Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1Br
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 50 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded 2-(4-methoxy phenylethynyl)benzaldehyde (2.1 g, 89%). The above compound (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, and concentrated to give the imine (2.4 g, 94%), which was used in the next step without further purification. To a solution of the above imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper (I) iodide, and the solution was flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark colored solid. Purification by column chromatography (silica gel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%), as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum, to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. Selected data: MS (ES) m/z: 222.89, 221.86; MP 218-219° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:21]=1[NH:33][C:34]([NH2:36])=[NH:35].C(O)C>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:36]=[C:34]([NH:33][C:21]3[CH:22]=[CH:23][C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:25][C:20]=3[O:19][CH3:18])[N:35]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1cc(N2CCN(C)CC2)ccc1NC(=N)N
Reactant: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)c1
Temperature: 110 °C
Yield: 57.3 %

Procedure:
To a suspension of 5-((E)-3-Dimethylamino-acryloyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.7 g, 7.20 mmol) in 30 mL of ethanol N-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine (1.9 g, 7.20 mmol) was added. The mixture was heated to 110° C. overnight. The resulting mixture was cooled at room temperature and diluted with water (70 mL). The solid was isolated by filtration, washed with 10 mL of water, dried in a vacuum oven at 40° C. affording to give 1.8 g (57% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:48]=[CH:47][C:39]([C:40]([NH:42][CH:43]2[CH2:46][O:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:49][CH3:50].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:48]=[CH:47][C:39]([C:40]([NH:42][CH:43]4[CH2:44][O:45][CH2:46]4)=[O:41])=[CH:38][C:37]=3[O:49][CH3:50])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NC2COC2)ccc1N
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2COC2)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% DCM in MeOH) to afford the title compound (crude) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z 686.1 [M+1]+.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:24])[CH3:23])[CH2:13][C:12]2=1)=[O:7])(C)(C)C.C(Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:23])[CH3:24])[CH2:13][C:12]2=1)(=[O:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4)cc3c2C1
Yield: 37.5 %

Procedure:
Beginning with 0.198 gm (0.60 mMol) 6-(t-butoxycarbonyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 9.7 μL (0.84 mMol) benzoyl chloride, 0.075 gm (38%) of the title compound were prepared as a light grey foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:5][N:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:8]=1
Reactant: COC(=O)/C=C/c1cnc(OC)nc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cnc(OC)nc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
A mixture of methyl (2E)-3-[2-(methyloxy)-5-pyrimidinyl]-2-propenoate (24.0 g, 124 mmol) and Pd/C (300 mg) in methanol (250 mL) was stirred at 50° C. under H2 for two days, filtered through a pad of Celite and concentrated to give the title compound as a yellow oil (20 g, 68%), which was used without further purification. LCMS: rt=1.17 min, [M+H+]=196
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][N:31](C(OC(C)(C)C)=O)[CH:30]([C:40]([O:42]C(C)(C)C)=[O:41])[CH2:29][CH2:28]2)[CH:9]=1.Cl>C(O)C>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][NH:31][CH:30]([C:40]([OH:42])=[O:41])[CH2:29][CH2:28]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: Nc1cc(C2CCC(C(=O)O)NC2)nc2c(-c3cnc4ccccc4c3)cnn12
Yield: 44.1 %

