Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH3:12]>>[NH2:12][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: N
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
Into an autoclave made of SUS-316 and having an internal capacity of 2 l, 363 g (2.0 mols) of 2-chloro-5-trifluoromethylpyridine, 19.8 g (0.2 mol) of cuprous chloride and 1,275 g (30.0 mols as NH3) of 40% aqueous ammonia were added, and the reaction was carried out at 120° C. for 16 hours under heating with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature and separated into an aqueous ammonia layer and an oil layer, whereby 335 g of an oil containing 1.5% of the starting material 2-chloro-5-trifluoromethylpyridine and 91% of 2-amino-5-trifluoromethylpyridine (as analyzed by liquid chromatography) was obtained.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4C=C[CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2[O:36]1.O1C=CC=C1B(O)O>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[O:36][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: OB(O)c1ccco1
Product: c1coc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and furan-2-boronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 7.61 (d, 1H, J=1.8 Hz), 7.12 (d, 1H, J=2.4 Hz), 7.08 (d, 1H, J=2.4 Hz), 6.93 (td, 2H, J=2.4 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), δ 6.68 (d, 1H, J=8.7 Hz), 6.58 (d, 1H, J=2.4 Hz), 6.54 (dd, 1H, J=1.8 and 3.6), 4.24 (s, 4H), 4.20 (bs, 4H); LCMS: ret. time: 15.03 min.; purity: 88%; MS (m/e): 445 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.C(O)C.[H][H].Cl>[Pd].C.C(O)(C)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([NH2:12])=[C:4]([CH3:15])[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Cc1nc(N)c(N)c(C)c1N

Procedure:
A 500 ml Parr Bottle was charged with 2-amino-4,6-dimethyl-3,5-dinitropyridine (21.2 g, 0.10 mole), 250 ml absolute ethanol, and 20 g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 60 psig. When no further uptake of hydrogen was observed, the mixture was filtered free of catalyst under a nitrogen atmosphere, and concentrated under vacuum to a volume of about 100 ml. The product concentrate was treated, under nitrogen at ice temperature, with a cold solution of hydrogen chloride (0.5 mole) in 85 ml anhydrous isopropyl alcohol. The trihydrochloride salt of 2,3,5-triamino-4,6-dimethylpyridine was obtained after vigorous stirring, filtering under nitrogen, and vacuum drying under high vacuum over P2O5 at 80° - 90° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[NH:9][N:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:8]1[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:9]1)(=[O:20])[CH3:19]
Reactant: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1nc(-c2cnccn2)nc1-c1cnccn1

