Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:20])=[C:4]([CH3:21])[C:3]=1[NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCCCCC.[C:36](OCC)(=[O:38])C>>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:7]3[C:2]([O:38][CH3:36])=[C:3]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]([CH3:21])=[C:5]([CH3:20])[C:6]=3[O:10][CH2:9]2)=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: Cc1c(C)c2c(c(Br)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(NC(=O)CC(C)(C)C)c(C)c(C)c2c1C(c1ccc(C(C)C)cc1)CO2
Yield: 21 %

Procedure:
Using N-(4-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 63, the title compound was synthesized in the same manner as in Example 36. Yield: 21%. Melting point: 161-162° C. (hexane-ethyl acetate).
Reaction SMILES: [CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH2:19][CH3:20])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-:23].OO>CCO>[CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH2:19][CH3:20])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]([NH2:10])=[O:23])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: CCO
Product: CCOc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (219.7, 0.15 g, 0.53 mmol) in EtOH (10 ml) was added NH4OH (0.18 ml, 2.66 mmol, 14.8 N in H2O) followed by H2O2 (1.8 ml, 26.6 mmol, 50% in H2O). The mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and quenched carefully with 1N Na2S2O3 solution (26 ml). The mixture was extracted with EtOAc (×2) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified with prep-TLC (5% MeOH in CH2Cl2). Yield: 0.1 g, white solid, 62.5%. m/z (ES−) 299 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(=O)Nc1cccc(OC[C@@H]2CO2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(NC(C)=O)c3)cc2)CC1
Yield: 28.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide 0.421 g, 1.0 mmol) was reacted with N-{3-[(2S)oxiranylmethoxy]phenyl}acetamide (0.207 g, 1.0 mmol) according to Procedure G (eluant. 20:1 chloroform-methanol) to give the title compound (0.168 g, 0.289 mmol).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2].[C:16](Cl)(Cl)=[S:17]>O>[N:13]([C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1)=[C:16]=[S:17]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a heterogeneous mixture of 2-cyano-3-(trifluoromethyl)-5-nitropyridine A11 (0.075 g, 0.4 mmol) in water (2 ml) was added thiophosgene (50 μl). The mixture was stirred for 2 hours and then washed with water and extracted with chloroform. The organic layer was dried over MgSO4 and concentrated to yield compound A12 (0.087 g, 0.38 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 113.61, 121.04 (q, J=273.1 Hz), 127.41, 130.38 (q, J=4.3 Hz), 131.44 (q, J=34.4 Hz), 133.55, 144.75, 150.30.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19](=[O:35])[C@H:20]([CH:32]([CH3:34])[CH3:33])[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:21][C@H:20]([C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([OH:36])=[O:12])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (200 ml) was added to a mixture of N-benzyloxycarbonyl-L-valyl-L-proline tert-butyl ester (80.0 g) in methylene chloride ((300 ml) at 0° C. over approximately 30 minutes. After stirring at 0° C. for one hour, the reaction mixture was allowed to rise to ambient temperature and stirred an additional 3 hours. The reaction mixture was then comcentrated under vacuum and reconcentrated four times from toluene to remove residual trifluoroacetic acid. The resulting viscous oil was dried under vacuum for 16 hours. The crude product was purified on by chromatography on silica gel, usimg methylene chloride as eluant, to give N-benzyloxycarbonyl-L-valyl-L-proline (A) (63.6 g) as a pale yellow viscous oil; NMR (d6 -DMSO): 0.92 (2d, 6H), 1.65-2.05 (2m, 4H), 2.25 (m, 1H), 3.60 (m, 1H), 3.80 (m, 1H), 4.05 (dd, 1H), 4.25 (m, 1H), 5.02 (2d, 2H), 7.35 (m, 5H), 7.50 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(Cl)cc4)CC3)c2cc1OC
Yield: 29.4 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-chloro-4-isocyanato-benzene (16.8 mg, 0.110 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (9.2 mg, 29%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.38-7.33 (m, 4H), 7.26 (m, 2H), 6.44 (br s, NH), 4.29-4.26 (m, 2H), 4.07 (s, 6H), 3.62 (m, 1H), 3.19 (m, 2H), 2.16 (m, 2H), 2.02-1.99 (m, 2H); LC/MS (ESI) calcd mass 426.2, found 427.2 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[CH2:1]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=2)[CH2:14][CH:13]([OH:15])[CH2:11]1)[CH3:2]
Reactant: ClCC1CO1
Reactant: CCNc1cccc(C)c1
Product: CCN1CC(O)Cc2ccc(C)cc21
Reaction time: 72 h

