Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][CH:29]=1)[CH2:8][C:9]1[N:10]=[C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])=[CH:18][CH:17]=2)[O:12][CH:13]=1)(C)(C)C.O.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.ClCCl>[N:38]1([CH2:37][CH2:36][CH:35]=[CH:34][C:31]2[CH:32]=[CH:33][C:28]([NH:7][CH2:8][C:9]3[N:10]=[C:11]([CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][C:19]([S:22]([C:24]([F:26])([F:27])[F:25])=[O:23])=[CH:20][CH:21]=4)[O:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(=O)C(F)(F)F)cc2)n1)c1ccc(C=CCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S(c1ccc(C=Cc2nc(CNc3ccc(C=CCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Yield: 10 %

Procedure:
The crude carbamic ester was stirred in a mixture of trifluoroacetic acid/dichloro methane (1:1, 28 ml) for 2 h. Water (50 ml) was added and the solution was neutralized by careful addition of sodium carbonate. The organic layer is separated, washed with water and concentrated. Purification was achieved by flash column chromatography (ethyl acetate/heptane 4:1) and washing with methanol yielding [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-{2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 38 (25 mg, 10%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9].CN(C)C=O.[N-:15]=[N+:16]=[N-:17].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[N:15]([CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9])=[N+:16]=[N-:17]
Reactant: Cc1nccn1CCCl
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CCN=[N+]=[N-]

Procedure:
To a solution of 8 parts of 1-(2-chloroethyl)-2-methylimidazole (U.S. Pat. No. 3,882,136) in 200 parts of N,N-dimethylformamide is added a slurry of 5 parts of sodium azide in 100 parts of N,N-dimethylformamide. The resultant mixture is stirred for 2 hours at approximately 65°, then cooled and thereupon diluted with 600 parts of water. Sufficient potassium carbonate is added to insure basicity. The mixture thus obtained is extracted with chloroform. The chloroform extract is dried over anhydrous magnesium sulfate and stripped of solvent by vacuum distillation, affording 1-(2-azidoethyl)-2-methylimidazole as the residue. The product has the formula ##SPC4##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][S:13][C:14](SC)=[N:15][C:16]#[N:17]>N1C=CC=CC=1>[C:16]([N:15]=[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[S:13][CH3:12])#[N:17]
Reactant: CSC(=NC#N)SC
Reactant: COC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=NC#N)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of methyl 3-aminobenzoate (6.04 g, 40 mmol) and dimethyl N-cyanodithioiminocarbonate (11.96 g, 80 mmol) in pyridine (70 mL) was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and upon standing overnight at room temperature the above compound (6.2 g) crystallized from the reaction mixture. The compound was used without further purification. 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3](=[CH:18][CH3:19])[CH:4]=[CH:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].O.NN.C(O)C>[OH-].[Na+]>[CH2:18]([C:3](=[CH:1][CH3:2])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:19]
Reactant: CC=C(C=CCN1C(=O)c2ccccc2C1=O)CC
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=C(C=CCN)CC
Yield: 83.6 %

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (500 mg), hydrazine monohydrate (147 mg), and ethanol (5 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine (205 mg) as an oil. This oil was used in the next reaction without further purification. To a solution of crude 4-ethyl-2,4-hexadien-1-ylamine (205 mg) in dichloromethane (2 ml) at 0° C. was added dropwise acetic anhydride (335 mg). After one hour, the reaction mixture was evaporated to dryness. The residue was chromatographed on silica gel (2% methanol in dichloromethane) to give 1-acetylamino-4-ethyl-2,4-hexadiene (122 mg) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[CH2:21][N:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCC2(CCN(CC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of the piperidine (B5) (24 mg, 0.09 mmol), 1-bromo -3,3-dimethylbutan-2-one (13.5 mg, 0.08 mmol) and sodium carbonate (32 mg, 0.3 mmol) in DMF (1 ml) was stirred at 50° C. in a sealed vial for 16 hours. The mixture was cooled and carefully neutralized with TFA and purified by reverse phase HPLC to give the title compound no. 19 as a TFA salt. LC-MS: m/e=357.30 (M+H). Rt=1.61 min. 1H-NMR (500 MHz, DMSO-d6): 9.60 (br. s, 1H), 8.21 (d, 1H), 7.44 (d, 1H), 7.32 (t, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 4.92 (q, 1H), 4.60 (d, 2H), 3.26 (m, 4H), 2.35 (m, 2H), 2.04 (dd, 1H), 1.87 (s, 3H), 1.80 (m, 3H), 1.71 (d, 1H), 1.63 (m, 1H), 1.16 (s, 9H).
Reaction SMILES: [Br-:1].[CH2:2]([N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.N1CCCCC1.CCOCC>CO>[Br-:1].[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCCCCC[n+]1ccccc1C
Agent: [Br-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCCCC[n+]1ccccc1C=Cc1ccc(N(C)C)cc1
Yield: 53.9 %

