Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>C1COCC1.[Cu](I)I>[CH2:10]([O:9][CH:8]([O:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[N:3][CH:4]=1)[CH3:11]
Reactant: CCOC(OCC)c1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C#C[Si](C)(C)C)nc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
In THF (10 mL) was dissolved 2-bromo-5-(diethoxymethyl)pyridine (1.00 g, 3.84 mmol) obtained in Step 1. To the solution were added trimethylsilyl acetylene (1.09 mL, 7.69 mmol), copper iodide (I) (37.0 mg, 0.192 mmol), (bistriphenylphosphine) palladium (II) chloride (135 mg, 0.192 mmol), and triethylamine (1.07 mL, 7.69 mmol), and the mixture was stirred at 70° C. for 6 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and water and ethyl acetate were added. The mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine (1.07 g). In methanol (10 mL) was dissolved 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine obtained. Potassium carbonate (1.06 g, 7.69 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure, and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 5-(diethoxymethyl)-2-ethynylpyridine (703 mg, 89% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[N:45]([C:46]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:44]=[N:43][N:42]=3)=[CH:31][CH:30]=2)[C:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][C:8]=2[N:27]=1)[CH2:2][CH2:3][CH3:4]>[C].[Pd].CO>[CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[N:45]([C:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:44]=[N:43][N:42]=3)=[CH:33][CH:34]=2)[C:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:9][C:8]=2[N:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CC(C(=O)OC)N(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CC(C(=O)OC)NC2
Yield: 88.6 %

Procedure:
Methyl 2-n-butyl-5-benzyloxycarbonyl-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (1.26 g) and a catalytic amount of 10 % palladium-carbon are added to methanol (300 ml), and the mixture is stirred under hydrogen atmosphere. After the reaction is completed, palladium-carbon is removed by filtration, and the filtrate is evaporated under reduced pressure to give methyl 2-n-butyl-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (0.94 g) as foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[C:42]([F:44])[CH:43]=1.[F-].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:37][C:38]1[CH:39]=[C:40]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=2)[CH:41]=[C:42]([F:44])[CH:43]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)cc(F)c3)ccc2c1
Yield: 101.1 %

Procedure:
Using the procedure demonstrated in Example 9, react trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (3.5 g, 6.67 mmol), 3,5-difluorobenzene boronic acid (3.1 g, 19.6 mmol), cesium fluoride (9.2 g, 60.4 mmol), palladium(II)acetate (145 mg, 0.64 mmol) and tricyclohexylphosphine (290 mg, 1.03 mmol) to obtain 3.3 g (100%) of the title compound: mass spectrum (ion spray) 490.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:14]([OH:15])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Solvent: C1CCOC1
Product: Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A solution of phenol (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (1.14 g, 5.00 mmol) in THF (15 mL) was cooled in a dry ice/acetone bath and treated dropwise with phenyllithium (7.5 mL, 13.5 mmol, 1.8M in cyclohexane/ethyl ether 70/30). The reaction mixture was allowed to warm gradually to ambient temperature. After 18 h, the reaction was quenched with aqueous saturated NH4Cl solution (1 mL) and partitioned between EtOAc (50 mL) and 1N HCl (20 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated to a brown oil (2.3 g). The crude product was purified by flash chromatography using hexanes:ethyl acetate (3:1 to 2:1) to give a pale yellow oil (1.42 g, 93%): 1H NMR (400 MHz, CDCl3) δ 2.79 (s, 1H), 4.92 (s, 2H), 5.95, (s, 1H), 6.51 (s, 1H), 6.81 (d, 3H, J=1.5 Hz), 7.28-7.38 (s, 10H); MS (ES) m/e 305 [M−1].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)#[N:2].S(=O)(=O)(O)[OH:21].[OH-].[NH4+]>O>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]([NH2:2])=[O:21])=[C:12]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[S:15][C:11]3=2)[CH:6]=[CH:7][N:8]=1
Reactant: N#Cc1cc2ccncc2c2sc3ccccc3c12
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc2ccncc2c2sc3ccccc3c12
Temperature: 0 °C

