Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Cl:12])=[C:4]([O:13][CH2:14][C:15]#[CH:16])[N:3]=1.C1OCCOCCOCCOCCOCCOC1.[F-:35].[K+].S1(CCCC1)(=O)=O>C(OC)(C)(C)C>[Cl:12][C:5]1[C:4]([O:13][CH2:14][C:15]#[CH:16])=[N:3][C:2]([F:35])=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=1
Reactant: C#CCOc1nc(Cl)c(C(F)(F)F)cc1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O=S1(=O)CCCC1
Product: C#CCOc1nc(F)c(C(F)(F)F)cc1Cl
Temperature: 152.5 °C
Reaction time: 5 h

Procedure:
47.3 g (0.175 mol) of 2,5-dichloro-6-propargyloxy-3-trifluoromethylpyridine, 0.5 g (1.89 mmol) of 18-crown-6 and 15.2 g (0.263 mol) of potassium fluoride were added to 150 ml of sulfolane and it was stirred at 150-155° C. for 5 hours. After cooling, the reaction mixture was stirred with methyl tert-butyl ether and separated off from the inorganic precipitate. The filtrate was extracted four times with water, dried and concentrated. The residue was filtered with suction with methylene chloride through a suction filter containing silica gel and concentrated, 31.4 g (71% of theory) of the title compound of n24D =1.4732 being obtained.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=3[O:9]C2=O)=[C:4]([F:23])[CH:3]=1.[OH-].[K+].Cl>C(O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:12](=[O:13])[C:11]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=2[OH:9])=[C:4]([F:23])[CH:3]=1
Reactant: COc1ccc2c(=O)n(Cc3ccc(Br)cc3F)c(=O)oc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)NCc2ccc(Br)cc2F)c(O)c1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
solution of 3-(4-bromo-2-fluoro-benzyl)-7-methoxy benzo[e][1,3]oxazine-2,4-dione (1.67 g, 4.4 mmol) in ethanol (80 ml, 0.06 M) was cooled to 0° C. and treated with aq KOH (0.673 g, 11.9 mmol, 1.2 M). After 3 h, the reaction was acidified to pH 1-2 with 2 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated. The crude solid was recrystallized from heptane and ethyl acetate to give N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-4-methoxy-benzamide as a white crystalline solid (1.10 g, 71%): mp 128-129.5° C.; Rf 0.28 (25% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 12.70 (br s, 1H), 9.14 (br t, J=5.2 Hz, 1H), 7.80 (d; J=8.5 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.40-7.25 (m, 2H), 6.50-6.48 (m, 2H), 4.45 (d, J=5.2 Hz, 2H), 3.75 (s, 3H). ESI-LC/MS m/z calcd for C15H13BrFNO2: 353.0; found 352.0 (M−1)−. Anal. calcd for C15H13BrFNO2: C, 50.87; H, 3.70; N, 3.95. Found C, 50.70; H, 3.73; N, 3.91.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(Cl)CCl>CC#N>[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[NH:19][C:18]3[CH:17]=[CH:16][C:4]([O:5][C:6]4[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: CC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Solvent: ClCCCl
Solvent: CC#N
Product: CC(=O)Nc1cccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[3-(3,4-diamino-phenoxy)-phenyl]-acetamide (Step B, 320 mg, 1.2 mmol, 1.0 eq.) in 20 mL of anhydrous CH3CN was added drop-wise to a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (300 mg, 1.2 mmol, 1.0 eq.) in 10 mL of CH3CN. The reaction was stirred for 2 h at RT. EDC (360 mg, 1.9 mmol, 1.5 eq.) was added and the reaction was heated to 80° C. and stirred for 1 h. The mixture was cooled and concentrated. The residue was dissolved into EtOAc and washed with H2O and sat. NaHCO3 (aq.). The organic layer was dried (MgSO4), filtered and concentrated. The crude was further purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) followed by recrystallization from CH2Cl2 to give pure N-(3-{2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1H-benzimidazol-5-yloxy}-phenyl)-acetamide. MS m/z=506.2 (M+H)+; Calc'd for C27H29N6O2: 504.20.
Reaction SMILES: [CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([Cl:20])=[O:9])[CH2:3][CH2:2]1
Reactant: CN(C/C=C/C(=O)O)C1CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C/C=C/C(=O)Cl)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (2.00 g, 12.9 mmol) in DCM (60 mL) was added DMF (0.2 mL) and oxalyl chloride (4.42 mL, 51.6 mmol). The mixture was stirred at RT for 4 h and concentrated in vacuo to dryness to afford (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. In a similar manner as described in Example 70, (R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (85) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. MS found for C27H35N9O4 as (M+H)+ 550.2, (M−H)− 548.3. UV: λ=248 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[CH3:21])(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.O=S(Cl)[Cl:29]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([Cl:29])([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[CH3:21])[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnccc1C(C)(O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: Cc1cnccc1C(C)(Cl)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-methylpyridin-4-yl)propan-2-ol (300 mg, 0.813 mmol) in SOCl2 (4 mL) was stirred at RT for 1 h. Excess SOCl2 was removed under vacuum to obtain 8-chloro-5-[2-chloro-2-(3-methyl-pyridin-4-yl)-propyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (305 mg, 0.78 mmol) which was dissolved in NMP (3 mL). Powdered KOH (308.14 mg, 5.50 mmol) was added and the contents heated at 80° C. for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, The reaction mixture was poured on ice cold water. The aqueous phase was extracted with EtOAc (500 mL). The organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was subjected to reverse phase HPLC to yield 5 mg of the desired product. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.84 (s, 1H), 8.78 (d, 1H), 8.18 (d, 1H), 7.60 (s, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 6.98 (s, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.22 (m, 2H), 3.16 (s, 3H), 2.70 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19].O.C(#N)C.O>C(#N)C>[Cl:19][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][C:5]2[C:10]([N:9]=1)=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2
Reactant: Oc1nc2cc(F)ccc2nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: Fc1ccc2nc(C(F)(F)F)c(Cl)nc2c1
Temperature: 100 °C
Yield: 95 %

