Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:19])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH2:26][CH:28]3[CH2:29][O:30]3)=[CH:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: ClCC1CO1
Reactant: COc1ccc2c(=O)cc(-c3ccccc3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OCC3CO3)cc(-c3ccccc3)nc2c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a solution of 7-methoxy-2-phenyl-1H-quinolin-4-one (1.5 g, 6 mmol) in DMF (11 ml) were added successively K2CO3 (1.66 g, 12 mmol) and (RS)-epichlorohydrin (1.9 ml, 24 mmol). The reaction mixture was stirred at 65° C. for 3 hours, then cooled to room temperature and diluted with CH2Cl2 (25 ml). Solid was filtrated, and filtrate was concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 4:1) to provide (RS)-7-methoxy-4-oxiranylmethoxy-2-phenyl-quinoline (1.05 g, 57%) as a colorless oil, MS: m/e=307 (M+).
Reaction SMILES: Cl.[CH2:2]([N:6]([CH2:11][CH2:12][CH2:13]Cl)[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CCC(C)=O>O>[CH2:2]([N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(CCCC)CCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 90.9 %

Procedure:
9.69 g of dibutylamino propylchloride HCl salt (IV) (0.04 mol, 1 eq), 5 g of 4-hydroxybenzaldehyde (III) (0.04 mol, 1 eq), 17 g of potassium carbonate (0.12 mol, 3 eq) and 30 mL of MEK are added to the reaction flask. The suspension is heated to 80° C. and it is stirred for 10 hours at this temperature. Then the mixture is cooled to room temperature, 40 mL of water is added and the brown solution is stirred for 30 min. After phase separation the organic phase is washed with 15 mL of water and the solvent is evaporated to obtain 10.6 g of compound (V) as a yellowish-brown solid (89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+]>CN(C=O)C>[CH3:23][O:24][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3ccc(Cl)nc3C2(C)C)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To solution of 2-chloro-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (intermediate A-16 [F], 3.15 g, 10 mmol) in DMF (30 mL) was added sodium methanolate (0.813 g, 15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours before it was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title compound (2.8 g, 90%) as a solid. MS: 313.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:22]=[CH:21][C:11]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C1C(=O)N([Cl:30])C(=O)C1>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:11]([CH:10]=[CH:9][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: CN1CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CN1CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Step F (2): To a solution of tert-butyl 4-(4-methylpiperazin-1-yl)benzylcarbamate (30 mg, 0.1 mmol) from step F (1) in CH2Cl2 (1.0 mL) was added NCS (14 mg, 0.1 mmol). The mixture was stirred at rt for 4 h, and then the mixture was concentrated to give tert-butyl 3-chloro-4-(4-methylpiperazin-1-yl)benzylcarbamate which was used without purification in the next step. LC-MS (M+H)+=340.29 1H-NMR (500 MHz, CD3OD) δ 7.30 (s, 1 H), 7.18 (d, J=8.24 Hz, 1 H), 7.10 (d, J=8.24 Hz, 1 H), 4.16 (s, 2 H), 3.00-3.15 (m, 4 H), 2.62-2.81 (m, 7 H), 1.50(s, 9 H).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([C:19](O)([CH:21]([CH3:23])[CH3:22])[CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH:21]([CH3:22])[CH3:23])=[CH2:20])[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C(C)(O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1)C(C)C
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Compound 89 (0.30 g; 8.73×10−1 mmol) was dissolved in pyridine (20 ml). While the solution was stirred at room temperature, phosphorus oxychloride (1.34 g; 8.73 mmol) was added dropwise. After completion of the addition, the mixture was stirred for 6 hours at 100° C., and left to cool to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, and extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.19 g of the target compound as yellow oily matter (yield: 64.9%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([F:24])([F:23])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)C.Br[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH:29]=[O:30]>>[F:24][C:5]([F:23])([C:6]1[CH:7]=[C:8]([C:27]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=2[CH:29]=[O:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:4]([OH:3])=[O:25]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)C(F)(F)c1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1ccc(C(F)(F)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: difluoro-[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde; the ester was hydrolyzed under the reaction conditions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2)[CH3:2].Cl[C:19]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]([S:30][CH3:31])[N:20]=1.C(N(CC)CC)C>C(O)CCC>[CH2:28]([O:27][C:25]([C:24]1[C:19]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)=[N:20][C:21]([S:30][CH3:31])=[N:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.2 %

