Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13](OC)=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:13][OH:14])([CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=CCc2ccccc2C1(CO)CCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of Example 178A (0.3 g, 1 mmol) in tetrahydrofuran (5 mL) was added a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (1.2 mL, 1.2 mmol) dropwise. The solution was stirred at room temperature for 1 h and then quenched carefully with a saturated solution of NH4Cl (5 mL). The mixture was diluted with water (25 mL) and extracted with ethyl acetate (3× 15 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) afforded product as a colorless oil (0.20 g, 74%). 1H NMR (300 MHz, CDCl3) δ ppm 0.79 (m, 8H), 1.37 (m, 1H), 1.55 (m, 1H), 1.98 (m, 1H), 3.53 (d, J=3.68 Hz, 2H), 3.63 (s, 3H), 3.71 (d, J=10.66 Hz, 1H), 3.95 (m, 1H), 5.09 (t, J=3.68 Hz, 1H), 7.22 (m, 4H); MS m/z 261.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.O.O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccc(Cl)cc2Cl)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl2.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>O>[C:13]1([N:19]2[C:5](=[O:7])[CH:4]=[C:3]([C:2]([F:1])([F:11])[F:12])[NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: O=c1cc(C(F)(F)F)[nH]n1-c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 184 parts of ethyl trifluoroacetoacetate, 120 parts of phenylhydrazine, 200 parts by volume of ethanol and 20 parts by volume of 22° Be hydrochloric acid was heated under reflux, with stirring, for one hour, then 500 parts of water were added and the product was cooled in ice. The yellow precipitate obtained was filtered off, drained, washed, with a small portion of chilled toluene until decoloration took place. Thereafter it was dried in an oven (50° C.). 215 parts of 1-phenyl-3-trifluoromethyl-5-pyrazolone was obtained of which the melting point was 193° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1)=[N:16][N:15]=[CH:14]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1CCCN(c2nncc3cc(Br)ccc23)C1
Temperature: 190 °C
Yield: 99.4 %

