Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])[C:4]=2[CH:3]=[CH:2]1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.[OH-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]3[C:4]4[CH:3]=[CH:2][O:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[C:12]([F:18])[CH:13]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1ccc(Oc2cccc3occc23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3cccc4occc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
32 mg (0.13 mmol) of 4-(1-benzofuran-4-yloxy)-3-fluorophenylamine (from example XXIII) and 28.5 mg (0.14 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidine-amine (from example XXIX) are suspended in 1.5 ml of water, and 19 μl of concentrated hydrochloric acid are added. The reaction mixture is heated at reflux overnight, resulting in the formation of a brown precipitate. Using 1N sodium hydroxide solution, the suspension is adjusted to pH 10. The precipitate is filtered off with suction and the filtrate is discarded. The crude product is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: C[C@H](N)c1cccc(-n2cccn2)c1
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-pyrazol-1-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].C1COCC1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24].Cl>O>[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[NH:24][C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[S:11]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NC1CCCCC1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A solution of 1,3-dichloro-2-isothiocyanatobenzene (100 mg) and abs. THF (3 ml) was added dropwise slowly over a half hour to a solution of trans-1,2-diaminocyclohexane (139.9 mg) and abs. THF (3 ml). The solution was stirred at room temperature for a further 90 minutes. The reaction mixture was subsequently added to water, acidified with hydrochloric acid and extracted once with ethyl acetate. Afterwards, the mixture was basified using potassium carbonate, and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 128 mg of the desired product were obtained.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[C:26]([Br:31])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[C:26]([Br:31])[C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1c(Br)cc(Br)cc1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1c(Br)cc(Br)cc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4,6-Tribromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered ans stripped of solvent under reduced pressure to yield the desired product N-(2,4,6-tribromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CO>CN(C)C=O>[Si:22]([O:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc2c(c1)CCC(CO)C2
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CCC(CO[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In N,N-dimethylformamide (5 ml), (2RS)-2-hydroxymethyl-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (1.71 g) was dissolved. To the resulting solution, imidazole (0.81 g) and tert-butyldimethylsilyl chloride (1.81 g) were added under ice cooling, followed by stirring at room temperature for 14 hours. After the addition of methanol, the mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (hexane:ethyl acetate=50:1), whereby a pale yellow solid (2.20 g, 85%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH:11][CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1.[OH-].[K+].Cl>CS(C)=O>[O:14]1[CH2:15][CH2:16][CH:12]([O:11][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:13]1
Reactant: OC1CCOC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OC2CCOC2)nc1
Temperature: 25 °C

Procedure:
To 6-chloro-nicotinic acid (415 mg, 2.59 mmol), was added 3-hydroxytetrahydrofuran (468 mg, 5.16 mmol), potassium hydroxide (579 mg, 10.3 mmol) and DMSO (5 mL). The mixture was heated at 120 C for 24 h. Further potassium hydroxide (579 mg) and 3-hydroxytetrahydrofuran (468 mg) was added and the mixture heated at 120 C for 24 h. The reaction was allowed to cool to room temperature, acidified to pH=1-2 with a 2M aq. solution of HCl (13 mL) and extracted into EtOAc (3×5 mL). The combined extracts were washed with water (5×20 mL), saturated brine (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as an orange solid which was dried under high vacuum to remove traces of solvent (209 mg, 39%). Method B HPLC-MS: MH+ requires m/z=210. Found: m/z=210, Rt=1.32 min (100%).
Reaction SMILES: O[C@H:2]([C:17]([O:19]CC)=[O:18])[C@H:3]([C:12]([O:14]CC)=[O:13])[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].Cl>C(O)(=O)C>[O:6]=[C:5]1[O:7][C@H:2]([C:17]([OH:19])=[O:18])[C@H:3]([C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: CCOC(=O)[C@@H](O)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)O)O1
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
16.49 g of 3-tert-butyl 1,2-diethyl (1S,2R)-1-hydroxy-1,2,3-propanetricarboxylate, 100 ml of acetic acid and 50 ml of concentrated hydrochloric acid were mixed and stirred at 70° C. for 5 hours. Acetic acid and hydrochloric acid were distilled off under reduced pressure. Then, the residue was again dissolved in 100 ml of acetic acid and 50 ml of concentrated hydrochloric acid and stirred at 70° C. for 12 hours. Acetic acid and hydrochloric acid were distilled off under reduced pressure. Then, 100 ml of trifluoroacetic acid was added to the residue, followed by stirring at 60° C. for 5 hours. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to obtain 9.38 g of the above-identified compound as white powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:35])=O)(C)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[CH2:48][C:46](=[O:47])[NH:45][CH:44]3[C:38]3[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=3[Cl:36])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1Cl)O[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Yield: 11.2 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.76 mmol) was reacted with 1-(2-chloro-5-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (23 mmol) in toluene to give the title compound as a white solid (400 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.12 g, 20.1 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.9 g, 37%) as a white solid: LC/MS m/e calcd for C20H22BrNO2 M+: 388.3, observed: 388.0, 390.0.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cnn(C3CCN(S(C)(=O)=O)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine hydrochloride (315 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) in DCM (15 mL) was added methanesulfonyl chloride (230 mg, 2.0 mmol) dropwise, the mixture was stirred at room temperature for 1 hour. Then the mixture was extracted with EA, wash with brine, dried and purified by flash column chromatography, eluting with EA/MeOH, to give product as light yellow solid. MS (m/z): 356 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[C:10]([C:11]=1[C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:9]([N+:17]([O-])=O)[CH:8]=[CH:7][CH:6]=2)[CH3:2].CCO>C1COCC1>[NH2:17][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c([N+](=O)[O-])cccc2n1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 30.2 %

