Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32]([O-:34])=O)[C:24]([C:38]([F:41])([F:40])[F:39])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:44]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:37]=[CH:36][CH:35]=1)[CH2:28][CH2:27][C:25]1[C:24]([C:38]([F:41])([F:39])[F:40])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=2)[N:26]=1)(=[O:34])[NH2:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)[O-])c4)n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Lithium 3-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I34) (0.100 g, 0.173 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.028 g, 0.21 mmol) and EDCl (0.040 g, 0.21 mmol) and N,N-diisopropylethylamine (0.121 mL, 0.693 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.067 g, 0.69 mmol) was added in one portion, and the reaction was stirred room temperature for 60 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the combined organic layers were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give an off-white solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 74% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.79 (s, 1H), 7.75-7.68 (m, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.40-7.29 (m, 3H), 6.93 (d, J=9.1 Hz, 2H), 3.50-3.41 (m, 4H), 3.14-3.00 (m, 8H), 1.42 (s, 9H).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH:5][C:6]1[CH2:10][CH:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH2:8][N:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[BrH:2].[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[CH:9]1[CH2:8][N:7]2[CH2:3][CH2:4][N:5]=[C:6]2[CH2:10]1
Reactant: Clc1cccc(Cl)c1C1CN=C(NCCBr)C1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1cccc(Cl)c1C1CC2=NCCN2C1

Procedure:
A stirred mixture of 2-β-bromoethylamino-4-(2,6-dichlorophenyl)-1-pyrroline hydrobromide (46.35 g.), anhydrous sodium bicarbonate (9.3 g.) and dry isopropanol (350 ml.) is heated under reflux for 4 hours with exclusion of moisture, the hot mixture is filtered and the solid residue is stirred and heated under reflux with dry isopropanol (350 ml.) for 1 hour. The hot mixture is filtered and the combined isopropanol filtrates are evaporated to dryness under reduced pressure. The residue is dissolved in boiling ethanol (200 ml.) and the solution is concentrated to 125 ml. and allowed to cool. The mixture is filtered and there is thus obtained as solid residue 6-(2,6-dichlorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo[1,2-a]imidazole hydrobromide, m.p. 297°-299° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36]
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Li]CCCC.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[CH2:24])[CH:19]=2)[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][CH2:24][N:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[CH3:1])[CH:17]=[CH:16]2
Reactant: CC1CCCN1
Reactant: C=Cc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CCCN1CCc1ccc2cc(Br)ccc2c1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a cooled solution of 2-methylpyrrolidine (2.0 mL, 20 mmol) in THF (30 mL) at −15° C. was added n-BuLi (1.6 M in hexane, 4.0 mL, 6.4 mmol) dropwise keeping the temperature below −10° C. The resulting mixture was stirred at −15° C. for 10 min. To the cooled solution was added a solution of 2-bromo-6-vinyl-naphthalene (3) (2.33 g, 10.0 mmol) in THF (30 mL) dropwise keeping the temperature below −15° C. The resulting mixture was stirred at −15° C. for 5 min. and quenched with H2O (1 mL) and then poured into 5% Na2CO3 (80 mL). To the mixture was added EtOAc (80 mL), and organic was separated, the aqueous layer was extracted with EtOAc (30 mL). The combined organic layer was washed with brine and treated with activated carbon, dried over Na2SO4 and concentrated. The residue was then further dried under high vacuum to give 2.47 g product. The crude product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) d 7.86 (d, 1H), 7.53–7.59 (m, 3H), 7.40–7.42 (dd,1H), 7.28–7.30 (dd, 1H), 3.04–3.22 (m, 1H), 3.98–3.04 (m, 1H), 2.85–2.91 (m, 2H), 2.23–2.33 (m, 2H), 2.14 (q, 1H), 1.81–1.88 (m, 1H), 1.62–1.78 (m, 2H), 1.32–1.39 (m, 1H), 1.04 (d, 3H). 13C NMR (400 MHz, CDCl3) d 138.50, 132.75, 131.65, 129.29, 128.90, 128.76, 128.21, 126.63, 126.34, 118.72, 60.11, 55.88, 54.15, 35.78, 32.93, 21.98, 19.28. [M+H]+ at m/z 319.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH2:14][NH:13][CH2:12]2)=[CH:5][CH:4]=1.[BrH:22]>>[BrH:22].[OH:9][C:8]1[CH:7]=[C:6]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[OH:2]
Reactant: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC
Agent: Br
Product: Cc1ccc2c(c1)C(c1ccc(O)c(O)c1)CNC2

