Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[B:18](OC)([O:21]C)[O:19]C.CC1C=C(C2C=CC(C(F)(F)F)=CC=2)SC=1C=O>>[CH:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[B:18]([OH:21])[OH:19])=[O:15]
Reactant: COB(OC)OC
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Product: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1B(O)O

Procedure:
The titled compound is prepared from 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10 mmole) and trimethyl borate (5.68 g, 50.0 mmole) in a similar manner to 3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)=[CH:4][C:3]=1I.C1C[O:18][CH2:17]C1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: Cc1cc(-n2cnnc2)cc(I)c1N
Reactant: C1CCOC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(-n2cnnc2)cc(C=O)c1N
Reaction time: 0.5 h

Procedure:
A stirred mixture of 4-(4-amino-3-iodo-5-methylphenyl)-1,2,4-triazole (3.0 g) and tetrakis (triphenylphosphine) palladium (0) (1.0 g) in THF (300 cm3) was deoxygenated with a stream of nitrogen for 0.5 hours. The mixture was then placed under carbon monoxide (ca 2 atmospheres pressure), warmed to 50°, and a solution of tri-n-butyltin hydride (3.2 g) in THF (200 cm3) was added dropwise over 4 hours. After a further 0.5 hours, the mixture was poured onto an aqueous solution of potassium fluoride (10 g) in water (200 cm3) and the mixture was extracted with dichloromethane (5×200 cm3). The combined and dried (MgSO4) extracts were evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with dichloromethane:methanol, 9:1. Combination and evaporation of the appropriate fractions gave a solid which was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 250°-252° (1.87 g), characterised spectroscopically to be identical to the product of Preparation 30.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]3[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=3[S:22][N:21]=2)=[O:19])=[CH:13][C:12]=1[C:30]([F:33])([F:32])[F:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]3[CH:25]=[CH:26][C:27]([O:29][C:6]4[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:28][C:23]=3[S:22][N:21]=2)=[O:19])=[CH:13][C:12]=1[C:30]([F:32])([F:31])[F:33]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1nsc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)nsc3c2)n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 72 mg (0.44 mMol) 2-amino-4,6-dichloropyrimidine, 143 mg (0.40 mMol) 6-hydroxy-benzo[d]isothiazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide and 280 mg (1.32 mMol) K3PO4 in 2 ml NMP is stirred for 6 h at 70° C. Then the mixture is diluted with EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/EtOH 9:1) gives the title compound: MS: [M−1]=482/484; TLC(CH2Cl2): Rf=0.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH2:14]O)[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C1COCC1>[Br:40][CH2:14][C:12]1[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(CO)cc(-c2ccccc2Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CBr)cc(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
187 mg (0.68 mmol) of the compound from Example 111A and 266 mg (1.01 mmol) of triphenyl-phosphine were dissolved in 6 ml of THF, and 336 mg (1.01 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). This gave 275 mg (>100% of theory) of the target compound, which were immediately reacted further.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][N:22]([O:23][CH3:24])[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC(=O)O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.4 %

Procedure:
A solution of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-butanoic acid (291 mg, 1.07 mmol, from Step A), N,O-dimethylhydroxylamine hydrochloride (177 mg, 1.82 mmol), EDC (350 mg, 1.82 mmol), and triethylamine, 0.25 mL, 1.82 mmol) were stirred together in 5 mL CH2Cl2 for 16 h. The mixture was diluted with 100 mL CH2Cl2 and washed with 1M HCl. The organic layer was dried over MgSO4 and concentrated. Flash chromatography (1/1 hexane/EtOAc) afforded 237 mg (71%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:28]3[CH:29]=[CH:30][N:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[N:27]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1ccn(-c2cccnc2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cccnc2)n1
Yield: 98.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.050 g, 0.179 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.034 g, 0.179 mmol), DIPEA (0.094 ml, 0.538 mmol 1), HOBt hydrate (0.041 g, 0.269 mmol) and EDCI (0.052 g, 0.269 mmol) using the method of Example 274 affording 0.079 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 4.38 (m, 2H), 4.49 (m, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.59 (m, 1H), 7.88 (m, 3H), 8.30 (m, 1H), 8.35 (d, 1H), 8.59 (d, 1H), 8.65 (d, 1H), 9.18 (d, 1H).
Reaction SMILES: [OH:1][C:2]1([CH:13]([OH:15])[CH3:14])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16].O1CCOCC1>CO>[ClH:16].[OH:15][CH:13]([C:2]1([OH:1])[CH2:5][NH:4][CH2:3]1)[CH3:14]
Reactant: CC(O)C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(O)C1(O)CNC1

