Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]12([CH:19]=O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:9]12([CH2:19][NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH2:8])[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][CH:13]([CH2:12]3)[CH2:18]1)[CH2:16]2
Reactant: Nc1ccccc1N
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1NCC12CC3CC(CC(C3)C1)C2
Reaction time: 2 h
Yield: 10.1 %

Procedure:
1,2-Phenylenediamine (5 g) was added to a solution of 1-adamantanecarboxaldehyde (7.6 g) in methanol (100 ml). The solution was stirred at 23° for 2 h, then sodium borohydride (3.5 g) was added portionwise. The resulting mixture was stirred at 230 for 2 h, then diluted with ethyl acetate (400 ml) and filtered. The organic layer was washed with brine (300 ml), dried and concentrated in vacuo to a residue, which was taken up in ethyl ether and the inorganic salts still present were removed by filtration. The filtrate was concentrated in vacuo and purified by flash chromatography to give the title compound as a beige solid (1.2 g). M.p.86°-7° T.l.c. CH-EA (7:3), Rf 0.6.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[C:13]1[Se:14][CH:15]=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C([O:28][P:29](OCC)([O:31]CC)=[O:30])C.[OH-].[Na+]>>[C:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][O:12][P:29]([OH:31])([OH:30])=[O:28])[O:7][C@H:6]1[C:13]1[Se:14][CH:15]=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=1)(=[O:3])[CH3:2]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC(=O)O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1c1nc(C(N)=O)c[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](O)[C@@H](COP(=O)(O)O)O[C@H]1c1nc(C(N)=O)c[se]1

Procedure:
2-(2-O-Acetyl-β-D-ribofuranosyl)selenazole-4-carboxamide is treated with 1 to 5 equivalents of phosphoryl chloride in the presence of triethylphosphate at 0 degrees C. After complete dissolution is obtained, the solution is poured over crushed ice and adjusted with sodium hydroxide solution to pH 7, extracted with chloroform, and placed on a column of ion exchange resin (Dowex AG 1X8, formate). The column is first washed with water, then the product is eluted with a gradient of water-formic acid. The fractions containing pure product are pooled and evaporated to dryness. The residue is recrystallized from ethanol-water to provide the free acid of the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:32])[C:7]1[C:8](=[C:12](Cl)[C:13]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]=1Cl)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:1]([N:5]=[C:6]([OH:32])[C:7]1[C:8](=[C:12]([S:42][C:39]2[CH:40]=[CH:41][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[C:13]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]=1[S:42][C:39]1[CH:40]=[CH:41][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCCCN=C(O)c1c(Cl)c(Sc2ccccc2)c(Sc2ccccc2)c(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN=C(O)c1c(Sc2ccc([N+](=O)[O-])cc2)c(Sc2ccccc2)c(Sc2ccccc2)c(Sc2ccc([N+](=O)[O-])cc2)c1C(=O)O

Procedure:
2 g (4.09 millimols) of 4,5-bis-(phenylthio)-3,6-dichlorophthalic acid N-n-butylimide, 1.46 g (9.41 millimoles) of p-nitrothiophenol, 2.55 g (18.45 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 50° C. for 20 hours. The mixture is cooled, acidified and extracted with methylene chloride. After recrystallisation from tetrahydrofuran, 1.9 g (78% of theory) of the title compound are obtained; melting point 175°-7° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]2[CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2)no1
Reactant: O=CC1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2CC2CCOCC2)no1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg, 0.338 mmol) in N,N-dimethylformamide (2 mL) is added tetrahydro-pyran-4-carbaldehyde (77 mg, 0.676 mmol) and acetic acid (0.073 mL, 1.28 mmol). The reaction is stirred at room temperature for 45 minutes before adding sodium cyanoborohydride (42.5 mg, 0.676 mmol). The reaction is stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound with low purity and further purification by pre-HPLC yields pure title compound, m/z 352 [M+H+].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[C:8]([CH2:12][C:13]3[C:22](=[O:23])[O:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3O)=[C:7](O)[C:5]=2[CH:6]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[CH2:12]([C:8]1[C:9](=[O:10])[O:11][C:4]2[C:3]([C:7]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:13]1[C:22](=[O:23])[O:21][C:20]2[C:15]([C:14]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1oc2ccccc2c(O)c1Cc1c(O)c2ccccc2oc1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2c(Cc3c(S(=O)(=O)c4ccc(C)cc4)c4ccccc4oc3=O)c(=O)oc3ccccc23)cc1

