Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=O>C1COCC1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)OCC(=O)N2C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OCCN2C

Procedure:
Still following the procedure of Example 1, 21 g of 4-methyl-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazin-3-one were reduced with 1M BH3 in THF solution. The reaction was carried out and the product isolated by the procedure of Example 1 to yield 4-methyl-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine; B.P.=105° C. at 0.025 torr; yield=16 g. Following the procedure of example 1, 16 g of the above 4-methyl-7-methoxy-2H-[1,4]benzoxazine was subjected to a Birch reduction with lithium metal in anhydrous ammonia as follows: the oxazine was dissolved in 75 ml of THF and the solution added to a solution of 4.42 g of lithium metal dissolved in 300 ml of anhydrous ammonia. 100 ml of anhydrous ethanol were added during the course of the reaction. The product, 4-methyl-7-methoxy-3,4,5,8-tetrahydro-2H-[1,4]benzoxazine, weighed 15.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:15]([NH:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1-c1ccccc1F
Solvent: ClCCl
Product: O=C(NC(=S)Nc1ccccc1-c1ccccc1F)c1ccccc1

Procedure:
Reaction of 2-amino-2'-fluorobiphenyl (5 g) with benzoylisothiocyanate (4.4 g) in dichloromethane (120 ml) at ambient temperature for 8 hours gave N-benzoyl-N'-(2'-fluoro-2-biphenylyl)thiourea (m.p. 110°-111° C.).
Reaction SMILES: [CH2:1]([C:3]1[C:11](/[C:12](/[CH3:15])=[CH:13]\[CH3:14])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(C1C(C(CC)=C)=C2C=CC=CN2N=1)C.C1CCCCC=1>[Pd]>[CH:12]([C:11]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)([CH2:13][CH3:14])[CH3:15]
Reactant: C/C=C(/C)c1c(CC)nn2ccccc12
Agent: [Pd]
Agent: C=C(CC)c1c(CC)nn2ccccc12
Solvent: C1=CCCCC1
Product: CCc1nn2ccccc2c1C(C)CC
Temperature: 85 °C
Yield: 86 %

Procedure:
A 0° C. solution of 1-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)ethanone (1.33 g, 7.1 mmol) in THF (20.0 mL) was treated with 1.0M THF solution of ethyl magnesium bromide (9.0 mL, 9.0 mmol). The reaction was allowed to warm to room temperature and stirred for 2.5 hours. An additional amount of ethyl magnesium bromide (2.0 mL, 2.0 mmol) was added and the reaction stirred for 1.5 hours. The reaction was quenched with 2N HCl then extracted with ethyl acetate, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (20% ethyl acetate/heptane) to give 0.55 g (39%) of a yellow oil as a 4:1 mixture of the regio-isomers of 2-ethyl-3-[(1Z)-1-methylprop-1-enyl]pyrazolo[1,5-a]pyridine and 2-ethyl-3-(1-ethylvinyl)pyrazolo[1,5-a]pyridine. The mixture (0.22 mg, 1.1 mmol) was placed in a flask with cyclohexene (8.0 mL), 10% palladium on carbon (0.05 g) and AICl3 (0.016 g) and heated to 85° C. for 39 hours. The reaction was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (20% ethyl acetate/heptane) to give 0.19 g (86%) of a clear oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=7.0 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.00–6.96 (m, 1H), 6.64–6.60 (m, 1H), 2.93–2.82 (m, 3H), 1.83–1.74 (m, 2H), 1.40–1.33 (m, 6H), 0.87 (t, J=7.4 Hz, 3H); MS (EI) m/z 203.1 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:26])[C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH2:16][CH2:15]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(C(C)C)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc(N2CCN(C(=O)C(=O)O)CC2)c(C(C)(C)C)c1
Yield: 97.3 %

Procedure:
To a stirred solution of ethyl {4-[2-tert-butyl-4-(1-methylethyl)phenyl]piperazin-1-yl}(oxo)acetate (Example 170, 0.113 g, 0.34 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 1 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide {4-[2-tert-butyl-4-(1-methylethyl)phenyl]piperazin-1-yl}(oxo)acetic acid (0.110 g, 97%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[O:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:25]1[O:26][C:27]([CH3:28])=[C:23]([CH2:22][O:21][C:18]2[N:19]=[CH:20][C:15]([CH2:14][O:1][C:2]3[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=3)=[CH:16][CH:17]=2)[N:24]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (533 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethoxy]-1-methyl-1H-pyrazol-4-yl]acetate (623 mg, yield 81%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [Cr]([O-])(OC(C)(C)C)(=O)=[O:2].[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[CH:12]1[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:10][C:11]1[C:16](=[O:2])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:18])[C:12]=1[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1C(C)CCCC1(C)C
Reactant: CC(C)(C)O[Cr](=O)(=O)[O-]
Product: CCCCC1=C(C)C(=O)CCC1(C)C