Procedure:
1,1-Dimethylethyl 3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate (200 mg, 0.922 mmol) was dissolved in methanol (5 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([NH2:17])(=[O:16])[CH2:14][CH3:15]>>[CH3:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:17][C:13](=[O:16])[CH2:14][CH3:15])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCC(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Product: CCC(=O)Nc1cc(C(=O)OC)cc(C)n1
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (2.16 g, a pale yellow solid) from methyl 2-chloro-6-methylisonicotinate (3.00 g, 16.2 mmol) and propionamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C:14]1([CH3:18])[CH2:17][O:16][CH2:15]1>ClCCl.N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C:14]2([CH3:18])[CH2:17][O:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 20 °C

Procedure:
4-Toluenesulfonyl chloride (20 g, 105 mmol) was dissolved in a mixture of dichloromethane (DCM) (50 ml) and pyridine (50 ml) and cooled in an ice bath. 3-(hydroxymethyl)-3-methyloxetane (100 mmol, 9.9 mL) was added dropwise. The temperature was increased to 20° C. overnight. The solution was diluted with DCM (100 mL) and extracted with water. The organic phase was dried over magnesium sulfate and filtered. The volatile solvents were removed by evaporation. The remaining material was concentrated several times with toluene to remove the residual pyridine and then with chloroform to remove the residual toluene. Yield: 22 g of a white crystalline solid (92%). TLC: Rf(petroleum ether/ethyl acetate, 1:1) 0.56.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Na].Cl>O1CCCC1.C(O)(=O)C>[CH:9]1([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC[C@H]1CCCNC1
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 21 h
Yield: 59.9 %

Procedure:
To a solution of 900 mg of (3S)-3-piperidylmethanol in 60 ml of tetrahydrofuran, 1.05 g of cyclohexanecarbaldehyde, 0.54 ml of acetic acid and 2.5 g of sodium triacetoxyborohydrate were successively added at room temperature by the order stated, followed by 21 hours' stirring at the same temperature. The reaction liquid was rendered acidic with 1N hydrochloric acid and washed with chloroform. The aqueous layer was rendered basic with 4N aqueous sodium hydroxide solution, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 990 mg of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:19]=2)[CH3:17])=[CH:6][CH:5]=1)([O-])=O.CC(O)=O.CCOC(C)=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:19]=2)[CH3:17])=[CH:6][CH:5]=1
Reactant: CC(COc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(COc1ccc(N)c2ccccc12)c1ccnc(NC(=O)OC(C)(C)C)c1
Yield: 107.6 %

Procedure:
A solution of the nitroarene (54) (0.61 g, 1.441 mmol) in a mixture of MeOH (20.0 mL), AcOH (5.0 mL) and EtOAc (10.0 mL) was passed through a Thales H-Cube (1.0 mL·min−1, 45° C., 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode). The solvent was evaporated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 solution and EtOAc. The organic layer was washed with water and brine and then dried (MgSO4) and evaporated in vacuo to furnish the title compound (55) (0.61 g, 97%): m/z 394 (M+H)+ (ES+).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(O[CH:13](OCC)[N:14]([CH3:16])[CH3:15])C>>[CH3:13][N:14](/[CH:16]=[N:9]/[C:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:8])[CH3:15]
Reactant: CCOC(OCC)N(C)C
Reactant: NC(=O)c1ccncc1
Product: CN(C)/C=N/C(=O)c1ccncc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
Isonicotinamide (2.00 g, 16.38 mmol) and N,N-dimethylformamide diethyl acetal (2.8 ml, 16.38 mmol) were combined and heated to 120° C. A short path distillation apparatus was used to collect the ethanol that was liberated during the reaction. The reaction mixture was an orange solution. After 15 minutes, additional N,N-dimethylformamide diethyl acetal (1.0 ml, 5.83 mmol) was added to the reaction mixture. After 1.5 hours, the reaction mixture was cooled to room temperature. The reaction mixture solidified upon cooling and was placed under high vacuum overnight to give the title compound (2.92 g, 16.48 mmol) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C(#N)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cn1ccnc1
Reactant: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nccn1C
Temperature: -20 °C
Yield: 59.9 %