Procedure:
To a solution of dicumarol (10 mmol) and p-toluenesulfonyl chloride (1.0 eq.) in dichloromethane (20 ml), triethylamine was added at room temperature under air atmosphere. After the reaction was complete, as monitored by TLC, the reaction mixture was evaporated and the residue was purified by flash chromatography (silica gel) to afford the product, 3,3′-methylenebis[4-tosylcoumarin].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1COc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2COc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3-fluorophenoxy)methyl]nicotinic acid (step 6) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=1.[C:15]([O:18][C:19](Cl)=[O:20])([CH3:17])=[CH2:16]>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH:13][C:19](=[O:20])[O:18][C:15]([CH3:17])=[CH2:16])[N:10]([CH3:14])[N:9]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Cn1nc(-c2ccccc2F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2ccccc2F)nn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
To a biphasic solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-amine (1.19 g, 6.22 mmol) in ethyl acetate (30 mL) and NaHCO3 solution (30 mL) was added isopropenylchloroformate (1.28 g, 10.6 mmol) and mixture was stirred at RT for 24 h. Both layers were separated; the aqueous layer was extracted with ethyl acetate (1×30 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford crude product which was purified by chromatography (ethyl acetate/hexane) to afford prop-1-en-2-yl 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-ylcarbamate (1.15 g, 82% yield) as a pasty mass. 1H NMR (400 MHz, DMSO-d6): δ 10.09 (brs, 1H), 7.90 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.38-7.22 (m, 3H), 6.54 (d, J=3.6 Hz, 1H), 4.79-4.77 (m, 2H), 3.76 (s, 3H), 1.96 (s, 3H); MS (ESI) m/z: 276.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=O.[CH2:13]([O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[CH3:14]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[CH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1cccc2c1C(=O)OC2=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1OC(=O)c2c(N)cccc21

Procedure:
500 mg (3.1 mmol) 4-amino-isobenzofuran-1,3-dione and 1.13 g (3.1 mmol) (ethoxy-carbonylmethylene)-triphenylphosphorane are dissolved in 5 ml of tetrahydrofuran (THF) and refluxed for 3 h. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[NH2:29][NH2:30].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:30][N:29]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C(Cc2ccccc2)C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(-c3ccc(OC)cc3)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), hydrazine (3.0 equiv.), conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 4-methoxy-1-[5-(4-methoxyphenyl)4benzylpyrazol-3-yl]benzene.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22](C(O)=O)[CH:21]=[CH:20][C:19]=12>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22]([C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH:21]=[CH:20][C:19]=12
Reactant: O=C(O)c1ccc2cncn2c1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2cncn2c1
Temperature: 90 °C

Procedure:
3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tertbutyl)acetal are added to 570 mg (3.52 mmol) of imidazo[1,5-a]pyridine-6-carboxylic acid [described in Bioorg. Med. Chem. Lett., (2002), 12(3), 465-470] in a mixture of 5 ml of dimethylformamide and 5 ml of toluene and the mixture is heated at 90° C. for 6 hours. 3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tert-butyl)acetal are again added to the reaction medium and the mixture is heated at 90° C. for a further 4 hours. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through a bed of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). After evaporation, 580 mg of a beige powder are obtained. Melting point: 77° C.; 1H NMR (d6-DMSO): 1.59 (9H, s), 7.71 (1H, d), 7.36 (1H, s), 7.58 (1H, d), 8.56 (1H, s), 9.03 (1H, s).
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CCOCC>[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][CH2:14][CH:16]2[O:18][CH2:17]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC2CO2)cc1
Temperature: 80 °C

