4.23 g (10.5 mmol) of the above ethyl 3,5-difluoro-4-hydroxy-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 50 mL of dichloromethane, 2.4 mL (13.7 mmol) of diisopropylethylamine and 0.96 mL (12.6 mmol) of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 4.33 g of ethyl 3,5-difluoro-4-methoxymethoxy-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 93%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19].O>C1(C)C=CC=CC=1>[CH2:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)[CH3:19]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: CCN1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCN(c2cc(-c3ccccc3)c3ccccc3n2)CC1
Yield: 86.8 %

Procedure:
A solution of 2-chloro-4-phenylquinoline (2.0 g) and 1-ethylpiperazine (2.7 g) in toluene (15 ml) is heated under reflux for 10 hours. To the reaction mixture is added water and the resulting mixture is extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (25 g) using chloroform as an eluent. Fractions containing the title compound are pooled and concentrated to give the title compound (2.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1[N:29]1[CH2:30][CH2:31][N:26]([C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:27][CH2:28]1)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (78) and 2-furoyl piperazine according to general procedure E. Yield 3.11 g (74%), MP 207° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=6.8 Hz, 3H), 3.11 (m, 4H), 3.90 (m, 4H), 4.29 (q, J=6.8 Hz, 2H), 6.65 (dd, J=2.0, 3.6, Hz, 1H), 7.04 (d, J=3.6 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 8.06 (dd, J=2.8, 8.0 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H) 12.40 (s, 1H); EIMS: 415 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[O:12]1[CH2:14][CH2:13]1>CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:14][CH2:13][OH:12])[S:4][CH:3]=1
Reactant: Cc1ccsc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1csc(CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 3-methylthiophene (5 g, 51.0 mmol) in dry ether (250 mL) at −65° C. was added n-BuLi (25 mL, 2.5 N in THF) dropwise. After stirring for 1 h, oxirane (2.7 g, 61.3 mmol) was added in one portion. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction was then quenched with water. After separation of layers, the organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (6.2 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[C:4]([OH:24])=[O:5]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde (4.5 g, 13.2 mmole) in 40 ml of acetone was added 13 ml (26 mmole) of Jones' reagent. The solution was stirred at ambient temperature for 2 hours and poured into 400 ml of water. The resulting solid was filtered and air dried overnight to afford 4.5 g (96%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-Pyrazol-3-yl]-4-fluoro-benzoic acid as a white solid. An analytical sample was recrystallized from ether/hexanes; mp 179°-181° C.
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[CH3:13][CH2:14][CH:15]([OH:18])[CH2:16][CH3:17].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]3=[N:34][CH:35]=[N:36][C:37]([O:38][CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)=[C:32]3[CH:31]=[N:30]2)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C>CS(C)=O>[CH2:14]([CH:15]([O:18][C:6]([N:42]1[CH2:43][CH2:44][CH:39]([O:38][C:37]2[N:36]=[CH:35][N:34]=[C:33]3[N:29]([C:26]4[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:24][CH:25]=4)[N:30]=[CH:31][C:32]=23)[CH2:40][CH2:41]1)=[O:7])[CH2:16][CH3:17])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CCC(O)CC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and pentan-3-ol (0.51 mmol, 56 μL) were dissolved in DMSO (1 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 μL) were added and heated in a microwave at 120° C. for 6 minutes. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with water and the product was extracted with ethylacetate. Removal of organic solvents in vacuo and purification by HPLC provided Compound A118 as a white solid (14 mg, 14%). Exact mass calculated for C23H29N5O5S 487.57, found 488.20 (MH+).