Procedure:
18 g Of the mixture of alkenes obtained by dehydration of dihydro-β-ionol as described in example 1 was dissolved in 150 ml of methanol and hydrogenated at atmospheric pressure using 0.5 g of a catalyst consisting of 5% Palladium on charcoal. Hydrogenation was stopped when the uptake of hydrogen markedly slowed down. A 1:1 mixture of 1,3,3-trimethyl-2-(but-1-yl)-cyclohex-1-ene and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane was obtained. This mixture was oxidized with tert.butyl chromate as described in example 1, yielding a mixture of the title compound and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane. The mixture was fractionated yielding 6.75 g of the title compound boiling at 90°-92° C. (4 Torr).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[N:25]=[CH:26][N:27]([C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2Cc2ccccc2)n1
Temperature: 110 °C
Reaction time: 17 h
Yield: 65.6 %

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.47 mmol, from Example 62, Step 2) and 4-(tributylstannyl)-1-trityl-1H-imidazole (0.28 g, 0.47 mmol, Synthonix) in toluene (9.0 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol) was added and the reaction was stirred at 110° C. for 17 h. Solvent was removed in vacuo and the product was purified by flash chromatography, eluting with a gradient from 0-35% EtOAc in hexanes to afford product as a white solid (0.17 g, 66%).
Reaction SMILES: CO.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:4][CH2:5][CH3:6].Cl[C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C[O-].[Na+]>O>[Cl:14][C:12]1[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:13]=1[S:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Reactant: Sc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCOc1cc([N+](=O)[O-])c(OCCCC)c(Sc2ccccc2)c1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 110 parts of methanol was added 51 parts of 2,5-dibutoxy-4-chloronitrobenzene. The mixture was heated to 50° C. A methanol (50 parts) solution of 25 parts of p-chlorobenzenethiol and 9.8 parts of sodium methylate was added dropwise thereto over a period of about one hour to carry out a reaction. After completion of the dropwise addition, the reaction was further continued under reflux for 5 hours. After completion of the reaction, 85 parts of water were added to the reaction mixture to precipitate a crystal. The resulting crystal was recovered by filtration and recrystallized from methanol to obtain 59 parts of 4-chlorophenylthio-2,5-dibutoxynitrobenzene having a m.p. of 74° to 75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(N(CC)CC)C>C(Cl)Cl>[N:17]1([CH2:16][CH2:15][CH2:14][NH:13][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCCCn1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 4-nitrobenzoyl chloride (18.5 g, 0.1 mol) in DCM (200 ml) was added dropwise to a stirred solution of 1-(3-aminopropyl)imidazole (14.0 g, 0.112 mol) and triethylamine (15 ml, 0.107 mol) in DCM (200 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour, and the solid which had separated out was collected by filtration and washed with water (100 ml) and acetone (100 ml) to give the product (21.6 g, 79%). NMR: 1.9-2.0 (m, 2H), 3.2-3.3 (m, 2H), 4.0 (t, 2H), 6.85 (s, 1H), 7.2 (s, 1H), 7.65 (s, 1H), 8.05 (d, 2H), 8.3 (d, 2H), 8.8 (br s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:22][C:23]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=O.[C:40]1(=[O:47])[CH2:45][CH2:44][CH2:43][C:42](=[O:46])[CH2:41]1>C(O)(CC)(C)C>[Cl:22][C:23]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:29]=[CH:28][C:24]=1[C:25]([CH:41]1[C:42](=[O:46])[CH2:43][CH2:44][CH2:45][C:40]1=[O:47])=[O:27]
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: O=C1CCCC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CCCC2=O)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
0.28 g of potassium carbonate and 0.77 g of N,N'-dicyclohexylcarbodiimide were added to a solution mixture comprising 1.0 g of 2-chloro-4-methanesulfonyl-3-methoxycarbonyl benzoic acid, 0.38 g of 1,3-cyclohexanedione and 30 ml of t-amyl alcohol. The mixture was stirred at 80° C. for 3 hours. It was concentrated under reduced pressure, and an aqueous potassium carbonate solution was added thereto. Insoluble substances were removed by filtration. The filtrate was washed with chloroform, then acidified by an addition of concentrated hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a crude desired product. This crude product was crystallized from ethanol to obtain 0.3 g of the desired product. Melting point: 160°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[P-](F)(F)(F)(F)F.[CH2:22]([O+](CC)CC)[CH3:23]>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:22][CH3:23])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Br)ccc2[nH]ncc12