Procedure:
1-Hexyl-2-methylpyridinium bromide (7.8 g, 0.03 mole) and 4-dimethylaminobenzaldehyde (6.0 g, 0.04 mole) were refluxed in methanol (50 ml) in the presence of piperidine (1.0 ml) under nitrogen for four hours. On cooling and the addition of about 100 ml of ether a solid crystallised which was collected and washed with a little isopropanol to give 2-[4-(dimethylamino)styryl]-1-hexylpyridinium bromide (6.3 g), melting point 217°-218° (decomposition).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][C:8]1=[CH2:9]>>[N:1]1([C:11](=[O:12])[CH2:10][C:8](=[CH2:9])[C:7]([OH:14])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)OC1=O
Reactant: C1COCCN1
Product: C=C(CC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C

Procedure:
Morpholine (20 mL, 228.6 mmol) was slowly added to a stirring solution of itaconic anhydride (25.1 g, 228.6 mmol) suspended in dichloromethyl at 0° C. The reaction mixture was allowed to slowly warm to room temperature. Upon completion (LCMS), volatiles were removed by vacuum under reduced pressure. Crude yield: 44.96 g, 99%. Product was used without further purification.
Reaction SMILES: [N+](C1C=CC(O[C:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20](=[O:30])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][N:25]=4)[N:23]=[C:14]23)=[O:12])=CC=1)([O-])=O.[CH3:31][O:32][C:33]1[C:38]([NH2:39])=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=1>C(#N)C.CN(C)C1C=CN=CC=1.O.ClCCl>[CH3:31][O:32][C:33]1[C:38]([NH:39][C:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20](=[O:30])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][N:25]=4)[N:23]=[C:14]23)=[O:12])=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Reactant: COc1ccc(N)c(OC)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc(NC(=O)C2CCCCn3c2nc(-c2ccncn2)cc3=O)c(OC)n1
Yield: 26 %

Procedure:
To a solution of 0.450 g (1.10 mmol) of (+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylic acid 4-nitro-phenyl ester in 10 mL of dry acetonitrile in a sealed tube, were added 0.341 g (2.21 mmol) of 2,6-dimethoxy-pyridin-3-ylamine and 0.270 g (2.21 mmol) of dimethyl-pyridin-4-yl-amine. The resulting mixture was stirred under reflux for 16 hours. The mixture was dissolved in water and dichloromethane. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 100/0/0 to 98/2/02) to afford 0.121 g (26%) of a white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:24][C:25](N(OC)C)=[O:26])=[CH:19][CH:18]=1.Cl>O1CCOCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:24][C:25]([C:2]2[C:3]([CH3:10])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: COc1cc(C)c(Br)cn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Product: Cc1cc(=O)[nH]cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxy-4-methylpyridine was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4). The product of this reaction was reacted with concentrated aqueous HCl in 1,4-dioxane in analogy to example 162, step 2 to give the title compound as a colorless foam, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:5]([C:4]([F:3])([F:14])[F:15])=[N:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% [w/w] dispersion in mineral oil, 632 mg, 15.8 mmol) was added portionwise to a stirred solution of 4,5,6,7-tetrahydro-3-(trifluoromethyl)-indazole (3.00 g, 15.8 mmol) in DMF (60 mL), and the mixture stirred at RT for 30 min. Tert-butyl bromoacetate (2.33 mL, 15.8 mmol) was added and the reaction mixture stirred at 80° C. for 2 h, and allowed to cool to RT. Water (50 mL) was added and the resulting solution extracted with EtOAc (3×200 mL), washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to afford (3-Trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[C:23]=1[CH3:30])=[O:18])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[C:23]([CH3:30])[C:24]=3[CH3:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Reactant: ClCc1cccnc1SC1CCC1
Product: Cc1c(OCc2cccnc2SC2CCC2)ccc(C2CC2C(=O)O)c1C
Yield: 82.3 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.032 g, 0.149 mmol) obtained in Step C of Preparation Example 23 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.047 g, 82%).
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[CH2:6][CH2:5]1.[CH3:31][O-:32].[Na+]>CO>[OH:1][CH:2]([CH2:22][O:23][C:24]1[C:29]([O:32][CH3:31])=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[CH2:6][CH2:5]1
Reactant: C[O-]
Reactant: O=C1N(c2ccccc2)CCN1C1CCN(CC(O)COc2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1OCC(O)CN1CCC(N2CCN(c3ccccc3)C2=O)CC1