Procedure:
7-Fluoro-3-(trifluoromethyl)quinoxalin-2-ol (24.1 g) and POCl3 (158.1 g) were combined and warmed to 100° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with acetonitrile (104 mL). To a separate vessel was charged water (320 g) and acetonitrile (124 g), then cooled to 10° C. The reaction mixture was added to the acetonitrile/water mixture over 1 hour. The slurry was cooled to 10° C. for 30 min, then it was filtered and the cake was washed with 2:1 (v/v) water:acetonitrile (3×65 mL). The solid was dried under vacuum at 50° C. for 14 h (24.7 g, 95% yield).
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:3]=1.[N:28]#[C:29]Br>CCO.C(OCC)C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:3][C:2]4[NH:1][C:29]([NH2:28])=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: CN1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Reactant: N#CBr
Solvent: CCOCC
Solvent: CCO
Product: CN1CCN(c2cc3[nH]c(N)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1

Procedure:
To a solution of 4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide (2 mmol; see Example 181) in 10% aqueous EtOH (6 mL) was added cyanogen bromide (2.2 mmol), and the mixture was heated at reflux for 4 h. The reaction mixture was then concentrated in vacuo, and the residue obtained was suspended in diethyl ether with vigorous stirring. The solid obtained was collected by filtration, washed with diethyl ether, and dried in vacuo to afford 2-amino-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrobromide salt. MS: m/z 391 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([CH3:12])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[N:38]1([S:43]([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[CH:48]=O)(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:1]1([C:7]2[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([CH3:12])=[C:10]([CH2:48][C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:43]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)(=[O:44])=[O:45])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cn1c(C)ccc1C1CCCCC1
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)Cn1c(C2CCCCC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Yield: 33.9 %

