Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(NC1C=C(C2C3N(C4C=CC=CC=4)C=NC=3C=C(C#N)C=2)C=CC=1)(=O)C>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.C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:17]=[C:16]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2cccc(F)c2)c2c(c1)ncn2-c1ccccc1
Yield: 42.8 %

Procedure:
This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-fluorophenylboronic acid (70 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar manner to 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by a similar procedure afforded the title compound (67 mg, 43%) m/z, 314.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6](P(OCC)(OCC)=O)[C:7]([O:9][CH3:10])=[O:8])[CH3:4].[Cl:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>O1CCCC1>[Cl:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:6]([O:5][CH2:3][CH3:4])[C:7]([O:9][CH3:10])=[O:8])=[CH:25][CH:24]=1
Reactant: CCOC(C(=O)OC)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=Cc1ccc(OCCCl)cc1)C(=O)OC
Reaction time: 1 h

Procedure:
To 150 ml of freshly distilled tetrahydrofuran, placed in a bath of ice-cold water at 0° C., under argon, add sodium hydride (0.0473 mol) and then methyl 2-ethoxy-2-diethylphosphonoacetate (0.0394 mol) while maintaining the temperature at 0° C. After stirring for 1 hour, add 4-(2-chloroethoxy)benzaldehyde (0.0394 mol) dissolved in a minimum of freshly distilled tetrahydrofuran, under argon at 0° C. Stir the solution for 1 hour at 0° C. Allow the solution to return to ambient temperature while stirring for 16 hours. Evaporate off the tetrahydrofuran. Add 100 ml of water and then extract with 100 ml of dichloromethane twice. The organic phase is washed with water, dried over MgSO4 and then evaporated. The oily product is purified over a column of silica gel using the eluant mixture: petroleum ether/dichloromethane (1/1). The title compound is obtained in the form of an oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[C:49]([O:52][CH2:53]C)(=[O:51])C>CN(C)C=O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[CH3:53][O:52][C:49]([C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1)=[O:51]
Reactant: CCOC(C)=O
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(N)(=O)=O)s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromothiophene-2-sulfonamide (0.50 g, 2.1 mmol), triethyl amine (1 mL), methanol (1 mL), palladium acetate (0.046 g, 2.1 mmol) and 1,3-bis(diphenylphosphino) propane (0.085 g, 2.1 mmol) (addition in that order) in dimethylformamide (5 mL, anhydrous) is saturated with carbon monoxide gas, at room temperature. This reaction mixture is heated to 100° C. and stirred overnight, under a carbon monoxide atmosphere. 10 mL of brine and 10 mL of ethyl acetate are added to the reaction mixture. The organic phase is separated and the aqueous layer is extracted with 10 mL ethyl acetate. The combined organic layers are dried over sodium sulfate, concentrated in vacuo, and then chromatographed on silica (0–1% methyl alcohol in methylene chloride) to give the title compound, as a yellow solid (0.15 g, 34% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:27])[C:9]=2[N:8]=[C:7]1[CH2:28][CH3:29].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:27][C:10]1[C:9]2[N:8]=[C:7]([CH2:28][CH3:29])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:13][C:12]=2[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 35.2 %