Procedure:
N-methylimidazole (320 g, 3.9 mol) was combined with 2 L acetonitrile and 1 L triethylamine in a 12 L flask equipped with a mechanical stirrer and the solution cooled to −20° C. Ethyl chloroformate (1000 g, 9.2 mol) was added with stirring, keeping the temperature between −20° C. and −25° C. The reaction was allowed to lowly warm to room temperature and stir for 36 h. Precipitated triethylamine hydrochloride was removed by filtration and the solution concentrated in vacuo at 65° C. The resulting oil was purified by distillation under reduced pressure (2 torr, 102° C.) to provide a white solid (360 g, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[C:13]([C:20](OCC)=[O:21])#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[N:7]1([C:4]2[S:3][C:2]3=[N:1][C:20](=[O:21])[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nnc(N2CCCCC2)s1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N3CCCCC3)nn12

Procedure:
The procedure used was as described in Example 5. However, there were used 9.2 g of 2-amino-5-piperidino-1,3,4-thiadiazole, 8.5 g of diethyl acetylenedicarboxylate and 200 ml of ethanol. Thus 9.8 g (63.7% of the theoretical yield) of ethyl 2-piperidino-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylate, melting at 125° to 127° C., were obtained.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].CON(C)[C:9]([C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:15]2[CH:14]=[C:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=1)=[O:10]>O1CCCC1.[NH4+].[Cl-]>[C:9]([C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:15]2[CH:14]=[C:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=1)(=[O:10])[CH2:1][CH2:2][CH3:3]
Reactant: CCC[Mg]Cl
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)N(C)OC)n2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12

Procedure:
Propylmagnesium chloride (1.00 mL) was cooled to 0° C. then charged with 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methoxy-methyl-amide (252 mg, 0.682 mmol) in tetrahydrofuran (4.00 mL). After 24 h the reaction was diluted with tetrahydrofuran and neutralized with NH4Cl. The organic was dried over magnesium sulfate and concentrated leaving a solid. The crude was recrystallized (ethyl acetate) to afford the final product 1-(5-butyryl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)-3-ethyl-urea. MS (APCI+): m/z 353.4 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (500 mg, 1.3 mmol) and ethanesulfonyl chloride (270 mg, 2.1 mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), and sodium hydrogen carbonate (270 mg, 3.2 mmol) was added thereto. The mixture was stirred at room temperature for 3 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (101 mg, 21%) as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]2[N:12]=[C:13]([O:28][C:29]3[CH:30]=[C:31]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:33][CH:34]=3)[C:14]3[CH:19]=[CH:18][N:17]([CH2:20][O:21]CC[Si](C)(C)C)[C:15]=3[N:16]=2)[CH:7]=[N:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:13]1[C:14]2[CH:19]=[CH:18][N:17]([CH2:20][OH:21])[C:15]=2[N:16]=[C:11]([NH:10][C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:43])[CH3:1])[CH:9]=2)[N:12]=1
Reactant: CN(C)CCn1cc(Nc2nc(Oc3cccc(NC(=O)OC(C)(C)C)c3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3ccn(CO)c3n2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (3-{[2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}phenyl)carbamate in DCM (5 mL) was added TFA (3 mL) and stirred at rt for 4 hrs. This was concentrated down to give the title compound as a dark oil that was taken on to the next step with no purification. m/z (ESI+) for O20H24N8O2 409.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([NH2:17])[CH2:15][NH2:16]>C(Cl)Cl>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][CH2:15][CH2:14][NH2:17]
Reactant: COc1ccc2nccc(Cl)c2n1
Reactant: NCCN
Solvent: ClCCl
Product: COc1ccc2nccc(NCCN)c2n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 8-chloro-2-methoxy-1,5-naphthyridine (1.71 g, 8.81 mmol) and ethylenediamine (1.18 mL, 2 eq.) was heated slowly to 80° C. over 1 h and subsequently up to 100° C. for 2 h. After cooling to rt, the yellow solution was taken in DCM and successively washed with NaHCO3. The aq. layer was back extracted with DCM (3 times) and the combined org. layers were concentrated to afford the title intermediate as a pale yellow oil (0.98 g, 51% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: NCc1ccccc1Cl
Product: O=C(O)c1ccnc(-c2cn(CCNCc3ccccc3Cl)cn2)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-chlorobenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.90 (2H, t, J=6.0 Hz), 3.80 (2H, s), 4.11 (2H, t, J=6.0 Hz), 7.23-7.27 (2H, m), 7.38 (1H, dd, J=4.5 and 1.5 Hz), 7.45 (1H, dd, J=4.6 and 2.2 Hz), 7.55 (1H, dd, J=3.2 and 1.5 Hz), 7.76 (1H, s), 7.81 (1H, s), 8.27 (1H, s), 8.56 (1H, d, J=5.0 Hz). [M+H] Calc'd for C18H17ClN4O2, 358. Found, 358.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C(N(CC)CC)C>C(O)C>[OH:14][NH:13][C:10](=[NH:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CC(=N)NO)cc1