Procedure:
To 450 mg of 4-(4,5-dimethoxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline, was added 9 ml of 48% hydrobromic acid, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and the crystals which separated out were collected by filtration, giving 390 mg of 4-(3,4-dihydroxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[NH:4][N:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O-:29])=O)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18]([O-:20])=O)=[CH:14][CH:13]=1>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:4][N:3]=[C:2]([NH:1][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[S:8][CH:9]=[CH:10][CH:11]=5)[NH:4][N:3]=4)=[O:20])=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[O:29])[CH:6]=1
Reactant: Nc1cc(-c2cccs2)[nH]n1
Reactant: O=C([O-])c1ccc(-c2ccc(C(=O)[O-])cc2)cc1
Product: O=C(Nc1cc(-c2cccs2)[nH]n1)c1ccc(-c2ccc(C(=O)Nc3cc(-c4cccs4)[nH]n3)cc2)cc1

Procedure:
Compound 469 was prepared from 3-amino-5-(2-thienyl)pyrazole and 4,4′-biphenyldicarboxylate. [M+H]+ calcd for C28H21N6O282: 537.12; found: 536.93.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=4)[N:23]=3)=[CH:19][C:6]1=2.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([S:39]([NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=5)[N:23]=4)=[CH:19][C:6]2=3)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(NCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21)c1ccccc1

Procedure:
11-(2-Aminoethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and phenylsulfonyl chloride were used and reacted in the same manner as in Example 34 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1.[C:19]1(=[O:30])[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1.C1(C)C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:30])[CH2:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Cc1ccc(N)cc1/C=C/c1nc(C(C)C)cs1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Cc2ccccc2C(=O)O)cc1/C=C/c1nc(C(C)C)cs1
Yield: 61.4 %

Procedure:
A mixture of 0.5 g of (E)-4-methyl-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]benzenamine, 0.5 g of homophthalic anhydride and 35 ml of toluene was heated to reflux for 1 hr. After cooling and dilution with hexane, 0.5 g of (E)-2-[2-[4-methyl-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid was isolated by filtration; m.p. 181°-183° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[F-].[K+].[OH-].[Na+]>CN(C=O)C>[CH:15]([C:14]1[C:13]([O:20][CH3:21])=[C:12]([CH:19]=[CH:18][CH:17]=1)[O:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:16]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: COc1c(O)cccc1C=O
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1nc(C)ccc1C#N
Yield: 69.9 %

Procedure:
2-Chloro-6-methylnicotinonitrile (0.25 g, 1.6 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.25 g, 1.6 mmol) and potassium fluoride (0.29 g, 4.9 mmol) were heated with stirring in dry DMF (4 mL) at 120° C. for 5 h. The reaction mixture was cooled, poured into 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (3×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-2-methoxy-phenoxy)-6-methyl-nicotinonitrile (0.30 g, 68%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11](C=O)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH:17]1([O:16][C:8]2[C:9]3[O:10][C:11](/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25])=[CH:12][C:13]=3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate (21.0 g, 0.0868 moles) in toluene (250.0 mL) was added malonic acid (13.5 g, 0.1302 moles) and Piperidine (5.0 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (19 g) as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].CN(C=O)C.Cl.Cl.[NH:47]1[CH:51]=[CH:50][N:49]=[C:48]1[CH2:52][NH2:53].C(N(CC)C(C)C)(C)C>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:53][CH2:52][C:48]3[NH:47][CH:51]=[CH:50][N:49]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCc2ncc[nH]2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 33.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL)/DMF(3 mL)/DCM(3 mL) were added (1H-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at 40° C. over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (7 mg, 33%). LC-MS m/z 585 (M+H)+; 1H-NMR (MeOD) δ 2.33 (s, 3H), 4.13 (s, 2H), 4.42 (s, 2H), 6.92 (m, 2H), 7.15 (m, 4H), 7.50 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1>C(OCC)(=O)C.[Pd]>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH3:2])[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
A solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.5 g, 0.0013 mol) in ethyl acetate (50 ml) was stirred with 10% palladium on charcoal catalyst under a hydrogen atmosphere at 50 p.s.i. and room temperature. After 1 hour, the mixture was filtered and the filtrate evaporated under vacuum to give a pale green solid. Chromatography on silica gel (4 g) using a methanol in dichloromethane elution gradient gave a white solid, crystallisation of which from hexane-ethyl acetate gave the title compound as colourless needles (0.12 g, 26%), m.p. 115°-116° C. Found: C,66.66; N,7.12; N,16.55. C19H24N4O2 requires C,67.04; H,7.11; N,16.46%.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:10][C:8]([F:11])([F:9])[C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:17]1[C:16](=[C:25]3[C:20](=[CH:19][CH:18]=1)[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12]2(=[O:13])=[O:14]
Reactant: Nc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccc(C(F)(F)F)cc21
Yield: 7.9 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-quinolin-8-yl-5-trifluoromethyl-benzenesulfonamide (Intermediate 300) (330 mg, 0.9 mmol), t-butyl nitrite (0.16 ml, 1.3 mmol), AcOH (3.3 ml) and THF (3.3 ml) gave the title compound (25 mg, 7%) after purification by column chromatography with DCM/MeOH (99.8:0.2) as the eluent.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: ClCCN1CCOCC1
Reactant: Cc1nc(N)sc1C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1sc(=N)n(CCN2CCOCC2)c1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (1.0 g, 7.8 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.6 g, 8.6 mmol) and triethylamine (2.4 mL, 17.2 mmol) were heated at 80° C. After 3 hours, additional triethylamine (1.1 mL, 7.9 mmol) was added and the mixture was stirred at 80° C. for 14 hours, then cooled to ambient temperature and concentrated. The residue was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate and water. The organic extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 0.26 g (14%) of a 3:1 mixture of title compound to 4,5-dimethyl-thiazol-2-ylamine. MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[C:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cc(-c2ccccc2)ccn1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)ccn2)CC1
Yield: 20.1 %