Procedure:
To a solution of 3-(indan-5-ylamino)-propionic acid ethyl ester (5 g, 21.4 mmol) and ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (5 g, 21.4 mmol) in 40 mL of n-butanol was added triethylamine (3 mL, 21.4 mmol). The solution was stirred at rt for 2 days. The solvent was removed under vacuum. The residue was extracted into EtOAc, washed with water, brine and then dried with Na2SO4. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:10-1:6, v/v), gave 8.2 g (90%) of the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 4.35 (t, 2H), 4.06 (q, 2H), 3.55 (q, 2H), 2.82 (m, 4H), 2.69 (t, 2H), 2.58 (s, 3H), 2.06(m, 2H), 1.20 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1>CC#N>[NH2:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of 4-methoxybenzoyl chloride (1.03 g, 6.02 mmol) in CH3CN (6 ml) was added drop wise to a solution of methyl 3,4-diaminobenzoate (106) (1.00 g, 6.02 mmol) and pyridine (0.49 ml, 6.02 mmol) in CH3CN (25 ml) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and the solvent was evaporated. Ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 1-3% MeOH in DCM), 1.03 g (56%) of compound 107 was obtained as a off white solid. 1H NMR: (DMSO) δ(ppm): 9.51 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.75 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 5.80 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H). MS: (calc.) 300.1; (obt.) 301.1 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[N:31]=[C:7]3[NH:8][C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([C:4]2[N:31]=[C:7]3[N:8]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C3CC3)nn12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C3CC3)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 4′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.17 mL), potassium carbonate (0.34 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.N12CCCN=C1CCCCC2.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[CH3:27][NH:28][C:29]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1)=[O:30]
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=O)CC1
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopent[b] indol-3(2H)-one (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH:5]=1.[CH3:23][N:24](C=O)C>C(OC)(C)(C)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:23]#[N:24])[CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(Br)c2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(OC)c(OCCc2cccc(C#N)c2)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A flask was charged with zinc cyanide (129 mg, 1.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.0547 mmol). Under an atmosphere of argon, a solution of the compound of step 1 (400 mg, 1.10 mmol) in DMF (1.9 ml) was added to the mixture. After stirring at 150° C. for 1 h and cooling, the mixture was diluted with methyl tert-butyl ether and filtered over celite. The filtrate was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to give 275 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:15][CH:16]=[C:11]2[C:10]([O:26]C(OC(C)(C)C)=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>N.CO>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:15][CH:16]=[C:11]2[C:10]([OH:26])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1nn(C(=O)OC(C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(O)c2cnc(Oc3ccc(F)cc3F)nc21
Reaction time: 12 h

Procedure:
3-tert-Butoxycarbonyloxy-6-(2,4-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid tert-butyl ester was dissolved in a solution of NH3 in methanol (6 mL, 2 M) and stirred at room for 12 hours. The mixture was concentrated under reduced pressure to give 190 mg of 6-(2,4-difluoro-phenoxy)-3-hydroxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid tert-butyl ester as a white solid residue that was used without purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH:9]=O)([O-:3])=[O:2].[C:14]([OH:20])(=[O:19])[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH:9]=[C:15]([C:14]([OH:20])=[O:19])[C:16]([OH:18])=[O:17])([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=CC=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=C(O)C(=CC=Cc1cccc([N+](=O)[O-])c1)C(=O)O

