Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[N:6]=[CH:5]1)[CH2:2][CH3:3].[Li+].[OH-].Cl>CO>[CH2:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cnc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCn1cnc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 25-2 (0.6 g, 3.6 mmol) in anhydrous MeOH (2 ml) was added 3N LiOH (2.6 ml, 7.9 mmol). The reaction mixture was heated at 80° C. for 1 h. The heat was reduced and the mixture was stirred at 40° C. overnight. The reaction was then neutralized with 12N HCl and subsequently concentrated in vacuo. The residue was dried azeotropically with toluene to afford the desired product 25-3 as a solid. MS calculated M+H, 155.2. Found 155.1
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1>[Pd]>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CC1CNCc2[nH]c3ccccc3c21
Agent: [Pd]
Product: Cc1cncc2[nH]c3ccccc3c12
Temperature: 160 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
4-methyl-2,3,4,9-tetrahydro-1H-β-carboline (214 mg, 1.17 mmol) was suspended in xylenes (10 ml). Pd (10% wt. on carbon, 21 mg) catalyst was added thereto and the reaction mixture was stirred at 160° C. for 24 hours, then cooled to RT and filtered through celite. The filtrate was concentrated to dryness to give 4-methyl-9H-β-carboline (210 mg). 1H-NMR (300 MHz, DMSO-d6): δ 11.73 (br s, 1); 8.78 (br s, 1); 8.19 (d, 1); 8.13 (s, 1); 7.62 (br s, 1); 7.53 (t, 1); 7.25 (t, 1); 2.78 (s, 3). NH4OAc standard conditions. DAD Rf=2.24 min. M+H=183.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([CH3:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:21]([CH3:33])[CH:20]=3)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]3[N:37]=[CH:38][CH:39]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile (1.0 g) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (10 mL), and the mixture was stirred at 60° C. for 12 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 1 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (5 mL)-tetrahydrofuran (5 mL). Sodium borohydride (0.074 g) was added thereto at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.88 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl)=[CH:23][CH:22]=1)#[N:20]>CN(C)C=O>[C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])=[O:7])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CC(C)N(C(=O)c1ccc(O)cc1)C(C)C
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-hydroxy-N,N-bis(1-methylethyl)benzamide (2.47 g, 11.2 mmol) in 50 mL of N,N-dimethylformamide is treated with 60% sodium hydride (500 mg, 12.5 mmol). After stirring at 0° C. for 10 minutes, the reaction is treated with 5-(4-cyanophenoxy)pentyl chloride (3.25 g, 14.5 mmol) and stirred at 70° C. for 2 hours. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (60 g) with 70-80% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH3:30])[N:22]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccc(F)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 10 mg (10%). MS (m/e) 365.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:15]=[N+:16]([O-])[CH:17]=[CH:18][C:19]=2[N+:20]([O-])=O)=[CH:5][CH:4]=1>C(O)C.O=[Pt]=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[NH2:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2c[n+]([O-])ccc2[N+](=O)[O-])c2ccccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(Oc2cnccc2N)c2ccccc12
Reaction time: 6 h
Yield: 84.7 %