Procedure:
1-(4-Aminobutyl)-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (7.0 g, 18 mmol) was mixed with chloroform (180 mL), and the suspension was cooled with an ice/water bath. Methanesulfonyl chloride (1.59 mL, 20.5 mmol) was added dropwise, and the reaction was stirred for 18 hours. Saturated aqueous sodium carbonate was added to the solution, and the layers were separated. The precipitate in the aqueous layer was isolated by filtration, washed with ethanol and diethyl ether, and recrystallized from a mixture of methanol and chloroform. During the recrystallization, the hot solution was filtered through a glass fiber filter. N-[4-(4-Amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (2.96 g) was isolated as an off-white solid. The organic layer was concentrated under reduced pressure, and the residue was stirred with boiling methanol and isolated by filtration to afford 1.90 g of N-[4-(4-amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white solid, mp 213.5-215° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[C:23]5[NH:29][CH2:30][CH2:31][NH:32]C(=O)OCC4C=CC=CC=4)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Si](I)(C)(C)C>C(#N)C.CO>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[C:23]5[NH:29][CH2:30][CH2:31][NH2:32])=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCNc1n[nH]c2ccc(-c3ccc(NCC4(c5ncccc5F)CCC4)nn3)cc12)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: NCCNc1n[nH]c2ccc(-c3ccc(NCC4(c5ncccc5F)CCC4)nn3)cc12
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
Benzyl 2-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-ylamino)ethylcarbamate (48 mg, 84 μmol) was dissolved in acetonitrile (5 mL), and TMSI (0.5 mL) was added. The reaction was stirred for 15 min, diluted with methanol (15 mL), concentrated, and was directly purified by reverse phase column chromatography to yield 20 mg (88%) of N1-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-yl)ethane-1,2-diamine as a yellow solid, m/z=433 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: NCc1ccccc1Br
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(NCc1ccccc1Br)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 2-Bromo-benzylamine to produce N-(2-Bromo-benzyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26].[C:27](OCC)(=[O:29])[CH3:28]>C1COCC1>[C:27]([CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([CH3:19])[C:21]1=[O:26])(=[O:29])[CH3:28]
Reactant: CN1CCCCC1=O
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)C1CCCN(C)C1=O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
20.6 g of diisopropylamine (0.2 mol) were placed in 200 ml of dry THF under nitrogen and cooled to −80° C. 80 ml n-butyllithium in hexane (2.5 M, 0.2 mol) were slowly added dropwise. After the addition it was allowed to stir for 15 min and then 22.6 g N-methyl-2-piperidone (0.2 mol) were added dropwise. The reaction mixture was stirred for 30 min and then 17.6 g of dry ethyl acetate (0.2 mol) was added. The reaction mixture with stirring overnight was allowed to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml 6M HCl. The aqueous phase was extracted five times with 100 ml ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The product (keto form:enol form=1:1) was fractionated by distillation at 0.6 mbar and obtained as a yellowish liquid (bp 70° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.CN([C:23]([O:27][N:28]1N=NC2C=CC=C[C:29]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNOC.[NH4+].[Cl-]>CN(C=O)C.CCN(CC)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10]([N:28]([O:27][CH3:23])[CH3:29])=[O:11])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccccc1C(CC(=O)O)c1ccc(Br)cc1
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-3-o-tolyl-propionic acid (3.7 g) in DMF (45 mL) was added TBTU (5.2 g) and Et3N (4.8 mL) at 0° C. The reaction mixture was stirred at rt for 10 min and again cooled down to 0° C. N,O-dimethylhydroxylamine hydrochloride (1.36 g) was added and the mixture was stirred at rt for 1.5 hour. A saturated solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:2) to yield the title compound as a colorless oil (4.1 g, 97%), MS (ESI+): m/z=362.0750 ([M+H]+, 1Br).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of methyl 4-(methylamino)benzoate (2.0 g, 12.1 mmol) in THF (30 mL) was added LAH (6.1 mL, 2.4 M in THF, 14.5 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The reaction was quenched with EtOAc (50 mL) and water (2 mL). The mixture was dried (Na2SO4) and concentrated. Purification by silica gel chromatography (PE:EtOAc=3:1) gave 1.0 g (60%) of the title compound as a yellow oil. [M+H] Calc'd for C8H11NO, 138. Found 138.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH2:2]1.CC[N:12](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C.Cl>CN(C=O)C>[S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([NH2:12])=[O:9])[CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1=CCCSC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)C1=CCCSC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,6-dihydro-2H-thiopyran-3-carboxylic acid (0.84 g, 5.8 mmol) in DMF (29 mL) was added DIPEA (3.4 g, 26 mmol), followed by TBTU (4.1 g, 13 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes, then HMDS (2.1 g, 13 mmol) was added. The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was acidified with 1N aqueous HCl, and extracted with EtOAc (3×). The combined organic extracts were again washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH/DCM). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 6.68-6.69 (m, 1H); 3.38 (q, J=2.2 Hz, 2H); 2.70 (t, J=5.8 Hz, 2H); 2.50-2.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[Cl:14])[CH2:7][N:6]1[C:2]([NH:1][CH3:21])=[C:3]([C:16]([NH2:18])=[O:17])[N:4]=[N:5]1
Reactant: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1c(C(N)=O)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide (2.86 g, 10.0 mmol), methyl iodide (1.42 g, 10.0 mmol), and potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylformamide (20 ml) is stirred 48 hours at ambient temperature, poured into water (150 ml), and filtered. Chromatography provides 1-(3,4-dichlorobenzyl)-5-methylamino-1,2,3-triazole-4-carboxamide.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].Br.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=O>C(O)C>[F:12][C:2]([C:3]1[S:4][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:5]=1)([F:1])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: NC(=S)C(F)(F)c1ccccc1
Agent: Br
Solvent: CCO
Product: FC(F)(c1ccccc1)c1nc(-c2ccncc2)cs1
Yield: 47.9 %