Procedure:
A Grignard solution freshly prepared from 12.15 g (0.50 gram atom) magnesium chips and 91.7 g (0.50 mole) 4-tert.-butylbenzyl chloride in 550 ml dry ether is dripped with agitation into a precooled solution of 92.5 g (1.00 mole) epichlorohydrin in 165 ml dry ether, so that the temperature does not exceed -40° C. After addition is complete, the cooling bath is removed, the solution is allowed to stand for several hours at room temperature, and then hydrolyzed with ice water and dilute hydrochloric acid. The ether phase is separated, washed with water and dried over sodium sulfate. After the ether has been drawn off, the bath temperature is raised to 80° C. and the volatile components carefully removed at 0.1 mbar. The residue is taken up in 270 ml methanol and a freshly prepared solution of 6.90 g (0.30 g atom) sodium in 200 ml methanol added at room temperature. After three hours the sodium chloride precipitated is separated, the filtrate concentrated in vacuum, the residue taken up in ether and washed with water. After drying over sodium sulfate the solvent is removed and the oily residue distilled in vacuum. A colorless liquid with a boiling point of 79°-81° C./0.1 mbar is obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]1([CH2:18][CH2:19][OH:20])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:18][CH2:19][OH:20])=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(CCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)cc1
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylchlorosilane (9.68 mL) was added to a solution of 2,2′-(1,4-phenylene)diethanol (example 5, step a) (8.64 g) and imidazole (10.21 g) in dry DMF (100 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate, washed three times with water and evaporated in vacuo. Purification was by silica gel chromatography, eluting with 5:1 isohexane:ethyl acetate to give the subtitled compound as a colourless oil. Yield 6.20 g.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]CC)=[O:16])[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:3]1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1([C:15]([OH:17])=[O:16])[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)C1(C)C=CN(c2ccc(OC)cc2)N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N2C=CC(C)(C(=O)O)N2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 3-methyl-1-(4-methoxyphenyl)-1H-pyrazolecarboxylate (0.01997 mol, 5.197 g) and potassium hydroxide (3.362 g, 3.0 eq.) in ethanol (70 mL) was stirred at ambient temperature for 5 h. The solvent was removed in vacuo and the residue was taken up in water. This was extracted with methylene chloride (3×) to remove unreacted starting material. The aqueous was made acidic (pH 3) by the dropwise addition of conc. HCl at 0° C. to give white precipitation of acid. The solid acid was obtained by filtration and pumped on for several hours to dry. This procedure gave 4.23 g of pure product (91%); mp: 161.8° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]=[CH:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([NH:24][C:25]4[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=4[C:27](O)=[O:28])=[CH:21][CH:22]=3)[N:17]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:16]=2)[CH:8]=1>CC(OC)(C)C>[CH3:5][C:2](=[CH2:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[NH:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH:14]=[CH:13][C:9]3[CH:8]=[C:7]([CH3:6])[CH:12]=[CH:11][N:10]=3)=[N:16][N:17]2[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:22][CH:21]=1
Reactant: C=C(C)CN
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Solvent: COC(C)(C)C
Product: C=C(C)CNC(=O)c1ccccc1Nc1ccc2c(C=Cc3cc(C)ccn3)nn(C3CCCCO3)c2c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using 2-Methyl-allylamine and 2-[3-[2-(4-Methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid. 1H NMR (DMSO-d6) δ 9.86 (1H, s), 8.81 (1H, t, J=5.5 Hz), 8.46 (1H, d, J=4.9 Hz), 8.07 (1H, d, J=8.9 Hz), 7.86 (1H, d, J=16.4 Hz), 7.75 (1H, d, J=7.7 Hz), 7.54 (1H, s),7.50 (1H, d, J=16.4 Hz), 7.43 (3H, m), 7.11 (2H, m), 6.92 (1H, t, J=8.1 Hz), 5.81 (1H, dd, J=2.5, 9.8 Hz), 4.83 (2H, d, J=11.5 Hz), 3.81 (4H, m), 2.41 (1H, m), 2.35 (3H, s), 2.00 (2H, m), 1.76 (1H, m), 1.73 (3H, s), 1.58 (2H, m). Anal. Calcd for C31H33N5O2.0.80 TBME: C, 72.71; H, 7.43; N, 12.11. Found: C, 72.43; H, 7.57; N, 12.02.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[CH:15]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:22]([NH2:23])=[N:21][CH:20]=[N:19][C:18]=3[N:14]([CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:15]=2)=[CH:29][CH:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of (S)-2-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.03 mmol) in 10 ml of DCM, TFA (10 ml) was added. The reaction mixture was stirred at RT for 2 h. The mixture was concentrated to give (S)-5-(4-phenoxyphenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (400 mg), which was subjected to the next step without any further purification.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][S:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[C:15](O)=[N:16][CH:17]=[N:18][CH:19]=2)[CH:9]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:3][C:15]1[C:14]([C:10]2[CH:9]=[C:8]([S:7][CH3:6])[N:13]=[CH:12][N:11]=2)=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: CSc1cc(-c2cncnc2O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(-c2cncnc2Cl)ncn1
Temperature: 85 °C