Procedure:
Di-tert-butyl 5-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate (45 mg, 0.056 mmol) was dissolved in ethanol (1 ml) and treated with 3N hydrochloride solution (1.4 ml) at 65° C. for 4 h. The reaction solution was concentrated and purified by prep-LC to afford the title compound (9.6 mg): LC/MS RT=2.01 min. Mass calculated for, M+H 389.17, observed 389.17.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[C:8]([O:24][CH3:25])=[C:9]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([C:15]#[N:16])=[C:11]([CH3:14])[C:12]=1I.[CH:26](/B(O)O)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Br:6][C:7]1[C:8]([O:24][CH3:25])=[C:9]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([C:15]#[N:16])=[C:11]([CH3:14])[C:12]=1[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(Br)c(C=Cc2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 5.5 μmol) was added to an N,N-dimethylformamide (1.0 ml) suspension of N-(3-bromo-6-cyano-4-iodo-2-methoxy-5-methylphenyl)-2,2-dimethylpropionamide (I-6) (50 mg, 111 μmol), trans-β-styreneboronic acid (17.2 mg, 116 μmol), potassium phosphate n-hydrate (74-78%, 64 mg, 222 μmol), followed by stirred overnight at 95° C. The reaction liquid was cooled, then ethyl acetate (30 ml) was added, followed by washing with saturated brine (30 ml×2), drying over anhydrous magnesium sulfate, concentrating under reduced pressure.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:46])[CH:15]([C:20]1[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:52]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([F:35])[CH:31]=1)[CH2:27][O:26][C:24]1[CH:25]=[C:20]([C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:46])=[O:52])[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=2)[CH:23]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](C(=O)O)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (0.425 g, 0.67 mmol) in THF (10 mL) was added water (3.5 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (0.028 g, 0.67 mmol) and 30% H2O2 (304 mL, 2.68 mmol), drop-wise, maintaining the internal temperature below 5° C. The resulting cloudy solution was stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (1.79 mL, 2.68 mmol) and stirred at room temperature for 5 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×25 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (S)-2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (0.295 g, 92%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.[CH3:26][Si:27]1([CH2:40][CH2:41][CH3:42])[CH2:32][CH2:31][CH:30]([C@H:33]2[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]2)[CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][C@H:36]2[CH2:35][CH2:34][C@H:33]([CH:30]3[CH2:29][CH2:28][Si:27]([CH3:26])([CH2:40][CH2:41][CH3:42])[CH2:32][CH2:31]3)[CH2:38][CH2:37]2)=[O:22])=[CH:19][CH:18]=1
Reactant: CCC[Si]1(C)CCC([C@H]2CC[C@H](O)CC2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC[Si]1(C)CCC([C@H]2CC[C@H](OC(=O)c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g of N,N'-dicyclohexylcarbodiimide (DCC) was added to a mixture of 1.80 g of 4-fluorobenzoic acid, 2.54 g of trans-4-(4-methyl-4-n-propyl-4-silacyclohexyl)cyclohexanol, 1.50 g of 4-dimethylaminopyridine and 30 ml of methylene chloride at room temperature. The resultant reaction mixture was agitated for 8 hours at room temperature, after which the resultant N,N'-dicyclohexyl urea was removed by filtration. The filtrate was washed with brine, dried and concentrated to obtain a residue, followed by silica gel chromatography to obtain 2.12 g (yield: 56%) of the intended product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]4[OH:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[CH3:14][C:13]12[C:12](=[O:21])[CH2:11][CH2:10][CH:9]1[C:8]1[CH:7]=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:18]=3[C:17]=1[CH2:16][CH2:15]2
Reactant: COc1ccc2c3c(ccc2c1)[C@@H]1CC[C@H](O)[C@@]1(C)CC3
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1ccc2c3c(ccc2c1)C1CCC(=O)C1(C)CC3
Temperature: 0 °C