Procedure:
Two hundred mg of 6-cyanobenzothieno[3,2-h]isoquinoline (4), prepared in the preceding Example, was mixed with a solution of 2 ml water ,and 3 ml concentrated sulfuric acid. The reaction mixture was heated at 110° C.-120° C., and gave rise to a yellowish brown solution. After heating for approximately 5 hr, when TLC indicated the absence of starting material, the reaction mixture was poured onto 40 ml ice and water. The yellow solution thus obtained was made alkaline (to a pH of about 8) with concentrated ammonium hydroxide. The gray flocculent solid that precipitated was collected and washed with water to yield 130 mg dried product. This material was recrystallized from 75 ml CHCl3, to give 85 mg of a white solid, m.p. 295° C.-302° C. characterized as compound 5 by I.R. and mass spectrometry.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:32])([F:31])[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][O:29][CH:26]2[CH2:25][CH2:24][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][C:12]([F:32])([F:11])[F:31])=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:28][CH2:27]2)=[O:10])=[CH:4][CH:3]=1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 32.9 %

Procedure:
1-Fluoro-4-isocyanatobenzene (96 mg, 0.70 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl) hydroxylamine (238 mg, 0.70 mmol) and pyridine (111 mg, 2.1 mmol) in CH2Cl2 (6 ml), and the whole was stirred at room temperature for 17 hours. The resulting precipitation was collected, washed with aqueous 1 N HCl solution (10 ml×3), aqueous NaHCO3 solution (10 ml×3), diethyl ether (10 ml×2) to give 1-(4-fluorophenyl)-3-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)urea (110 mg, 33%) as a white solid: LCMS: 478 [M+1]+. 1H NMR (DMSO-d6) δ: 1.81 (m, 2H), 1.92 (m, 2H), 2.85 (m, 2H), 3.22 (m, 2H), 3.78 (m, 1H), 7.10 (m, 2H), 7.51 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.62 (s, 1H), 9.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C(C2C=CC=CC=2)=[N+](Cl)[O-])C=CC=CC=1>C(O)C>[C:11]1([CH:10]=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O-:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ONc1ccc(Cl)cc1
Reactant: O=Cc1ccccc1
Agent: [O-][N+](Cl)=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: [O-][N+](=Cc1ccccc1)c1ccc(Cl)cc1

Procedure:
p-Chlorophenylhydroxylamine (0.05 moles) was dissolved in warm 95% ethanol (20 cc) and was treated with benzaldehyde (0.05 moles) with vigorous stirring. The solid which formed was collected, washed with 95% ethanol, and recrystallized from ethanol to give 512 g. of α-phenyl-N-chlorophenylnitrone (m.p. 179°-82°).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.CCCCCC.FC(F)(F)[C:32](O)=[O:33]>>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[CH:32]=[O:33])([CH3:12])[CH3:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCCCCC
Product: CC(C)c1cc(C=O)cc(C(C)C)c1O
Yield: 26 %

Procedure:
18 g of 2,6-di isopropyl phenol and 1.8 g HMTA (hexamethylene tetraamine) in 60 ml TFA (trifluoro acetic acid) was refluxed 3.5 hours. Workup, chromatography on silica gel (CH2Cl2) and trituration with hexane gave 5.3 g, 26% yield, white solid, mp-103° C. (3,5,-di-iso-propyl 4 hydroxybenzaldehyde). NMR CDCl3 δ 9.87 (1H, S, CHO), 7.63 (2H, S), 3.19 (2H, septet, J=7.7 Hz), 1.30 (12H, d, J=7.7 Hz).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=1[CH3:11])=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>CN(C)C=O>[CH3:11][C:10]1[NH:9][C:8](=[O:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=1[C:3]1[N:18]=[C:15]([CH3:16])[S:17][CH:2]=1
Reactant: CC(N)=S
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(C#N)c(=O)[nH]c2C)cs1
Reaction time: 5 h
Yield: 38.2 %