Procedure:
POCl3 (1.51 mL, 16.2 mmol, 3.0 eq.) is added slowly to a suspension of 6-methylsulfanyl-[4,5′]bipyrimidinyl-4′-ol 6 (1.20 g, 5.44 mmol) and triethyl amine (0.76 mL, 5.44 mmol, 1.0 eq.) in acetonitrile (30 ml). After heating at 85° C. for 2 hours, the reaction mixture is cooled to room temperature, poured into ice-water, neutralized by saturated NaHCO3 solution, and then extracted with ethyl acetate. The organic layer is washed with brine and dried over Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 40% to give 4′-chloro-6-methylsulfanyl-[4,5′]bipyrimidinyl as a white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.19 (s, 1H), 9.12 (d, 1H, J=1.2 Hz), 9.07 (s, 1H), 7.91 (d, 1H, J=1.6 Hz), 2.62 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1.[CH3:17][C:18]1[C:26]2[CH2:25][O:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[C@H:28]1[CH2:30][O:29]1.CCN(C(C)C)C(C)C>C(O)C>[OH:29][C@H:28]([C:19]1[C:18]([CH3:17])=[C:26]2[C:22](=[CH:21][CH:20]=1)[C:23](=[O:27])[O:24][CH2:25]2)[CH2:30][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)C(=O)Nc2ccccc23)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
Commercially available spiro[indoline-3,4′-piperidin]-2-one hydrochloride (500 mg, 2.10 mmol) was combined with 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A) (398 mg, 2.10 mmol) and DIEA (439 μL, 2.51 mmol) in ethanol (7 mL) and heated at 80° C. for 3 h. The reaction mixture was concentrated and purified by MPLC eluting first with 30% ethyl acetatehexanes and then with 10% methanol/DCM to afford the title compound which was a mixture of regioisomers. MS-ESI (m/z): 393 (M+1)+;
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a yellow solid (310 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Br
Yield: 72 %

Procedure:
4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-trifluoromethylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 155-158° C., yield 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=1)[C:33]([NH:32][C:24]1[C:23]([CH:20]([CH3:21])[CH3:22])=[CH:28][CH:27]=[CH:26][C:25]=1[CH:29]([CH3:31])[CH3:30])=[O:34]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Product: CC(C)c1ccc(N(Cc2ccc(Cl)cc2Cl)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 9.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(2,4-dichlorophenyl)methyl](4-isopropylphenyl)amine (2.7 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N-[(2,4-dichlorophenyl)methyl]-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.43 g) was obtained.