Procedure:
A suspension of 3,5-dipyrazinyl-1,2,4-triazole (0.5 grams) in 20 ml. of acetic anhydride is heated on a steam bath for 17 hours. The resulting solution is filtered and concentrated to a solid. After recrystallization from benzene-hexane, 250 mg. of 1-acetyl-3,5-dipyrazinyl-1,2,4-triazole is obtained, m.p. 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19]C)[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>C(Cl)Cl>[Cl:1][C:2]1[N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: COc1ccc2cccc(-n3c(Cl)nn(C)c3=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cn1nc(Cl)n(-c2cccc3ccc(O)cc23)c1=O
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of the title compound of Step E (2.9 g) in methylene chloride (35 mL) was cooled to 0° C. while stirring under N2, and aluminum trichloride (4.0 g) was added in portions. The reaction mixture was allowed to warm to room temperature and then was heated to reflux for 18 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (1:4 ethyl acetate:hexane as eluent) to afford 2.2 g of the title compound of Step F. 1H NMR (Me2SO-d6): δ 10.08 (s,1H), 8.02 (d,1H), 7.95 (d,1H), 7.59 (dd,1H), 7.41 (t,1H), 7.18 (dd,1H), 6.71 (d,1H), 3.49 (s,3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and piperidine (3.51 ml, 35.6 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.94 g, 79%).
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=2)[CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH2:2])[S:16][CH:17]=2)[CH:8]=1
Reactant: O=Cc1cc(-c2cc(Cl)ccn2)cs1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (180 mg, 0.5 mmol) in THF (3 mL) was added n-BuLi (1.6 M, 0.34 mL) at 0° C. After the mixture was stirred for 30 minutes, a solution of 4-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (100 mg, 0.45 mmol) in THF (2 mL) was added. The resulting mixture was stirred at room temperature for 5 hours. Water was added and THF was removed. The water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 4-chloro-2-(5-vinyl-thiophen-3-yl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([CH2:13]C(O)=O)#[N:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[CH:5]=[CH:13]\[C:11]#[N:12]
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: N#C/C=C\c1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorobenzaldehyde (175 gms; 1 m), cyanoacetic acid (100 g; 1.15 m), and pyridine were refluxed for one day. Evaporation produced an oil which was fractionally distilled using a column (1 ft. long, 1/2 inch diameter) filled with glass helices. Overall yield 88.9 g (45%; 30% cis/70% trans).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[H-].[K+].Br[CH2:19][CH:20]=[CH:21][CH3:22]>O1CCCC1>[CH2:19]([N:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:20]=[CH:21][CH3:22]
Reactant: Clc1ccc(CNc2cccnc2)cc1
Reactant: CC=CCBr
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCN(Cc1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A solution of 4.4 g of N-[(4-chlorophenyl)methyl]-(3-pyridyl)amine dissolved in 50 ml of tetrahydrofuran was added to a suspension of 4 g of a 24.6% suspension of potassium hydride in oil in tetrahydrofuran. The mixture was allowed to stir at room temperature for approximately 30 minutes whereupon 4 g of 1-bromo-2-butene was added dropwise to the reaction mixture. The mixture was allowed to stir at room temperature overnight at which time the solution was evaporated to dryness. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The oil residue was chromatographed over silica gel. Fractions containing the major component were combined and the solvent was evaporated therefrom to provide 3 g of N-(2-butenyl)-N-[(4-chlorophenyl)methyl]-(3-pyridyl)amine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2/[CH:18]=[CH:19]/[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc(/C=C/c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 1-(4-fluorophenyl)-2-(2,3,6-trifluorostyryl)-1H-imidazole-5-carboxylate (17) (60 mg, 0.16 mmol) in ethanol (10 mL) was added Pd/C (10% Degussa type, 10 mg). A balloon of hydrogen gas was attached and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenethyl)-1H-imidazole-5-carboxylate (18).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccc(C(F)(F)F)cc2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccc(C(F)(F)F)cc3)cc2=O)n1
Yield: 9 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 23) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(4-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a yellow solid (23.1 mg, 9%); ES+-HRMS m/e calcd for C26H30F3N5O4 [M+H+] 534.2323 found 534.2324. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.16-1.79 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.49 (dd, J=4.3, J=11.1 Hz, 1H), 6.01 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.16 (d, J=2.9 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=O)[O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7].[NH2:15][NH2:16].O>CCO>[Br:7][C:6]1[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:16][NH:15][C:3](=[O:4])[CH:2]=1
Reactant: NN
Reactant: O=C1OC(c2ccccc2)C(Br)=C1Br
Solvent: CCO
Solvent: O
Product: O=c1cc(Br)c(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dibromo-5-phenylfuran-2(5H)-one (4.951 g, 15.57 mmol) in EtOH (5 mL) at 0° C. was added hydrazine, H2O (0.840 mL, 17.13 mmol). The reaction mixture was stirred at room temperature for 10 min before heating to reflux for 2 h. The reaction was cooled to room temperature. The precipitate formed was collected by filtration and washed with cold ethanol to yield the title compound as a pale yellow solid (2.530 g). LCMS m/z=351 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47-7.49 (m, 3H), 7.51-7.54 (m, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([O:24][C:33](=[O:35])[CH3:34])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3)cc(OC)c21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OC(C)=O)c3ccccc3)cc(OC)c21
Yield: 98.7 %

Procedure:
A solution of 136 mg (0.30 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-phenyl-methanol, 46 μl (0.66 mmol) acetyl chloride and 125 μl (0.90 mmol) triethylamine in 3 ml dichloromethane is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 140 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].Cl.[NH2:6][CH2:7][C:8]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1)=O>N1C=CC=CC=1>[C:21]([C:12]1[CH:11]=[C:10]([C:8]2[N:2]([CH3:1])[C:3]([SH:4])=[N:6][CH:7]=2)[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN=C=S
Reactant: CC(C)(C)c1cc(C(=O)CN)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cnc1S
Yield: 18.8 %