Procedure:
A glass microwave reaction vessel was charged with nipecotamide (0.17 g, 1.4 mmol), 6-bromo-1-chlorophthalazine (0.110 g, 0.45 mmol), potassium carbonate (0.062g, 0.45 mmol) and 3 mL acetonitrile. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 190° C. for 20 min (watts, Powermax feature on, ramp time 1 min). The mixture was purified directly via flash chromatography (silica gel) eluting with 4/1 hexanes/EtOAc to 4/1 hexanes/EtOAc to give (0.15 g) 1-(6-bromophthalazin-1-yl)piperidine-3-carboxamide as a white solid. Found MS (ES+): 335, 337(M+H)+.
Reaction SMILES: N[C:2]1[C:3]([C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.N([O-])=[O:35].[Na+]>C(O)(C(F)(F)F)=O>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:3]1[C:2](=[O:35])[NH:13][C:6]2[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: CSc1ncc2cc(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)c(N)nc2n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc2cc(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)c(=O)[nH]c2n1
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
To a solution of N-[3-(7-amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-6-yl)-4-chloro-phenyl]-3-trifluoromethyl-benzamide (1.0 g, 2.04 mmol) in TFA (10 mL) is slowly added NaNO2 (423 mg, 6.12 mmol) at 0° C. with stirring for 20 minutes. The solvents are evaporated, diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(93/7%), to give the title intermediate as a solid (0.644 g, 64.4%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C)C=O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: Clc1ccc2ccccc2n1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(-n3ccc4cccnc43)ccc2c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
0.894 g of 60% sodium hydride (37.25 mmol) was added with stirring to 20 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C. and then a solution of 4 g (33.86 mmol) of 1H-pyrrolo[2,3-b]pyridine in 20 cm3 of dimethylformamide was gradually added. After stirring at a temperature in the region of 20° C. for 30 minutes, a solution of 5.816 g (35.55 mmol) of 2-chloroquinoline in 20 cm3 of dimethylformamide was added and then the reaction mixture was heated at a temperature in the region of 100° C. for 15 h. After concentrating to dryness under reduced pressure (2.7 kpa), the residue was taken up in 150 cm3 of water. The residual oil was taken up in 50 cm3 of diethyl ether. The light yellow crystals that formed were filtered off and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 20° C. 4.39 g of 1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine were thus obtained in the form of an off-white solid melting at 129° C.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.N[C:15]1[C:19]([C:20]#[N:21])=C[NH:17][N:16]=1>C(O)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:17]3[N:16]=[CH:15][C:19]([C:20]#[N:21])=[C:13]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 17.61 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 10.8 g. of 3-aminopyrazole-4-carbonitrile in 75 ml. of glacial acetic acid is heated at reflux temperature for 6 hours. The procedure described in Example 1 is continued to give the product of the example as tan crystals, m.p. 258°-260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([NH2:13])=[S:12].BrBr.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[N:10]=[C:11]([NH2:13])[S:12][C:4]=2[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(NC(N)=S)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(F)c2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2-fluoro-5-methoxyphenyl)thiourea (C11) (17.30 g, 86.40 mmol) in chloroform (160 mL) at 0° C. was added bromine (4.44 mL, 86.4 mmol) drop-wise. The reaction mixture was stirred at room temperature for 30 minutes and was then heated to reflux for 18 hours. It was poured into ice water (1.0 L) containing an excess of sodium bicarbonate. The resulting precipitate was collected by filtration and washed with water and hexanes to afford the title compound as a white solid. Yield: 15.40 g, 77.69 mmol, 90%. 1H NMR (300 MHz, DMSO-d6): δ 3.84 (s, 3H), 6.60 (m, 1H), 7.03 (m, 1H), 7.73 (s, 2H),
Reaction SMILES: [I:1][C:2]1[C:10]2[S:9][C:8]([CH2:11][O:12][CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1N.N(OC(C)(C)C)=O.O>C1COCC1>[I:1][C:2]1[C:10]2[S:9][C:8]([CH2:11][O:12][CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nc2ccc(N)c(I)c2s1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Product: COCc1nc2cccc(I)c2s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a cooled (0° C.) solution of 7-iodo-2-methoxymethyl-benzothiazol-6-ylamine (1.8 g, 5.62 mmol) in THF under nitrogen was added tert-butyl nitrite (3.3 mL, 28.1 mmol) dropwise. The reaction mixture stirred 3 h at 50° C. Water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by column chromatography afforded 1.0 g (60%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.19-7.21 (m, 1H), 4.8 (s, 2H), 3.58 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.Cl.Cl.Cl.[NH2:11][C:12]1[S:16][N:15]=[C:14]([C:17](=[N:41][O:42][C:43]([C:46]([O:48]C(C)(C)C)=[O:47])([CH3:45])[CH3:44])[C:18]([NH:20][C@@H:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([O-:38])=[O:37])=[C:25]([CH2:28][N+:29]4[N:30]([CH3:35])[C:31]([NH2:34])=[CH:32][CH:33]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:13]=1.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:11][C:12]1[S:16][N:15]=[C:14]([C:17](=[N:41][O:42][C:43]([C:46]([OH:48])=[O:47])([CH3:44])[CH3:45])[C:18]([NH:20][C@@H:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([O-:38])=[O:37])=[C:25]([CH2:28][N+:29]4[N:30]([CH3:35])[C:31]([NH2:34])=[CH:32][CH:33]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:13]=1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Reaction time: 4 h
Yield: 20.2 %

Procedure:
Trifluoroacetic acid (7 ml) was added dropwise to a suspension of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (3.3 g) and anisole (3.5 ml) in methylene chloride (10 ml) at ambient temperature. After being stirred at the same temperature for 4 hours, the mixture was poured into diisopropyl ether (300 ml), and the resulting precipitate was collected by filtration. The precipitate was dissolved in water (100 ml), and the solution was adjusted to pH 2 with 5% aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20". The desired product was eluted with 5% aqueous isopropyl alcohol solution and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (515 mg).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[BH4-].[Na+]>C1COCC1>[S:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2s1
Yield: 99.4 %

Procedure:
A solution of benzo[b]thiophene-2-carbaldehyde (2.216 g, 13.66 mmol) in THF (60 mL) was reacted with sodium borohydride (0.517 g, 13.66 mmol) at room temperature for 3 h. The reaction was quenched with 1N hydrochloric acid at 0° C., the THF evaporated under vacuum and the aqueous residue extracted with diethyl ether. The organic extract was washed with brine, dried over MgSO4 and concentrated to afford the title compound as a yellow solid (2.23 g, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2]
Reactant: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 16.5 h
Yield: 15.6 %