Procedure:
To a slurry of PtO2 (0.3 g) in 5 ml of ethanol was added 3-(4-methoxy-1-naphthyloxy)-4-nitropyridine-N-oxide (7.2 g) in 245 ml of ethanol. The material was hydrogenated under pressure (50 PSI) by shaking the slurry on a Parr apparatus for six hours. The mixture was filtered and the filtrate concentrated to yield an oil (5.2 g). This oil was eluted with 5% methanol/DCM on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil which solidified on standing (4.36 g). This material was triturated with ether to yield a solid, 2.85 g, m.p. 126°-129° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[C:8](=[O:23])[N:9]([CH3:22])[CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1)=[O:5])[CH3:2].Br[C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([N:46]([CH3:48])[CH3:47])[CH:42]=3)[C:37]2=[O:49])[C:26]=1[CH2:27][O:28]C(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>>[CH3:47][N:46]([CH3:48])[C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:49])[N:36]([C:32]1[C:26]([CH2:27][OH:28])=[C:25]([C:11]3[CH:12]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:8](=[O:23])[N:9]([CH3:22])[CH:10]=3)[CH:35]=[CH:34][CH:33]=1)[CH:45]=[CH:44]2
Reactant: CC(=O)OCc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Reactant: CCNC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Product: CCNC(=O)Nc1cc(-c2cccc(-n3ccc4cc(N(C)C)ccc4c3=O)c2CO)cn(C)c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To 1-Ethyl-3-[1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydro-pyridin-3-yl]-urea (50 mg, 0.16 mmol), acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-benzyl ester (65 mg, 0.16 mmol), potassium phosphate (66 mg, 0.31 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (4.4 mg, 0.0092 mmol), and bis(dibenzylidineacetone)palladium(0) (2.6 mg, 0.0045 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 2 hours. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This was dissolved in 2 mL tetrahydrofuran, 1 mL methanol, and 1 mL water. 1M aq. lithium hydroxide solution (0.47 mL, 0.47 mmol) was added. After stirring for 3 hours, the resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 1-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-ethyl-urea (33 mg, 0.068 mmol). MS (ESI) 488.1(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Br:17])[CH:19]=2)[N:25]=1)=[O:15]
Reactant: NNc1cccc(Br)c1
Reactant: COC(=O)C(=O)C=Cc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2cccc(Br)c2)C(c2ccccc2Cl)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
4-(2-Chloro-phenyl)-2-oxo-3-butenoic acid methyl ester (1.4 g, 6.0 mmol) prepared in Step 2 of Preparation 24 and 3-bromophenylhydrazine hydrochloride (1.4 g, 6.1 mmol) were added to acetic acid (20.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting yellow liquid residue was crystallized from methanol to give 1.2 g of the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:20]([CH2:27][CH2:28][CH2:29]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:20]([CH2:27][CH2:28][CH2:29][O:17][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: OCCCOc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.5 mmol) of (3-phenoxy)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.39 g).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1.C(=O)([O-])O.[Na+].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[N:10][CH:11]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl chlorooxoacetate (78.7 ml) was added dropwise to a suspension of 2-amino-5-chloropyridine (100 g) and sodium hydrogencarbonate (78.4 g) in tetrahydrofuran (2000 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was added to a mixture of diethyl ether (2000 ml), ammonium chloride (62.4 g) and water (1000 ml), liquid separation was performed. The resultant water layer was extracted with methylene chloride. Organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (162 g). Water (450 ml) and lithium hydroxide (18.2 g) were added to a solution of this ester (160 g) in tetrahydrofuran (1800 ml). After the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and hexane (3000 ml) was added to the resultant residue to stir the mixture for 3 hours. Solids were collected by filtration and dried. Acetonitrile (1000 ml) was added to the solids (190 g), and the mixture was stirred for 1 hour. Solids formed were collected by filtration, washed with diethyl ether (500 ml) and then dried to obtain the title compound (158 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2c1ccccc1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
A mixture of intermediate 15, ethyl 3-(benzyloxy)-9-bromo-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, (0.477 g, 1.18 mmol) in acetonitrile (15 ml) and water (15 ml) was treated with phenylboronic acid (0.190 g, 1.53 mmol), sodium carbonate (0.275 g, 2.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.200 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then concentrated in vacuo, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.325 g (68% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ (PPM): 1.26 (3H, t, J=7.1 Hz, CH3), 2.68 (2H, m, CH2), 4.27 (2H, q, J=7.1 Hz, OCH2), 4.32 (2H, t, J=7.6 Hz, CH2), 5.34 (2H, s, OCH2), 6.73 (1H, t, J=4.8 Hz, CH), 7.3–7.55 (10H, m, aromatics). HRMS (ESI+) calculated for C24H23N2O4 [M+H+]: 403.1658; found: 403.1659.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([O:35][CH3:36])[C:29](N(OC)C)=[O:30])=[CH:24][CH:23]=2)[CH:21]=[CH:20][N:19]=[N:18]1>>[N:17]1([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([O:35][CH3:36])[C:29]([C:12]3[O:11][C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)=[CH:14][CH:13]=3)=[O:30])=[CH:26][CH:27]=2)[CH:21]=[CH:20][N:19]=[N:18]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2ccnn2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-n4ccnn4)cc3)o2)cc(OC)c1Br
Yield: 7 %

Procedure:
2-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-(1H-1,2,3-triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (50% EtOAc/hexanes) gave 2-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a yellow solid (0.025 g, 7% yield). MS: m/z 498.2 [M+H]+.
Reaction SMILES: [N+]1([O-])C=CC=CC=1.Br[C:9]1[C:10]([C:15]#[N:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#N)(C)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(#N)C>[C:15]([C:10]1[C:9]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:16]
Reactant: N#Cc1ncccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: C[Si](C)(C)C#N
Agent: [O-][n+]1ccccc1
Solvent: CC#N
Product: Cc1ccc(-c2cccnc2C#N)cc1