Procedure:
N-ethyl-m-toluidine (1.0 mole) and epichlorohydrin (225 g) were mixed and allowed to stand three days at room temperature. The reaction mixture was heated at 140°-145° C. for 6 hrs. and then distilled under vacuum. The product (100 g) which boiled at 143° C. at 1.1 mmHg was recovered in 52% of the theoretical yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCCCC1
Yield: 98.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.200 g, 0.465 mmol) was dissolved in acetone (30 ml) and after adding thereto anhydrous sodium carbonate (0.077 g, 0.558 mmol) and methyl bromoacetate (0.078 g, 0.512 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.230 g, 0.459 mmol, 99%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][CH2:4]1.CC(C)([O-])C.[Na+].[C:16]([C:20]1[S:24]/[C:23](=[N:25]\[C:26](=[O:38])[C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2F)/[N:22]([CH2:39][C@H:40]2[CH2:44][CH2:43][CH2:42][O:41]2)[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([C:20]1[S:24]/[C:23](=[N:25]\[C:26](=[O:38])[C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=2[O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:9])[N:7]2[CH3:8])/[N:22]([CH2:39][C@H:40]2[CH2:44][CH2:43][CH2:42][O:41]2)[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CN1C(=O)CC[C@H]1CO
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 22 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (108 mg, 0.84 mmol) (Williams, P. D. et al. Journal of Medicinal Chemistry 1991, 34, 887-900) in 5 mL of THF was added sodium tert-butoxide (100 mg, 1.05 mmol). The mixture was stirred at 22° C. for 20 minutes. The mixture was cooled to 5° C. and a solution of Example 1A (180 mg, 0.42 mmol) in 2 mL of THF was added. The mixture was stirred at 5° C. for 2 hours, then at 22° C. for 1 hour. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on SiO2 using an Analogix® Intelliflash280™ (eluted with CH2Cl2:10% MeOH and 3N NH3 in CH2Cl2: 0 to 100%) to afford the title compound; 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 9 H), 1.58-1.73 (m, 1 H), 1.74-2.14 (m, 4 H), 2.14-2.42 (m, 2 H), 2.44-2.64 (m, 1 H), 2.91 (s, 3 H), 3.72-3.91 (m, 2 H), 3.93-4.03 (m, 1H), 4.07 (dd, J=12.0, 4.8 Hz, 1 H), 4.14-4.32 (m, 3 H), 4.39 (dd, J=13.3, 2.6 Hz, 1 H), 6.88 (s, 1 H), 6.99 (d, J=8.7 Hz, 1 H), 7.60 (dd, J=8.7, 2.4 Hz, 1 H), 8.11 (d, J=2.4 Hz, 1 H); MS (ESI) m/z 540 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[C:5]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)[nH]c2=O)cc1C
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2Cl)cc1C
Temperature: 110 °C
Yield: 88 %

Procedure:
A mixture of 2-amino-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3H-pyrimidin-4-one in phosphorus oxychloride (5 ml) was heated at 110° C. for 40 minutes and stirred at room temperature over night. Solvent was removed under reduced pressure and ice water was added. The aqueous solution was basified with potassium carbonate to pH 9, and extracted with methylene chloride. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure to yield 4-chloro-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-pyrimidin-2-ylamine as yellow solid (0.043 g, 88%). MS M+H=308.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>C(OC(C)C)(C)C>[CH3:14][O:13][C:8]1[CH:7]=[C:4]([CH:5]=[C:23]([N+:20]([O-:22])=[O:21])[CH3:24])[C:3]([O:2][CH3:1])=[C:10]([CH3:11])[C:9]=1[CH3:12]
Reactant: COc1cc(C=O)c(OC)c(C)c1C
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Product: COc1cc(C=C(C)[N+](=O)[O-])c(OC)c(C)c1C
Yield: 67 %