Procedure:
To a solution of 2,2-difluoro-2-phenylthioacetamide (1.57 g, 0.0092 mol) in 95% ethanol (20 mL) was added α-bromo-4-acetylpyridine hydrobromide (3.20 g, 0.012 mol) and the mixture warmed on a steam bath for thirty minutes. The product was isolated in the usual way and recrystallized from ethyl acetate/hexane to afford 1,1-difluoro-1-phenyl-[4-(4-pyridyl)-2-thiazolyl]methane (1.27 g, 48%). mp. 54.5°-55.5° C.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[C:8]([CH3:10])=O.C([O-])(=O)C.[Na+]>O>[CH2:13]([O:12][C:7](=[O:11])[C:8](=[N:2][NH:3][C:4](=[O:5])[NH2:6])[CH3:10])[CH3:14]
Reactant: NNC(N)=O
Reactant: CCOC(=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)=NNC(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 100 mL round bottomed flask is charged with semicarbazide hydrochloride (2 g, 17.93 mmol), ethyl pyruvate (11.8 mL) and sodium ethanoate (2.97 g). Then water (9 mL) is added. The mixture is stirred at room temperature for 90 minutes, then it is filtered and solids are washed with more water. White solid is dried under vacuum in an oven (40° C.) overnight. 2.66 g of ethyl-2-(carbamoylhydrazono)-propanoate is obtained pure. Phosphoryl chloride (3.28 mL) is added dropwise to dimethylformamide (7.13 mL) at 0° C. Cooling bath is removed to reach room temperature Then, the mixture is heated to 40° C. and ethyl-2-(carbamoylhydrazono)propanoate previously obtained (2.66 g, 15.36 mmol) is added in several portions over 15-20 min (gas evolution during the addition). When internal temperature is 55° C., heating bath is removed so internal temperature is maintained in the range 60-70° C. Then, the mixture is heated to 80° C. Almost no more gas evolution is observed once the reaction is stabilized at 80° C. The resulting suspension is stirred at 80° C. for 2 h. Reaction mixture is poured over ice/water (30 mL) mixture and stirred to get a suspension. 50% solution of sodium hydroxide is added dropwise until pH 10 is reached. The solution is stirred at 50° C. for 5 min. Solution is then cooled with ice/water bath and 35% aqueous solution of hydrochloric acid is added until pH 7. The mixture is extracted with ethyl acetate. Organic layer is decanted, dried over magnesium sulfate and solvent is evaporated under reduced pressure. The residue is triturated with hexane and some drops of dichloromethane to give 1.6 g of ethyl 4-formyl-1H-pyrazole-3-carboxylate that is used in the next step without further purification. MS (m/z): 169 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:19])[CH2:15][N:16]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:19])[CH2:15][NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCCCCc1ccccc1
Yield: 106 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 4.5 g of 3-(5-phenylpentyloxy)-2-hydroxypropylazide (prepared as described in Preparation 50), 1.3 g of lithium aluminum hydride and 250 ml of anhydrous tetrahydrofuran were used, to give 4.3 g of the title compound as a pale yellow oil having an Rf value of 0.09 (on silica gel thin layer chromatography, using a 10:2:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]1[CH2:21]OC[CH2:18]1>>[CH2:21]([O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH:17]=[CH2:18]
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCOc1cc(Cl)ccc1C=O
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 4-chloro-2-hydroxybenzaldehyde (254 mg, 1.62 mmol) and cesium carbonate (793 mg, 2.43 mmol) in THF (3 mL) was heated to reflux for 3 h. After the reaction mixture was cooled at room temperature, the solvent was evaporated and the residue partitioned between ethyl acetate and hydrochloric acid (1N). The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (AcOEt/Hexanes, 1:9) to give the title product (97%): 1H NMR (400 MHz, Cl3CD) δ 10.46 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.05 (dd, J=0.78, 8.3 Hz, 1H), 6.99 (d, J=0.78 Hz, 1H), 6.09 (m, 1H), 5.45 (m, 2H), 4.67 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH2:3][CH2:2]1.[NH2:17][CH2:18][CH:19]([OH:31])[CH2:20][N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>CC#N>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][CH:19]([OH:31])[CH2:18][NH:17][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:9]=1
Reactant: O=C(O)c1cccc(CN2CCOCC2)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CN2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 3.6 %