Procedure:
A solution of 2-bromo-4-phenylpyridine (1.34 g, 5.72 mmol), 1-(tert-butoxycarbonyl)piperazine (3.19 g, 17.2 mmol) and pyridine (20 ml) was stirred at 125° C. for 7 days, and the solvent was distilled away under reduce pressure. To the residue was added water, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound 390 mg (20.1%) as solid product.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=[O:15].[C:16](C#N)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:16]([CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][NH:8][C:9]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCNC(=O)C1
Reactant: N#CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCNC(=O)C1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
Dry triethylamine (1.33 g) was added at 0°-5° C. to a stirred suspension of piperidine-2,4-dione (1.13 g), anhydrous zinc chloride (1.64 g) and benzoyl cyanide (1.31 g) in dry dichloromethane (50 ml) and the mixture stirred at ambient temperature for 18 hours. The mixture was washed successively with 2N hydrochloric acid (2×30 ml) and water (3×30 ml) dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow solid which was recrystallised from acetonitrile (0.5 ml) to give 3-benzoylpiperidine-2,4-dione (0.5 g), mp 164°-165° C., as a cream crystalline solid.
Reaction SMILES: [C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[O:42]=[C:43]([C@H:49]([CH3:65])[C@@H:50]([O:56][C:57]([O:59][CH2:60][C:61]([Cl:64])([Cl:63])[Cl:62])=[O:58])[C@@H:51]([CH3:55])[CH2:52][CH:53]=[CH2:54])[C:44]([CH3:48])([CH3:47])[CH:45]=[O:46]>C(Cl)Cl>[O:42]=[C:43]([C@H:49]([CH3:65])[C@@H:50]([O:56][C:57]([O:59][CH2:60][C:61]([Cl:62])([Cl:63])[Cl:64])=[O:58])[C@@H:51]([CH3:55])[CH2:52][CH:53]=[CH2:54])[C:44]([CH3:48])([CH3:47])[C@@H:45]([OH:46])[C@H:2]([CH3:3])[C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S)-3-propionyl-4-benzyloxazolidinone (91 mmol) in 200 mL of CH2Cl2 at 0° C. is treated sequentially with dibutylboron triflate (27 mL) and triethylamine (16.7 mL) at such a rate so as to keep the reaction temperature below 3° C. After stirring for 30 minutes, the mixture is cooled to −78° C. and treated with a solution of (4R,5S, 6S)-3-oxo-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonenal (90 mmol) in 10 mL of CH2Cl2. After 1 hour, the mixture is allowed to warm slowly to 0° C. and stirred an additional 1 hour. The reaction is quenched by addition of 100 mL of pH 7 phosphate buffer and 300 mL of methanol. A mixture of 2:1 methanol/30% aq. H2O2 (300 mL) is then added while maintaining the temperature below 10° C. After stirring for 1 hour, the mixture is concentrated under vacuum to a slurry, which is extracted with ether. The extract is washed sequentially with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated. The product is isolated by silica gel chromatography.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[O:16]=[C:17]([CH3:27])[CH2:18]P(=O)(OCC)OCC>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:18][C:17](=[O:16])[CH3:27])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)C=Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
EX-626A) Tetrabutylammonium iodide (0.4 g, 0.05 mol) was added to a well-stirred biphasic mixture of 12 mL of 50% NaOH and 20 mL of methylene chloride under a nitrogen atmosphere. A solution of 3-trifluoromethoxybenzaldehyde (4.0 g, 0.021 mol) and diethyl (2-oxopropyl)phosphonate (4.08 g, 0.021 mol) in 4.0 mL of methylene chloride was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 15 min, then quenched with water and extracted with hexane. The hexane layer was dried over MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1:10 ethyl acetate in hexane to give 2.6 g (54%) of the desired 4-[3-(trifluoromethoxy)phenyl]-3-buten-2-one product as a yellow oil. 1H NMR (CDCl3) δ −7.43 (m, 4H), 7.20 (d, 1H), 6.65 (d, 2H), 2.29 (s, 3H). 19F NMR (CDCl3) δ −62.05 (s, 3F).