Procedure:
was followed using ethyl 2-(2-cyclohexyl-5-methyl-1H-pyrrol-1-yl)acetate (1.00 g, 4.01 mmol), triethylsilane (1.92 mL, 12.0 mmol), trimethylsilyl trifluoromethanesulfonate (1.45 mL, 8.02 mmol) and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (0.960 g, 4.01 mmol) to afford ethyl 2-(5-cyclohexyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (642 mg, 1.36 mmol, 34% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:27][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]3[CH:8]=[CH:7][S:27][C:10]=3[N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Reactant: c1nc[nH]n1
Product: c1ncn(-c2nc(NCCc3ccc4c(c3)OCO4)c3ccsc3n2)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH:2](Cl)[CH2:3][O:4][CH2:5][CH:6](Cl)Cl.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:4]1[CH2:5][CH2:6][C:11]([C:10]#[N:14])([C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: ClC(Cl)COCC(Cl)Cl
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCOCC1
Yield: 51.7 %

Procedure:
A mixture of 28.6 g of dichloroethyl ether, 13.2 g of malononitrile, 55.28 g of potassium carbonate and 800 ml of acetonitrile was refluxed on a steam bath for 24 hours, then filtered while hot. The filtrate was evaporated and the residue crystallized with charcoal treatment from 100 ml of ethanol, giving 9.5 g of tetrahydro-4H-pyran-4,4-dicarbonitrile as colorless plates, mp 110°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:24])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16](=[O:22])[CH2:15][C:14]1=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:15]2[C:14](=[O:23])[C:13]([CH3:24])([CH3:12])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16]2=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)C(C(=O)Cc2ccc(Cl)cc2)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. Afer dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[S:7][C:6]=2[CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)[S:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3ccc(Cl)cc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2cc(C3=CCNCC3)sc2c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A solution of 6-chloro-2-(4-hydroxy-N-t-butoxycarbonyl-piperidin-4-yl)benzo[b]thiophene (1.04 g, 2.83 mmol) in methylene chloride (30.0 ml) was treated with 4.36 ml of trifluoroacetic acid and stirred at 23° C. for 4 hours. The reaction was concentrated to a foam under reduced pressure and the residue chromatographed (silica gel, CHCl3 /MeOH 95:5) to give 0.640 g (90%) of a tan powder. FDMS m/e=250 (M+ of free base)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[OH-].[Na+]>>[C:15]([NH:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(Cl)c2c1CCN(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10.5 g. (0.05 mole) of 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 50 ml. of acetic anhydride is stirred and heated at 60°-65° C. for 4 hours. The resulting solution is poured into ice/water and stirred at 25° C. for 16 hours, then it is made alkaline by addition of sodium hydroxide at 5°-10° C. The precipitate is immediately filtered to give 9-acetamido-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O-]CC.[Na+].O.[N+:20]([CH3:23])([O-:22])=[O:21]>C(O)C>[OH:1][C:2]1([CH2:23][N+:20]([O-:22])=[O:21])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (52.65 g, 264 mmol) in nitromethane (21 mL) and ethanol (8 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 5.0 mL, 13.4 mmol). The mixture was stirred at rt and more ethanol (30 mL) was added. The mixture was sonicated for 15 min, stirred overnight, then sonicated again. To the mixture was added water (400 mL). The solid was isolated by filtration, washed with water (300 mL), and dried to yield tert-butyl 4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate as a white solid, 67.60 g (98%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:21]=2)[NH:16][CH:15]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]([CH3:34])[S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH:21]=2)[NH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(CNS(=O)(=O)C(F)(F)F)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)S(=O)(=O)C(F)(F)F