Procedure:
C-1. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile--A mixture containing 25.4 g of 5-(bromoacetyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 7.5 g of thioacetamide and 100 ml of dimethylformamide was heated with stirring on a steam bath for 5 hours and then concentrated on a rotary evaporator. To the residual material was added 100 ml of water and 10 ml of concentrated aqueous ammonium hydroxide. The resulting mixture was filtered and the filtrate reacidified by adding acetic acid. The solid that separated was collected, washed with water and dried, and then recrystallized from dimethylformamide to produce 8.8 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile, m.p. 305°-307° C. with decomposition.
Reaction SMILES: C[N:2]([CH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:16][CH2:15]1)[CH2:3][CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl>[O:27]=[C:25]1[NH:24][C:23]2[CH:28]=[CH:29][C:20]([CH:17]3[CH2:16][CH2:15][CH:14]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:19][CH2:18]3)=[CH:21][C:22]=2[O:26]1
Reactant: CN(CCNC(=O)c1ccccc1)C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCNC1CCC(c2ccc3[nH]c(=O)oc3c2)CC1)c1ccccc1
Yield: 76.9 %

Procedure:
Coupling of N-(2-{methyl-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl)cyclohexyl]amino}ethyl)benzamide (755 mg, 1.81 mmol) and p-formaldehyde (0.50 mL of a 37 wt % aqueous solution, 6.1 mmol), following the procedure described in Example 17 except NaOH (1.8 mL of a 1.0N aqueous solution, 1.8 mmol) and CH2Cl2 (5 mL) were added, gave N-{2-[4-(2-oxo-2,3-dihydrobenzoxazol-6-yl)cyclohexylamino]ethyl}benzamide (528 mg, 66%), as a white solid (a mixture of cis/trans isomers): mp 167-175° C.; IR (KBr): 2940, 1770, 1647 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.51 (s, 1H), 10.41 (br s, 0.7H), 10.03 (br s, 0.3H) 8.96-8.94 (m, 1H), 8.00-7.92 (m, 2H), 7.60-7.40 (m, 3H), 7.15 (s, 1H), 7.00 (s, 1H), 3.79-3.65 (m, 2H), 3.45-3.19 (m, 2H), 2.82-2.79 (m, 4H), 2.58-2.50 (m, 1H), 2.20-2.10 (m, 2H), 1.92-1.81 (m, 3H), 1.70-1.51 (m, 4H); ESI-MS (m/z): 394 [M+H]+; HPLC: method A, 4.89 minutes (95.0%); method B, 10.0 minutes (>99%); Anal. Calcd for C23H27FN3O3.HCl.0.75H2O: C, 62.30; H, 6.71; N, 9.48. Found: C, 62.43; H, 6.68; N, 9.62.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:3]1([CH2:2][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=3)[CH:22]=[CH:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1cccc2ccccc12
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cccc4ccccc34)c2c1

Procedure:
The titled compound (30 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 1-(chloromethyl)naphthalene according to the method of the process (7) of Example 4.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:27]=[CH:26][C:10]2[C:11]3[C:12](=[CH:23][NH:24][CH:25]=3)[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1.[C:28](=O)([O-])[O-:29].[Na+].[Na+]>C(Cl)Cl.CN(C)C=O>[Cl:6][C:7]1[CH:27]=[CH:26][C:10]2[C:11]3[C:12](=[C:23]([CH:28]=[O:29])[NH:24][CH:25]=3)[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1[nH]cc2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reaction time: 2 h