Procedure:
After stirring a mixture of 100 ml of pyridine, 6 g of methyl isothiocyanate, and 3 g of 4-(2-aminoacetyl)-2,6-di-tert-butylphenol hydrochloride at room temperature for 2 hours, the resulted mixture was maintained at an inside temperature of 80°-90° C. for 1.5 hours. The reaction mixture was concentrated udner reduced pressure and then the residue was extracted with 100 ml of ethyl acetate. The extract was washed with diluted hydrochloric acid, dried, and concentrated under reduced pressure. The residue was recrystallized from ethanol to provide 0.6 g of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercapto-1-methylimidazole.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=3[CH3:22])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([CH3:22])=[CH:16][C:17]([NH:21][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][C:19]=3[CH3:20])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(N)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C)c1

Procedure:
210 mg of 4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylaniline (Example XV) are brought under reflux with 119 mg of ethyl bromoacetate and 117 mg of sodium acetate in 10 ml of ethanol for 24 h. After addition of water, the mixture is extracted with ether, and the organic phase is dried and concentrated in a rotary evaporator. By chromatographic purification (cyclohexane/ethyl acetate), 143 mg (53%) of ethyl N-{4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylphenyl} glycinate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:35][CH2:34][NH:33][C:32]3=[O:36])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=C1NCCN1c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCNC3=O)cc2F)cn1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)imidazolidin-2-one. MS (ESI): mass calcd. for C19H16FN5O, 349.13; m/z found, 350.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.10 (s, 1H), 7.94 (m, 1H), 7.81-7.77 (m, 1H), 7.51-7.46 (m, 5H), 3.51 (t, J=6.2, 2H), 3.37 (t, J=6.2, 2H).
Reaction SMILES: [Br: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][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[C:16]=1[CH3:25]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[C:16]([CH3:25])[C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1sc2c(c1C)C(C)NCC2
Product: Cc1sc2c(c1C)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2
Yield: 64 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,3,4-Trimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C.O>[C:1]1([C:7]2[CH:11]=[C:10]([N:12]3[C:16](=[O:17])[C:15]4[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]3=[O:18])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(-c2ccccc2)n[nH]1
Temperature: 120 °C
Yield: 91 %

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-amine (6 g, 0.038 mol), phthalic anhydride (5.6 g, 0.038 mol) in acetic acid (60 mL) was heated at 100° C. for 2 h and at 120° C. for 2 h and cooled to room temperature. The reaction mixture was diluted with water and the suspension was filtered. The collected solid was washed with water, dried, yielding the title compound as a solid (10 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[C:31]([O:34][CH3:35])=[CH:32][CH:33]=[C:25]([Br:24])[C:26]=3[O:36][CH3:37])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), 3-bromo-2,6-dimethoxybenzoic acid (23 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH2:14]([NH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:16]([CH2:14][CH3:15])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN1Cc2cc(Br)ccc2C1=O

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.5 g, 2 mmol) (AstaTech Cat. No. 27012), ethylamine in THF (1.0 mL, 2.0 M) (Aldrich Cat. No. 395072), and potassium carbonate (0.34 g, 2.4 mmol) in ethanol (5 mL) in a sealed vial was stirred at 40° C. overnight. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.28 g). LCMS (M+H)+=240.0/242.0.
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([NH:13][C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([S:23][CH3:24])=[N:21]3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)(O)[O-].[Na+]>>[CH3:24][S:23]([C:20]1[N:19]=[CH:18][C:17]2=[CH:16][CH:15]=[C:14]([NH:13][C:12]3[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[N:8][CH:9]=[CH:10][CH:11]=3)[N:22]2[N:21]=1)=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(Nc3cccnc3N(C)S(C)(=O)=O)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(c1ncccc1Nc1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
N-Methyl-N-[3-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylamino)-pyridin-2-yl]-methanesulfonamide (125.0 mg, 0.3430 mmol) was dissolved in Methylene chloride (5.00 mL, 78.0 mmol) and the solution was treated with m-Chloroperbenzoic acid (76.87 mg, 0.3430 mmol). The reaction was then allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 100 mg of N-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide. 1H NMR (400 MHz, DMSO, d6) δ 9.11 (s, 1H), 8.24 (m, 1H), 8.07 (m, 1H), 7.46 (d, 1H, J=7.93 Hz), 7.33 (m, 1H), 7.26 (m, 1H), 7.14 (m, 1H), 3.23 (s, 3H), 3.18 (s, 3H), 2.89 (s, 3H).