Procedure:
A mixture of (4-methoxyphenyl)acetonitrile (2.00 g, 14 mmol) and hydroxylamine hydrochloride (1.94 g, 28 mmol) in ethanol (25 mL) was treated with triethylamine (4.4 mL) and heated at reflux for 16 hours after which the solvent was evaporated under reduced pressure. Sodium carbonate solution (10%, 100 mL) was added and the solution extracted with ethyl acetate (150 mL). The organic extract was dried, filtered and evaporated under reduced pressure to give a green solid which was purified by recrystallization from ethyl acetate/hexane to give 1.43 g (57%) of (Via) as pale green prisms. mp 163-170° C. (lit.14 108-109°). MS m/z 181 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[N:11][NH:10][C:9]=2[C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([C:29]([O:31]O)=[O:30])[CH:23]=1>CCOC(C)=O>[Cl:28][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:27]=1)[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[N:11][NH:10][C:9]=2[C:13]2[C:21]3[C:16](=[N+:17]([O-:30])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cn[nH]c2-c2c[nH]c3ncccc23)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Cl)c1
Product: [O-][n+]1cccc2c(-c3[nH]ncc3-c3cccc(Cl)c3)c[nH]c21
Temperature: 0 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 3-[4-(3-chlorophenyl)-2H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (147 mg, 0.5 mmol) in EtOAc (5 mL) was cooled in an ice bath and m-CPBA (148 mg, 0.6 mmol) added in one portion. The resulting suspension was stirred at 0° C. for 3 hours. After this time a second portion of m-CPBA (62 mg, 0.25 mmol) was added and the reaction stirred for an additional 14 hours, during which time the reaction warmed to room temperature. The reaction mixture was then filtered and the solids washed with ethyl acetate (2 mL) and air dried on the pump. This afforded 3-[4-(3-chlorophenyl)-2H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine 7-oxide meta-chlorobenzoate salt as white solid in 67% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.[CH3:24]C1C=CC(S(OC[C@@H](NC(OC(C)(C)C)=O)C)(=O)=O)=CC=1>>[NH2:1][C@@H:2]([CH3:24])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(C[C@H](C)N)c2)c1

Procedure:
The title compound was synthesized according to procedure described for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide starting with (S)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate. Synthesis of (S)-2-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate was performed according to Bioorg. Med. Chem. 16 (2008) 1966-1982. LC-MS conditions B: tR=0.55 min, [M+H]+=326.11.