Procedure:
A solution of 3.0 ml (33 mmol) of phosphorous oxychloride in 20 ml of methylene chloride was added dropwise to a solution of 3.0 g (9.1 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 40 ml of dimethylformamide which was cooled to 0°. Stirring at 0° was continued for 2 hr. The mixture was poured into a saturated solution of aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 100 g; eluent, 50% (v/v) ethyl acetate in methylene chloride) gave a light pink solid, mp 270°-274°. Recrystallization from a mixture of ethyl acetate and methylene chloride gave peach colored prisms, mp 276°-277°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH2:20])=[O:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:22]([C:24]1[O:28][C:27]([CH2:29][CH2:30]N)=[N:26][CH:25]=1)[CH3:23].O1CCOCC1.CN(C=O)C>C(N(CC)CC)C>[CH2:22]([C:24]1[O:28][C:27]([CH2:29][CH2:30][NH:20][C:18]([NH:17][C:15]2[S:16][C:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=3)=[C:13]([CH3:21])[N:14]=2)=[O:19])=[N:26][CH:25]=1)[CH3:23]
Reactant: CCc1cnc(CCN)o1
Reactant: Cc1nc(NC(N)=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)o1

Procedure:
The title compound is prepared by the same procedure as -[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-Methyl-thiazol-2-yl]-urea (Example 177) by replacing ammonia (part 177b) with the hydrochloride salt of 2-(5-Ethyl-oxazol-2-yl)-ethylamine (details of preparation procedure follows below), by replacing dioxane with DMF and by using triethylamine as a base.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[N:43][CH:44]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>C1COCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][CH2:10][CH:9]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:39]3[CH:40]=[CH:41][C:42]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[N:43][CH:44]=3)=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Br)cc2)cc1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1
Yield: 93.3 %

Procedure:
In a microwave tube (size L, 20 mL) purged with nitrogen and sealed with a rubber septum, dissolved the product of Example 86A (160 mg, 0.342 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (153 mg, 0.512 mmol) in THF (6 mL), added a solution of potassium phosphate (176 mg, 0.803 mmol) in water (2 mL), and sparged the reaction solution with S nitrogen for 5 min. Added 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (12.02 mg, 0.018 mmol) and stirred at 25° C. for 15 min. During this process, the reaction darkened quickly to a brown color. Diluted the reaction with EtOAc (50 mL), washed with brine (10 mL), dried the organic phase over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. Dissolved the residue in CH2Cl2 and purified by flash chromatography (silica gel, Alltech Extract-Clean 10 g column, 20% EtOAc/CH2Cl2) to afford the title compound as a solid (176 mg, 93%) as a mixture of stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.82-1.94 (m, 2H), 2.53-2.62 (m, 2H), 3.37-3.47 (m, 4H), 3.64-3.74 (m, 4H), 5.03 (t, J=5.37 Hz, 2H), 6.40 (d, J=8.89 Hz, 2H), 6.82 (d, J=9.00 Hz, 1H), 7.34 (d, J=8.78 Hz, 2H), 7.69 (dd, J=8.84, 2.55 Hz, 1H), 7.83 (d, J=8.78 Hz, 4H), 8.28 (d, J=8.78 Hz, 4H), 8.29-8.31 (m, 1H); MS (ESI+) m/z 552 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:32][CH2:31][N:30]2[C:23](=[CH:24][C:25]3[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=32)[C:22]1=[O:35])(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:37]2[CH:38]=[C:39]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([N:52]4[CH2:57][CH2:56][N:55]([CH:58]5[CH2:59][O:60][CH2:61]5)[CH2:54][CH2:53]4)=[CH:48][N:47]=3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:32][CH2:31][N:30]2[C:23](=[CH:24][C:25]3[CH2:26][C:27]([CH3:33])([CH3:34])[CH2:28][C:29]=32)[C:22]1=[O:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 43 %

Procedure:
A sealed tube was charged with the mixture of (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate (335 mg, 0.7 mmol), 5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 188e (294 mg, 0.7 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol), K3PO4.3H2O(372 mg, 1.4 mmol), and NaOAc (115 mg, 1.4 mmol) in CH3CN (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 311a as a yellow solid (208 mg, 43%). MS: [M+H]+ 692.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]CC)=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:27][C:26]([CH3:28])([CH3:29])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1cccc(F)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccc(F)c2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(3-fluorophenylsulfonamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature, the reaction mixture was stirred at 85° C. overnight. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(3-fluoro-benzenesulfonylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 455.20.