Procedure:
To methyl 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (298 mg) dissolved in THF-methanol (10-5 ml) was added a 2 M aqueous solution of potassium carbonate (0.75 ml), and the resulting mixture was stirred at 60° C. for 16.5 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (45 mg) as white crystals. The mother liquor was concentrated under reduced pressure to obtain 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (340 mg) as a brown oil. This compound was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][CH2:5][CH2:6][CH:7]([OH:12])[CH2:8][CH2:9][CH:10]=[CH2:11].C1(CCCCOCCC=O)C=CC=CC=1>>[F:1][C:2]([F:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][O:4][CH2:5][CH2:6][C:7](=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCC(O)CCOCC(F)(F)c1ccccc1
Agent: O=CCCOCCCCc1ccccc1
Product: C=CCCC(=O)CCOCC(F)(F)c1ccccc1
Yield: 42.9 %

Procedure:
Obtained from Intermediate 83 (4.3 g, 15.8 mmol) by the procedure described in Intermediate 13. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (1:5) gave the title compound (1.82 g, 43%) as oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]=1[O:18][CH3:19].[C-:20]#[N:21].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[F:9][C:7]1[CH:6]=[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([O:18][CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=1
Reactant: COc1c(CCl)cc(F)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(CC#N)cc(F)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 1-(chloromethyl)-5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (6.82 g, 24.3 mmol) in DMF (60 mL) was added potassium cyanide (3.2 g, 48.6 mmol), and the resulting mixture was stirred at 50° C. for 2 h 20 min before cooling to rt. Water and brine were added, and the resulting aqueous mixture was extracted with ethyl acetate. The organic phase was washed twice with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80% hexanes, 20% ethyl acetate) to afford {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}acetonitrile (5.3 g, 19.5 mmol, 80% yield) as a colorless oil which eventually solidified. 1H NMR (400 MHz, CDCl3): δ 7.42-7.32 (m, 5H), 6.69-6.67 (m, 2H), 5.08 (s, 2H), 3.89 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:39](=[O:40])[CH2:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CC(C)(C)C)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure M using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and tert-butyl acetyl chloride as an orange solid (71%). 1HNMR (CDCl3, 300 MHz) δ: 7.91 (d, J=8.3 Hz, 1H), 7.43 (m, 2H), 7.39 (m, 2H), 7.16 (m, 2H), 7.14 (m, 2H), 6.76 (m, 0.5H), 6.73 (m, 0.5H), 6.55 (m, 1H), 4.88 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.09 (s, 2H), 1.71 (s, 6H), 1.67-1.54 (m, 2H), 1.41-1.27 (m, 2H), 1.00 (s, 9H), 0.92 (t, J=7.4 Hz, 3H). HPLC, Rt: 6.02 min, (Purity: 98.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:14]1([CH2:13][N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]2=[O:9])[CH2:16][CH2:15]1
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccn(CC2CC2)c(=O)c1C#N
Temperature: 110 °C
Yield: 94.5 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (12.2 g, 81.48 mmol) in acetonitrile (250 ml) were added (bromomethyl)cyclopropane (11 g, 81.48 mmol) and potassium carbonate (22.48 g, 162.9 mmol) and the mixture was heated at 110° C. for 24 hours. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was evaporated till dryness and the resulting crude residue was then triturated with diethylether to yield pure intermediate 1 (15.72 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6][C:7]=1[CH3:8].Cl>O1CCOCC1>[CH3:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCNCC2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxylate (100 mg, 0.24 mmol, Example 82) was suspended in a solution of 3 M hydrogen chloride in dioxane (10 mL). The reaction mixture was stirred at ambient temperature overnight, and then the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.32 (m, 2H), 1.84-1.92 (m, 5H), 2.25 (s, 3H), 12.43 (bs, 1H), 2.60-2.65 (m, 2H), 3.02-3.08 (m, 2H), 3.985-3.94 (m, 1H), 4.25 (d, J=8.3 Hz, 2H), 4.68 (d, J=5.3 Hz, 2H), 5.59 (bs, 1H), 7.12 (t, J=4.6 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.60 (t, J=6.4 Hz, 1H), 8.54 (d, J=4.2 Hz, 1H); MS (ESI) m/z 313.2 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21]3[C:26]([C:27]4[N:35]=[CH:34][N:33]=[C:32]5[C:28]=4[N:29]=[CH:30][N:31]5C4CCCCO4)=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[F:42])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>>[N:35]1[C:27]([C:26]2[C:21]([NH:20][C:15]3[C:14]([F:42])=[C:13]([NH:12][S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=4)(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=3[F:19])=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(Cl)c1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1cccc(Cl)c1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the 3-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH3:21])[C:17]([F:20])=[C:18]([CH:19]=1)[CH:25]=[O:26]
Reactant: Cc1cc(Br)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]−).