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCn1cc2c(C(=O)OC)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a solution of methyl 5-bromo-1H-indazole-4-carboxylate (2.00 g, 7.84 mmol) in ethyl acetate (80 mL) was added triethyloxonium hexafluorophosphate (2.92 g, 11.8 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=5/95→50/50) to give the title compound (2.03 g, yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.C[Si](C)(C)N[Si](C)(C)C.[K].[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41].Cl>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:28]([NH:29][C:43]([NH:42][CH2:40][CH3:41])=[O:44])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2nc(NCCCCN(CC)CC)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (5° C.) solution of 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (0.61 g) from Example 53 in THF (6 mL) was added potassium hexamethyldisilazane (0.308 g) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes. Then ethyl isocyanate was added, and the reaction mixture was stirred for an additional 18 hours at ambient temperature. The product was isolated by pouring the reaction mixture into approximately 200 mL of 0.25N aqueous HCl and filtering the resulting solution. The filtrate was made basic with 50% aqueous sodium hydroxide, and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and the filtrate concentrated under vacuum. The product was purified by radial chromatography eluting with a solvent mixture of 90:10:1 EtOAC:MeOH:TEA to afford the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:22]([NH:28][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and n-hexylamine were used to obtain N-n-Hexyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[CH3:26])=[CH:18][C:17]=1[OH:27]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[C:17]([OH:27])[CH:18]=4)[CH:23]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1cc2c(cc1O)CCNC2C
Product: COc1cc2c(cc1O)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[C:3]=1[CH3:19].[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:3]1([CH3:19])[C:4]2[C:5](=[O:18])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:17])[C:13]=2[C:14]([CH3:16])=[CH:15][CH2:2]1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(Cl)c(C)c2c1C(=O)c1ccccc1C2=O
Solvent: O
Product: CC1=CCC(C)(C2CNCCN2CCO)C2=C1C(=O)c1ccccc1C2=O
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-1,4-dimethylanthraquinone (1 g) and 1-(2-hydroxyethyl)piperazine (5 g) is heated at 150° C. for 30 min. After cooling to room temperature, water is added, and the material is filtered. Recrystallization from chloroform yields 1-[1-(2-hydroxyethyl)piperazinyl]-1,4-dimethylanthraquinone.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]#[N:38])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (0.12 g, 1.3 mmol) and triethyloxonium tetrafluoroborate (0.25 g, 1.3 mmol) in tetrahydrofuran (2 mL) became a solution after stirred for 15 min. After another 45 min, this solution was added to a mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (124 mg, 0.433 mmol) in ethanol (3.4 mL) and the resultant mixture was heated at reflux for 2 h. The crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (65 mg, 44%). LCMS calculated for C18H21N4OS (M+H)+: m/z=341.1. Found: 341.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.98 (1H, s), 8.00 (1H, d, J=5.2 Hz), 7.66 (1H, d, J=5.2 Hz), 5.86 (1H, d, J=6.4 Hz), 5.19 (1H, m), 4.92 (1H, m), 2.61 (2H, d, J=6.0 Hz), 2.43 (2H, m), 2.01 (5H, m), 1.64 (3H, d, J=6.4 Hz), 1.40 (2H, m) ppm.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:21]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:21]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: COC(=O)N1CCC(c2nccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (112 mg, 0.468 mmol), methyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (56 mg, 0.23 mmol), and cesium carbonate (153 mg, 0.468 mmol) in DMSO (0.8 mL) was heated at 80° C. for 20 h. The reaction mixture was partitioned between Teac and brine. The aqueous layer was back extracted with Teac (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% Teac in hexane, to provide methyl 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as white solid. MS (ESI, pos. ion) m/z: 458.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH3:33][N:34]1[C:38]([CH:39]=[O:40])=[CH:37][N:36]=[C:35]1[CH3:41]>C1COCC1>[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:39]([C:38]4[N:34]([CH3:33])[C:35]([CH3:41])=[N:36][CH:37]=4)[OH:40])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ncc(C=O)n1C
Reactant: FC(F)(F)c1ccc(Cc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)n1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline (1.00 g, 2.19 mmol, Intermediate 16) was dissolved in THF (20 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −78° C. in dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.74 mL, 2.79 mmol) was then added dropwise via syringe over approximately 5 minutes. The contents were stirred at −78° C. for approximately 10 minutes, then a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (0.30 g, 2.4 mmol) in THF (20 mL) was added via cannula and stirred for 10 minutes at −78° C. The dry ice bath was then removed and replaced with an ice water bath and stirred at 0° C. for approximately one hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was extracted with a saturated, aqueous NH4Cl solution and deionized water, then separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH; MeOH in DCM) to provide the title compound. MS (ESI): mass calcd. for C26H24ClF3N4O, 500.2; m/z found, 501.4 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.15-8.11 (m, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.26-7.21 (m, 2H), 7.59-7.55 (m, 1H), 6.52 (d, 1H), 5.97 (s, 1H), 4.35 (s, 2H), 4.13 (t, J=7.5 Hz, 4H), 3.49 (s, 3H), 2.33 (s, 3H), 2.28-2.20 (m, 2H).