Procedure:
In a similar manner to that described in Example 10(i), N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]-trifluoromethanesulphonamide (1.04 g), sodium hydride (80%, 0.72 g) and methyl iodide (0.6 ml) in dimethylformamide (15 ml) gave the title compound (0.51 g) as a yellow solid m.p. 131°-3° after column chromatography on kieselgel 60 (80 g) eluted with ether/cyclohexane (4:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=O>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[Cl:10])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NNc1cc(Br)ccn1
Solvent: CO
Product: Clc1ccccc1-c1nnc2cc(Br)ccn12
Temperature: 115 °C

Procedure:
A mixture of 1-(4-bromopyridin-2-yl)hydrazine (1.00 g, 5.3 mmol) and 2-chlorobenzoyl chloride (8.00 ml, 63 mmol, Aldrich) was heated to 115° C. for 3 h. The mixture was diluted with MeOH and concentrated over SiO2. The residue was purified using column chromatography (MeOH/CH2Cl2=0-10%) yielding the title compound as a tan solid. MS (ESI, pos. ion) m/z: 264.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:22]=[C:23]3[CH2:27][CH2:26][CH2:25][C:24]=23)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:35])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][C:6]=3[CH3:35])=[C:24]3[CH2:25][CH2:26][CH2:27][C:23]3=[N:22]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 137 %

Procedure:
To a solution of 4-{2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester (19 mg, 37 umol; example 1.5) in THF (0.7 ml) and MeOH (0.3 ml) was a added a 1 N aqueous lithium hydroxide solution (450 ul, 450 umol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred for 14 h at ambient temperature and poured onto ice water/1 N aqueous HCl solution 1/1. The mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to obtain the title compound (25 mg; quant.) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](C=O)=[CH:4][N:3]=1.C(O[CH:14]([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])(C)C.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:20]([O:19][CH:14]([O:15][CH:16]([CH3:17])[CH3:18])[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)([CH3:21])[CH3:22]
Reactant: Cc1ncc(C=O)cn1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1ncc(C(OC(C)C)OC(C)C)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.1 %

Procedure:
To a mixture of 2-methylpyrimidine-5-carbaldehyde (1.0 g, 8.2 mmol) and triisopropoxymethane (2.3 g, 12 mmol) in isopropanol (15 ml) was added methanesulfonic acid (0.079 g, 0.053 ml, 0.819 mmol). The reaction was stirred at room temperature for 23 hours. Potassium carbonate (1.132 g, 8.19 mmol) was added and the mixture was filtered and the solution was concentrated in vacuo. The crude mixture was purified by flash chromatography to yield 5-(diisopropoxymethyl)-2-methylpyrimidine (536 mg, 29%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH3:13][O-:14].[Na+].[Na]>CO>[CH3:13][O:14][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCc1ccc(C(=O)OC)cn1
Yield: 85 %

Procedure:
5.1 g (0.022 mol) of methyl 6-(bromomethyl)nicotinate [described in J. Med. Chem.; (2002), 45(23), 5005-5022], dissolved in 60 mL of methanol are added at room temperature to a solution of sodium methoxide obtained by adding 1 g (0.044 atom/g) of sodium to 40 mL of methanol. The reaction medium is then heated under reflux for 2 hours. The reaction medium is concentrated under vacuum and the residue is taken up in an aqueous solution of potassium hydrogen sulfate and dichloromethane. The organic phase is separated by decantation, dried over sodium sulfate and evaporated to dryness. 3.4 g of a yellow solid are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:18])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[C:23]([C:22]([OH:25])=[O:24])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Agent: Cl
Product: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Intermediate f (8.2 g, 0.035 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (200 mL). The mixture was filtered by suction and dried to produce Intermediate g (3.7 g) in a yield of 45.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(Cl)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,4-dichlorophenylboronic acid (176 mg, 0.85 mmol) the subtitle compound was obtained (176 mg, 74%). 1H NMR (CDCl3) δ 8.74(d, 1H), 8.44(dd, 1H), 7.89(d, 1H), 7.70(d, 1H), 7.65(d, 1H), 7.54(d, 2H), 7.44(dd, 1H), 7.26(d, 1H), 4.08(s, 3H).