Procedure:
3-nitro cinnamylidene malonic acid was prepared by reacting 3-nitro cinnamaldehyde (13.7 g) with malonic acid (8.05 g 0.077 mol.) in glacial acetic acid (20 ml) at 100° C. for 6 hrs. After cooling, the product was collected, washed and dried to yield 8.9 g. of the desired product m.p 185°-187° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH:20]=1.C(Cl)Cl>C(Cl)Cl.CO>[C:1]1([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH:17][CH:28]4[CH2:29][CH2:30][N:25]([C:21]5[CH:20]=[C:19]([CH3:18])[N:24]=[CH:23][N:22]=5)[CH2:26][CH2:27]4)[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1cc(C2=CCCCC2)c2nc(N)nn2c1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C2=CCCCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 1h, starting from 8-cyclohexenyl-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a yellow viscous oil (yield: 17%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 404.6 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]3[N:23]=[C:22](C(Cl)(Cl)Cl)[O:21][N:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].[BH4-].[Na+]>CO>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]3[N:23]=[CH:22][O:21][N:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCC(=O)N1CCN(c2cc(-c3ncon3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
1-(4,4-Dimethylpentanoyl)-4-{4-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}piperazine (43 mg) obtained in Example 68-1) was dissolved in methanol (3 mL), and sodium borohydride (46 mg) was added thereto and stirred at room temperature for 1 hour. Then, the solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 7.4 mg of the entitled compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]1=[O:15].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:21]1([CH:5]([C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([OH:1])[CH:3]=2)[CH:6]2[C:11](=[O:12])[O:10][C:9]([CH3:13])([CH3:14])[O:8][C:7]2=[O:15])[CH2:23][CH2:22]1
Reactant: COc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1O
Reactant: Br[Mg]C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)cc1O
Reaction time: 1 h

Procedure:
To a solution of 5-(3-hydroxy-4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (556 mg) in THF (10 mL) was added a 1.0 M solution of cyclopropylmagnesium bromide in THF (6.0 mL) at 0° C., and the mixture was stirred for 1 hr. 3N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was stirred for 15 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (300 mg) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)ccc1OC1CCOCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-pyran-4-yl ester (Example 32a) and potassium carbonate in dimethylformamide to give a solid. MS (H+), 225.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH2:11][O:10][CH3:9])[N:3]=1
Reactant: COCC1CCCN1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCC1CCCN1c1cncc(Cl)n1
Yield: 80.4 %

Procedure:
A solution of 2,6-dichloropyrazine (1.18 g), 2-(methoxymethyl)pyrrolidine (1.0 g) and potassium carbonate (1.64 g) in DMA (15 mL) was stirred at 80° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (1.45 g, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:21])[C:17]#[C:18][CH2:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:21][CH2:16][C:17]#[C:18][CH2:19][CH3:20])[N:3]=[CH:4][N:5]=1
Reactant: CCC#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
In 9 ml of N,N-dimethylformamide were dissolved 202 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 112 mg of 2-pentyn-1-ol, to which 54 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 211 mg of 4-(2,3-difluorophenyl)-6-(2-pentynyloxy)pyrimidine (the present compound (117)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[CH:12]=O>>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[CH:12]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Nc1ccccc1O
Reactant: COc1cccc(F)c1C=O
Product: COc1cccc(F)c1C=Nc1ccccc1O
Yield: 99.8 %

Procedure:
Preparation analogous to Example 1, step a, from 2-aminophenol (7.08 g, 64.93 mmol) and 2-fluoro-6-methoxybenzaldehyde (10 g, 64.93 mmol) gave the title compound (15.9 g, 99%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:2][C:3]#[CH:4].[OH:11][CH2:12][C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16]O[CH2:14]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]12[O:11][CH2:12][C:13]([CH2:17][CH2:18][CH3:19])([CH2:16][O:10]1)[CH2:14][O:9]2)[CH2:2][C:3]#[CH:4]
Reactant: CCCC1(CO)COC1
Reactant: C#CCCOCCC(=O)O
Product: C#CCCOCCC12OCC(CCC)(CO1)CO2

Procedure:
1-[2-(But-3-ynyloxy)ethyl]-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(but-3-ynyloxy)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using the methodology outlined in Example I.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>CCO.[Ni]>[NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][N:3]=1
Reactant: Nc1cc(N)c([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(N)c(N)cn1
Yield: 98.5 %

Procedure:
A solution of 5 (0.540 g, 3.5 mmol) in EtOH (50 ml) and Raney Nickel (0.600 ml) was stirred under H2 atmosphere for 3 h at room temperature. The product was freed from catalyst by filtration through celite to give 6 (0.428 g, 98%); 1H NMR (DMSO-d6, 500 MHz): δ 7.11 (1H, s), 5.65 (1H, s) 5.12 (2H, brs), 4.64 (2H, brs) 3.34 (2H, brs); EIMS m/z: 125 (M+1) and used as is in the next step.