Procedure:
To a solution of 3-(morpholinomethyl)benzoic acid (60 mg, 0.27 mmol) in MeCN (3 mL) were added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (60 mg, 0.29 mmol), TEA (70 mg, 0.69 mmol) and the resulting mixture was stirred at 20° C. for 10 min. BOPCl (70 mg, 0.28 mmol) was added and the reaction mixture was stirred at 20° C. for 16 h. The reaction solution was concentrated and the residue was purified by prep-HPLC to give the title compound (4 mg, Yield 3.6%). 1H NMR (CD3OD, 400 MHz): δ 7.77 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.07-7.14 (m, 3H), 7.00-7.06 (m, 1H), 4.11 (quin, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.64-3.72 (m, 4H), 3.43-3.59 (m, 4H), 2.83-2.93 (m, 4H), 2.61-2.74 (m, 2H), 2.44 (brs, 4H). LCMS (m/z): 410.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH:8]=[CH:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(CC=CC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1

Procedure:
A mixture of 2-11 (95 mg, 0.22 mmol) and 10% Pd/carbon (50 mg) in EtOH (3 mL) was stirred under a balloon of hydrogen for 2 h. Following filtration, evaporative removal of the solvent gave 2-12 as a clear oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[N:13]1[C:22]2[C:17](=[CH:18][N:19]=[CH:20][C:21]=2[CH:23]=O)[CH:16]=[CH:15][CH:14]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:23]2[C:21]2[CH:20]=[N:19][CH:18]=[C:17]3[C:22]=2[N:13]=[CH:14][CH:15]=[CH:16]3)[CH2:3][CH2:2]1
Reactant: O=Cc1cncc2cccnc12
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc2nc(-c3cncc4cccnc34)n(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.080 g, 0.48 mmol) in DMF (1.17 mL) and water (0.04 mL) were added the title compound from Example 8 Step A (0.084 g, 0.53 mmol) and OXONE® (0.192 g, 0.313 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (50% ethyl acetate in hexanes, then 100% ethyl acetate) provided the title compound: LCMS m/z 304.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1 H), 9.13 (m, 1 H), 9.07 (s, 1 H), 8.43 (d, J=8.3 Hz, 1 H), 7.78 (dd, J=8.7, 4.8 Hz, 1 H), 7.63 (dd, J=8.2, 4.2 Hz, 1 H), 7.34 (dd, J=8.7, 2.2 Hz, 1 H), 7.07 (m, 1 H), 3.55-3.53 (m, 1 H), 0.62-0.61 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23]C(=O)OCC=C)[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:23][C:19]1[C:18]([F:30])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:15])([CH3:14])[CH3:16])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1

Procedure:
A solution of 2-propen-1-yl {3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (220 mg, 0.515 mmol) in TBAF (1 mL, 1.0 mmol) in 1M THF was heated in a microwave reactor at 130° C. for 10 min. The crude reaction mixture was evaporated onto silica gel and chromatographed (1:9:90 NH4OH:MeOH:DCM in DCM 10-80%). The title compound was obtained as a white solid (100 mg, 56% yield). MS (ESI): 344.1 [M+H]+.