Procedure:
With stirring, 10.1 g of 1-{1-[2-hydroxy-3-(3-chloropyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one (see Example 6) and 1.41 g of sodium methylate in 110 ml of methanol are refluxed for 10 hours. The reaction mixture is concentrated in a water jet vacuum. The residue is dissolved in ethyl acetate and extracted with 2 N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried over sodium sulphate and concentrated in a water jet vacuum. The residue crystallises from methylene chloride-ether to yield 1-{1-[2-hydroxy-3-(3-methoxy-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one with a melting point of 128°-129° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].[OH-].[Na+]>Cl.C1(C)C=CC=CC=1>[CH2:9]([O:11][CH:12]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:13])[CH3:10]
Reactant: Oc1ccccc1O
Reactant: C=COCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(C)Oc1ccccc1O

Procedure:
220 parts by weight of pyrocatechol is suspended in 200 parts by weight of toluene. After 2 drops of concentrated hydrochloric acid have been added 150 parts by weight of ethyl vinyl ether is dripped in while stirring. The internal temperature is prevented from rising above 65° C. by external cooling with ice. All of the pyrocatechol has dissolved upon completion of the reaction. 5 parts by weight of 2-normal caustic soda solution is added, the whole is allowed to cool, and dried over sodium sulfate, the solvent is removed and the product is distilled in vacuo. The yield is almost quantitative; boiling point 78° to 81° C. at 1 mm; nD25 = 1.5032
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][C:15]([O:19][CH3:20])=[CH:14][C:13]=3[Cl:21])[N:7]([CH2:22][CH2:23][CH2:24]O)[C:6]=2[C:5]([C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([O:28][CH3:29])=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:13]([Cl:21])=[CH:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[Cl:18])[CH2:24][CH2:23][CH2:22][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(Cl)cc(OC)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(OC)cc1Cl
Yield: 85.5 %

Procedure:
To a mixture of methyl 4-chloro-2-[(2,6-dichloro-4-methoxyphenyl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (215 mg, 0.469 mmol) and triethylamine (0.327 mL, 2.35 mmol) in tetrahydrofuran (4.7 mL) was added methanesulfonyl chloride (0.148 mL, 1.87 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and concentrated in vacuo. After N,N-dimethylformamide (4.7 mL) and potassium carbonate (648 mg, 4.69 mmol) were added to the residue, the resultant mixture was stirred at 80° C. for 30 min, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (177 mg, 0.401 mmol, 86%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[CH3:6][C:7]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:3][CH:2]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Product: Cc1cnc2ccc(-c3cccc(C(F)(F)F)c3)nn12
Temperature: 150 °C
Yield: 28.8 %

Procedure:
A mixture of 5.18 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 4.60 g of aminoacetoneethyleneketal was heated at 150° C. under argon for 4 hours. The cooled mixture was dissolved in dichloromethane and the solution passed through a short pad of hydrous magnesium silicate. The filtrate was concentrated, diluted with hexane and chilled to give 0.8 g of crystals, mp 98°-100° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH3:22])([O-:21])=[O:20].C(O)(=O)C.C(N)CCC>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:22][N+:19]([O-:21])=[O:20])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCN
Product: COc1cc(C=C[N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
23.1 g (95.7 mmol) of 4-benzyloxy-3-methoxybenzaldehyde, 8.76 g (143 mmol) of nitromethane and 250 ml of acetic acid were mixed and 7.07 g (96.7 mmol) of butylamine was added dropwise thereto. The mixture was refluxed for 2 hours by heating, and then cooled and poured into ice-water. The precipitated crystals were dissolved with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 17.0 g of 1-benzyloxy-2-methoxy-4-(2-nitrovinyl)benzene.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[C:24]2[C:23]=1[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=4)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=3)[CH:29]=[C:24]2[C:23]=1[CH3:40]
Reactant: Cc1[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc2c1C
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1[nH]c2ncc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cc2c1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.34 g, 0.885 mmol) in toluene (30 mL) and EtOH (10 mL) were added 2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (B-6-5) (0.7 g, 1.77 mmol in theory) and 2 N aq. Na2CO3 (1.3 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (68 mg, 0.058 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-6) (0.170 mg, 23.6%) as a light yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][OH:12].Cl[C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]3[N:26]=[C:27]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:28]=[C:29]([C:30]4[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:37][C:38]5[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=5)=[N:34][CH:35]=4)[C:24]=3[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>O>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]3[N:26]=[C:27]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:28]=[C:29]([C:30]4[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:34][CH:35]=4)[C:24]=3[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(OCCN(C)C)nc3)cn2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a toluene solution (2 ml) of N,N-dimethylethanolamine (139 μl, 0.138 mmol) and {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (150 mg, 0.23 mmol) obtained in Step A in Example 1-D-48, 60% oily NaH (46 mg) was added, followed by refluxing for 4 hours. The reaction mixture was cooled to room temperature, and diluted with water, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, followed by filtering off the magnesium sulfate, and subsequently the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), to obtain a crude product of (5-{7-[6-(2-dimethylamino-ethoxy)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine as a yellow solid (67 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-72) as a yellow powder (12 mg, 29%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH:30]([CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[CH:30]([CH:33]1[CH2:38][CH2:37][CH:36]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.