Procedure:
This crude alcohol was dissolved in 10 ml of acetone and the resulting solution was stirred and cooled in an ice bath while 0.5 ml of Jones reagent (CrO3 --H2SO4) was added dropwise. After stirring for 5 min. the excess oxidant was decomposed with 1 ml of 2-propanol. The resulting mixture was treated with ice water and most of the acetone was evaporated at reduced pressure. Extraction of the residual suspension with three portions of chloroform followed by washing the extracts with saturated NaHCO3 solution then drying (MgSO4), filtration and concentration at aspirator pressure gave 0.262g of partially crystalline, crude equilenin methyl ether. A combination of preparative thin layer chromatography (silica gel; benzene:ethyl acetate, 95:5) and recrystallization from methanol gave 0.0775g (27.6%) of colorless needles, m.p. 192°-194° which was essentially pure equilenin methyl ether. Another recrystallization from methanol gave colorless solid, m.p. 195°-196°,[α]D25 + 88.72° (c 0.86, dioxane).
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[C:17]([C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)Cl
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
In a reaction vessel, 50.0 g (0.25 mol) of pyrene, 27.6 g (0.30 mol) of tert-butyl chloride, and 200 ml of methylene chloride were charged, and the resulting mixture was cooled to 0° C. Next, 35.3 g (0.27 mol) of aluminum chloride was charged, followed by stirring at room temperature for 2 hours. Then, iced water and methylene chloride were added, and an organic layer was extracted, washed with water, dried over magnesium sulfate, and recrystallized to produce 33 g of tert-butylpyrene crystals in a yield of 51%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:22]([NH:24][CH:25]([CH:30]([CH3:32])[CH3:31])[C:26]([O:28]C)=[O:27])=[O:23])[S:20][CH:21]=2)=[CH:13][CH:12]=1>C1COCC1.O.[OH-].[Li+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:33])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:22]([NH:24][CH:25]([CH:30]([CH3:31])[CH3:32])[C:26]([OH:28])=[O:27])=[O:23])[S:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)cs1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 2-(4-(4-(3-(2-chlorophenyl)ureido)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (Example 23, 120 mg) in THF (2 ml), 1N lithium hydroxide monohydrate (1.2 ml) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated and added water, dilute HCl was added under stirring to pH acidic. The reaction mixture was filtered, and the residue was washed by water, and dried. The residue was dissolved in acetone, pet ether was added, solid was filtered and dried obtain title compound as solid. Yield: 70 mg (60%). 1H NMR (DMSO-d6, 300 MHz): δ 12.98 (bs, 1H), 9.59 (s, 1H), 8.48 (d, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.17 (d, 1H), 8.03 (d, 2H), 7.58 (d, 2H), 7.46 (d, 1H), 7.30 (t, 1H), 7.02 (t, 1H), 4.33 (s, 1H), 2.26 (s, 1H), 0.98 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>CS(C)=O>[Cl:1][C:2]1[C:8]([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(C(F)(F)F)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (5 g, 24.15 mmol) in DMSO (15 ml) was added potassium carbonate (6.62 g, 47.90 mmol) and 4-(trifluoromethyl)phenol (6.6 g, 40.71 mmol) in several batches. The resulting solution was stirred for 8 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was then quenched by the addition of water (200 ml), extracted with ethyl acetate (5×100 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (3×100 m), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline as a yellow solid (1.43 g, 18%). Next, to a solution of 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline (499 mg, 1.50 mmol) in ethanol (30 ml) was added hydrogen chloride (conc) (0.4 mL) and Zn powder (586 mg) in several bacthes. The resulting solution was stirred for 1.5 h at 85° C. in an oil bath and then concentrated under vacuum. The residue was dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to afford 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a red solid (359 mg, 79%). Finally, a solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (100 mg, 0.33 mmol) in trifluoroacetic acid (5 ml) and HCl ((conc), 1 ml) was stirred for 4.5 h at 80° C. in an oil bath. The solution was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 11% ethyl acetate in petroleum ether to produce 5-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (78.2 mg, 62%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2].[N+](=[CH2:20])=[N-]>O1CCOCC1.C(OCC)C>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][O:17][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2]
Reactant: CCOC(=O)C(=NO)c1nccc(NC=O)n1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)C(=NOC)c1nccc(NC=O)n1

Procedure:
Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g.) was dissolved in dioxane (200 ml.) under heating and the resultant solution was cooled to ambient temperature in an ice bath, and then thereto was added a solution of diazomethane in diethyl ether with stirring until complete consumption of the starting materials. The reaction mixture was concentrated to give a brown oil, which was purified by column chromatography on silica gel (140 g.) using benzene as an developing solvent and a mixture of benzene and ethyl acetate (3:1) as an eluent to give a pale brown semisolid of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.4 g.).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([O:23][CH3:24])=[O:22].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[CH3:24][O:23][C:21]([C:4]1[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][N:25]=[N+:26]=[N-:27])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
In a 250 mL round-bottomed flask, methyl 3-(bromomethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (2.7 g, 6.64 mmol) and sodium azide (1.25 g, 19.2 mmol) were combined with DMF (40 mL). The reaction mixture was stirred at room temperature overnight, then it was concentrated and triturated in ethyl acetate. The product 3-azidomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (2.3 g, 94%) was obtained as a white solid.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4]([C:17](O)=[O:18])=[CH:3][CH:2]=1>O1CCCC1>[CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4]([CH2:17][OH:18])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1CCCCc1ccccc1-2
Solvent: C1CCOC1
Product: OCc1cccc2c1CCCCc1ccccc1-2
Yield: 86.4 %

Procedure:
The reaction between 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-carboxylic acid (1.7 g, 0.0067 mole) and borane-tetrahydrofuran complex (1.16 g of a 1.05 M solution in tetrahydrofuran) in tetrahydrofuran (50 ml) produced 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-methanol as an oil (1.38 g). The IR and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:18])[CH:16]=[CH2:17].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C=CC(=O)N1CCCCC1
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CC1=C2CCN(CCC(=O)N3CCCCC3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and acrylic acid piperidide are reacted in accordance with the process described in Example 6. Reaction period nine hours. M.P. of the hydrochloride of the title compound 219°-221° from ethanol (decomp.).