Procedure:
A mixture of 2,5-dimethoxy-3,4-dimethylbenzaldehyde (38.9 g, 0.20 mol), ammonium acetate (10 g, 0.13 mol) and nitroethane (200 mL) was heated to reflux for 2 hours. The reaction mixture was diluted with diisopropyl ether, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 33.6 g of the title compound.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][O:56][CH2:57][CH2:58][C:59]1N=C(N)[S:61][N:60]=1>ClCCl>[CH3:55][O:56][CH2:57][CH2:58][C:59]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:61][N:60]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: COCCc1nsc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCCc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 84 mg, 0.26 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol) and 1-hydroxybenzotriazole (45 mg, 0.33 mmol). The resulting solution was stirred for 5 min before 3-(2-methoxy-ethyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.31 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(2-methoxy-ethyl)-[1,2,4]thiadiazol-5-yl]-amide (34 mg, 28%) as a light orange solid: HR-ES-MS m/z calculated for C21H25ClN4O4S [M+H]+ 465.1359, observed 465.1358; 1H NMR (300 MHz, DMSO-d6) ppm 0.91 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.47 (br. s., 1H), 1.58-1.74 (m, 1H), 1.80-1.95 (m, 1H), 3.01 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 3.74 (t, J=6.4 Hz, 2H), 4.19-4.36 (m, 1H), 4.41-4.61 (m, 1H), 4.83 (s, 1H), 4.94-5.07 (m, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 13.32 (s, 1H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][NH2:14]>>[CH3:13][NH:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: CN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and methylamine comparable as in Example A. A crystallized colorless product with a melting point of 127° to 128° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:28])[C:26]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]3[CH:23]=2)=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:30][NH:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:30][N:31]([CH3:32])[C:26]1[C:25]([F:28])=[CH:24][C:4]([C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]4[CH:23]=3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: CNC
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(F)c(F)c4)cc3)cn2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(N(C)C)c(F)c4)cc3)cn2c1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
A stirred mixture of 3,4,5-trifluoro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]benzamide (0.10 g, 0.26 mmol), dimethylamine hydrochloride (0.087 g, 1.07 mmol) and potassium carbonate (0.147 g, 1.07 mmol) in dry DMSO (3 ml) was heated at 120° C. for 22.5 h. After cooling to room temperature, the reaction mixture was added to water (100 ml) and the precipitate was collected by vacuum filtration, and washed with water (40 ml). The solid was dried in an oven at 95° C., and then purified by flash chromatography (25:1 DCM/MeOH) to give the title compound (0.084 g, 80%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=1.B(Br)(Br)Br>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1
Reactant: COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To an ice-cooled solution of 5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)-pyrazole (3.0 g, 10.0 mmol) in methylene chloride (25 ml) was added boron tribromide (51 ml, 51 mmol, 1 M solution in methylene chloride). After 1 h, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (2.4 g).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[O:10]=[C:11]1[C:23]2[C:18](=[N:19][C:20](C#N)=[C:21]([C:24]#[N:25])[N:22]=2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2>[OH-].[Na+].C1COCC1>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([C:20]2[N:19]=[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:10])[C:23]3=[N:22][C:21]=2[C:24]#[N:25])[CH2:5][CH2:4]1
Reactant: FC1(F)CCNCC1
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1nc2c(nc1N1CCC(F)(F)CC1)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
4,4-Difluoropiperidine hydrochloride (249 mg, 1.58 mmol) was dissolved in 1N NaOH (5 ml) and extracted with CH2Cl2 (2×5 ml). Organic phase was dried over Na2SO4, filtered and evaporated. The residue was dissolved in THF (2 ml) and this solution was added to a solution of 1 (185 mg, 0.79 mmol) in THF (2 ml); the mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the crude solid washed with EtOH and dried under vacuum, affording 8 (245 mg, 95%) as yellow-brown solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH3:15])[CH2:10][CH2:11][C:12](Br)(Br)[C:5]2=[N:4][CH:3]=1.CS(C)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH3:15])[CH2:10][CH2:11][C:12](=[N:27][NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CC1CCC(Br)(Br)c2ncc(Br)c(=O)n21
Reactant: NNc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC1CCC(=NNc2ccccc2)c2ncc(Br)c(=O)n21
Reaction time: 72 h
Yield: 34.7 %

Procedure:
4.0 g. (0.01 moles) of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one are dissolved in 10 ml. of dimethyl sulfoxide. To the solution 2.8 ml. (0.03 moles) of phenylhydrazine are added. The reaction mixture is allowed to stand for three days whereupon 20 ml. of water are added. The solvent is decanted from the precipitated substance and the product is recrystallized from methanol. 1.3 g. (34.7%) of 3-bromo-9-(phenylhydrazono)-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one are obtained, melting at 190° to 192° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=1
Reactant: CCCCCC[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCCCCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-hexylmagnesium chloride following the general method of Preparation 1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:26][O:18][C:17]([C:15]1[CH:16]=[C:11]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[N:13][CH:14]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnc2c(c1)c(-c1ccccc1)nn2Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cnc2c(c1)c(-c1ccccc1)nn2Cc1ccccc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
100 mg of 1-benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid obtained by Example 32 was dissolved in 5 mL of N,N-dimethylformamide, added with 60 mg of potassium carbonate and 30 μl of methyl iodide, and stirred all day and night at room temperature. The residue was added with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, the reaction was crystallized from diisopropyl ether, to afford 100 mg of the title compound as a pale brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][C:24](O)=[O:25])=[CH:17][N:16]=1>>[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([C:23]2[C:24](=[O:25])[O:1][C:2]3[C:3]([C:10]=2[CH3:11])=[CH:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=3)=[CH:17][N:16]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: COc1ncc(CC(=O)O)c(OC)n1
Product: COc1ccc2c(C)c(-c3cnc(OC)nc3OC)c(=O)oc2c1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-(2-hydroxy-4-methoxy-phenyl)-ethanone and (2,4-dimethoxy-pyrimidin-5-yl)-acetic acid as the starting material.
Reaction SMILES: [CH:1]1([N:7]=[C:8]([CH3:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](Cl)([Cl:20])=[O:19]>C(Cl)(Cl)(Cl)Cl>[C:8]([N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:18]([Cl:20])=[O:19])([CH3:10])=[CH2:9]
Reactant: CC(C)=NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)N(C(=O)Cl)C1CCCCC1

Procedure:
139 parts of acetone cyclohexylimine and 111 parts of triethylamine are dissolved in 500 parts of carbon tetrachloride, and the whole reacted with 110 parts of phosgene as described in Example 1. 123 parts (61% of the theory) of N-isopropenyl-N-cyclohexylcarbamyl chloride is obtained having a boiling point of 85° C. at 0.01 mm.