Procedure:
A solution of 6.0 g (17.1 mmol) of 2-Ethyl-4-Nitro-α-oxo-1-(phenylmethyl)-1H-indole-3-acetamide in 140 ml of 1:1 THF:EtOH containing 1.0 g of 5% Pt/BaSO4 was hydrogenated at room temperature and 60 psi (4.22 Kg/cm2) for four hours. The catalyst was filtered and the filtrate evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAC to give 1.66 g (30%) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide melting at 140-144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]Cl)([O-:3])=[O:2].[OH-].[NH4+:13]>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][NH2:13])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: NSc1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
50 grams of o-nitrobenzenesulfenyl chloride was added to carbon tetrachloride with stirring, followed by 50 milliliters of ammonium hydroxide over a one-minute period. The stirring was continued over 5 minutes to obtain an o-nitrobenzenesulfenamide intermediate which precipitated in the reaction mixture. The o-nitrobenzenesulfenamide intermediate was recovered by filtration and dried.
Reaction SMILES: C([O:8][C:9]1[C:34]([F:35])=[CH:33][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[C:11]([F:36])[CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:35][C:34]1[CH:33]=[C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:31])[CH3:32])[CH:24]([CH3:25])[CH3:26])[CH:15]=2)[C:11]([F:36])=[CH:10][C:9]=1[OH:8]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccccc3)cc2F)c2cccnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(O)cc2F)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(4-Benzyloxy-2,5-difluoro-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (602, 0.70 g, 0.0014 mol) in methanol (30.0 mL) was added 50%© palladium hydroxide on carbon (0.1 g) under an atmosphere of hydrogen. The reaction was stirred at room temperature overnight. The reaction was filtered and concentrated to give a colorless oil (603, 0.47 g. 82.0%).
Reaction SMILES: [I:1]I.N1CCOCC1.[C:9]1(/[CH:15]=[C:16](\[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26])/[CH2:17][OH:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[I:1][C:26]#[C:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]#[C:19]/[C:16](=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH2:17][OH:18]
Reactant: C#CCCCCC#C/C(=C\c1ccccc1)CO
Reactant: II
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: OC/C(C#CCCCCC#CI)=C/c1ccccc1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To a solution of iodine (1.479 g, 5.83 mmol) in toluene (80 mL) was added morpholine (1.354 g, 15.54 mmol) followed by heating at 60° C. for 30 minutes. To the resultant mixture was added a solution of Compound 3 (462.3 mg, 1.94 mmol) in toluene (10 mL) and the mixture was heated at the same temperature for 6 hours. The reaction mixture was then allowed to cool down to room temperature and purified, without aqueous work up, by flash column chromatography (silica gel, 100 percent hexane and then 17 percent EtOAc in hexane) to give 630.3 mg (89 percent) of Compound 4: yellow oil; Rf=0.17 (17 percent EtOAc in hexane); IR (neat) 3362 (br), 2942, 2860, 2210, 1446, 1072 cm−1; 1H NMR (300 MHz, CDCl3) δ7.83-7.79 (m, 2H), 7.37-7.24 (m, 3H), 6.71 (s, 1H), 4.26 (d, J=1.20 Hz, 2H), 2.51-2.39 (m, 4H), 1.95 (br s, 1H), 1.76-1.62 (m, 4H); 13C NMR (75 MHz, CDCl3) δ136.7, 133.5, 129.1, 128.9, 128.8, 122.5, 98.7, 94.7, 79.4, 68.2, 28.3, 28.1, 21.0, 20.1, −5.9; MS (+CI) m/z (relative intensity) 365 (M+H+, 10), 220 (100); HRMS (+EI) calcd for C17H17IO 364.0324 (M+), found 364.0299.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>CN(C=O)C>[CH3:12][N:13](/[CH:15]=[N:1]/[C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1[nH]cnc1N
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]cnc1/N=C/N(C)C

Procedure:
A solution of ethyl 4-amino-1H-imidazole-5-carboxylate (0.65 g, 4.19 mmol) and DMF-DMA (11.22 ml, 84 mmol) in DMF (3 mL) was stirred at RT under nitrogen for 3 days. The excess DMF-DMA and DMF were removed under vacuum to give the desired compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34-13.68 (m, 1H), 8.09 (s, 1H), 7.36 (s, 1H), 4.12 (q, 2H), 2.96 (d, 6H), 1.22 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:5][C:4](=[O:14])[CH:3]=1.I[CH:16]([CH3:20])[CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:20][O:1][C:2]1[C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:5][C:4](=[O:14])[CH:3]=1
Reactant: CCCCCCC1(C)SC(=O)C=C1O
Reactant: CC(I)CCCl
Product: CCCCCCC1(C)SC(=O)C=C1OCCCCCl
Yield: 61.7 %

Procedure:
From 33 (36 mg, 0.17 mmol) and 3-iodo-1-chlorobutane (40 μL, 0.34 mmol) following general procedure H was obtained 42 (32 mg, 75%) after flash chromatography (20% EtOAc/Hexanes). 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=5.1 Hz, 3H), 1.09-1.14 (m, 1H), 1.25 (s, 6H), 1.44-1.53 (m, 1H), 1.63 (s, 3H), 1.77-1.85 (m, 2H), 1.90-2.00 (m, 4H), 3.59 (t, J=4.5 Hz, 2H), 3.95-3.99 (m, 2H), 5.28 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 13.7, 22.3, 25.1, 26.1, 26.4, 29.1, 29.1, 31.5, 39.0, 43.9, 59.5, 71.6, 101.5, 185.9, 192.9. IR (NaCl) 2927, 1683, 1607 cm−1. Analysis Calculated for C15H25C2S: C, 59.1; H, 8.27; Found: C, 59.3; H, 8.39.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[OH-].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(ccn4C)c3)c(Cl)c2Cl)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc2cc(Sc3ccc(/C=C/C(=O)N4CCC(C(=O)O)CC4)c(Cl)c3Cl)ccc21

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with ethyl ester from Example 339, and KOH with NaOH, to give a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 1.31-1.53 (m, 2H), 1.62-1.76 (m, 2H), 1.94-2.09 (m, 1H), 2.88 (brt, J=10.5 Hz, 1H), 3.13 J=10.5 Hz, 1H), 3.86 (s, 3H), 3.93 (br d, J=13.2 Hz, 1 H), 4.09 (br d, J=13.2 Hz, 1H), 6.41 (d, J=8.7 Hz, 1H), 6.53 (dd, J=0.9,3.0 Hz, 1H), 7.04 (d, J=15.3 Hz, 1H), 7.32 (dd, J=2.1, 8.7 Hz, 1H), 7.48 (d, J=3.0 Hz, 1 H), 7.64 (d, J=8.7 Hz, 1H), 7.69 (d, J=15.3 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H). MS (ESI+) (M+H)+ at m/z 489, 491, 493. Anal. Calcd for C24H21Cl2N2NaO3S.0 H20: C, 56.37; H, 4.14; N, 5.48. Found: C, 56.44; H, 4.38; N, 5.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 130 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 85 μL of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate. The reaction mixture is then stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica (eluent: 9/1 dichloromethane/methanol by volume). The fractions containing the expected product are concentrated under reduced pressure. 237 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=[C:19]3[NH:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[C:13]2[N:12]=[C:11]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[CH2:1]([S:8]([C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=[C:19]3[NH:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[C:13]2[N:12]=[C:11]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[CH:10]=1)=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(SCc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2cnn3c(S(=O)Cc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the reaction flask, 5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (4.1 g, 8.6 mmol) was added to dichloromethane (86 mL) along with m-chloroperbenzoic acid (5.9 g, 34.4 mmol). The mixture was allowed to stir at room temperature for 12 hours. The solid was collected by filtration, washed with dichloromethane then dried under vacuum overnight. The product, 5-((7-(benzylsulfinyl)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was recovered as a bright yellow solid in quantitative yield. LCMS (M+1=493)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.51) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.034 g, 17%). MS (ISP) 411.0 [(M+H)+]; mp 247.5° C.