Procedure:
Synthetic Scheme XXVIII shows the 4-step preparation of the alkylating reagent 2-cyano-3-(4-bromomethylphenyl)pyridine (79) from 3-bromopyridine (80) (Aldrich). In step 1, the pyridine 80 was reacted with hydrogen peroxide in acetic acid at reflux to give the pyridine N-oxide 81. In step 2, the N-oxide 81 was converted to 3-bromo-2-cyanopyridine (82) by reaction with trimethysilylcyanide and triethyl anine in acetonitrile at reflux. In step 3, the nitrile 82 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 2-cyano-3-(4-methylphenyl) pyridine (83). In step 4, 83 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 79. ##STR91##
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[OH:22])=[CH:17][CH:16]=1.[Li+].C[Si]([N-:40][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:40][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[OH:22])=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc2c(C(O)c3ccc(Br)cc3)ccnc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2c(C(O)c3ccc(N)cc3)ccnc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
In a 25 mL sealed tube under N2, were dissolved Pd2(dba)3 (84 mg, 92 μmol), t-Bu3P (1M in PhMe) (92 μl, 92 μmol), (4-bromophenyl)(7-methoxyquinolin-4-yl)methanol (316 mg, 918 μmol) and LiHMDS (1M in THF) (2.75 mL, 2.75 mmol) in 3.5 mL of toluene and the solution was then heated at 80° C. After 3 h, the crude reaction mixture was neutralized by adding 5 drops of MeOH and then directly purified by MPLC (ISCO, dichloromethane:MeOH 100:0 to 90:10) to afford (4-aminophenyl)(7-methoxyquinolin-4-yl)methanol (140 mg, 54% yield). MS (ESI pos. ion) m/z: 281 (MH+). Calc'd exact mass for C17H16N2O2: 280.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=1)([O-:3])=[O:2].[O:19]1CCO[CH2:21][CH2:20]1.C(N(CC)CC)C.BrCCO>C(Cl)Cl.[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:14][CH2:15][N:16]([CH2:21][CH2:20][OH:19])[CH2:17][CH:18]=1)([O-:3])=[O:2]
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
A suspension of 5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.55 g, 2.261 mmol) in dry CH2Cl2:1,4-dioxane (15 mL, 2:1) was treated with triethylamine (0.636 mL, 4.52 mmol), followed by 2-bromoethanol (0.176 mL, 2.487 mmol) at room temperature. Only starting material was observed after stirring for 4 h at room temperature. The reaction was then refluxed for 24 h. The reaction was brought to room temperature, diluted with 1 N NaOH solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain 2-(4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.24 g, 36.9%) as a dark yellow solid. 1H NMR (DMSO-d6) δ 11.86 (s, 1H), 8.68 (d, 1H, J=2.1 Hz), 8.01 (dd, 1H, J=2.4, 9.0 Hz), 7.65 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 6.16 (s, 1H), 4.42 (t, 1H, J=5.4 Hz), 3.56 (q, 2H), 3.18 (t, 2H, J=6.3 Hz), 2.69 (t, 2H, J=5.4 Hz), 2.54-2.50 (m, 4H); ESI-MS (m/z, %): 288 (MH+, 100).
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:5]2[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1C(=O)CCCc2cc(N)ccc21
Yield: 83 %

Procedure:
1-Isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (474 mg, 1.91 mmol) was charged to 10 ml ethanol and 100-200 mg 10% palladium on carbon was added. The suspension was hydrogenated at 30 psi hydrogen for 2.5 hours and followed by NMR. The reaction was filtered through a ¼″ pad of celite and the pad washed with 4×10 ml portions of methanol. The resulting solution was clarified through a 45 micron frit to yield 7-Amino-1-isopropyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (346 mg, 83% yield) as a clear oil. 1H-NMR (CDCl3) δ 6.96 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.3 Hz, 1H), 6.51 (s, 1H), 4.80 (m, 1H), 3.67 (br s, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.20 (m, 3H), 1.84 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H). LC/MS (ESI+)=219 (M+H).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][CH2:12][NH2:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2].[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[N+:1]([CH2:4][C:5]1([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: NCCC1(C[N+](=O)[O-])CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1(C[N+](=O)[O-])CCCCC1
Yield: 68.1 %

Procedure:
The amine hydrochloride salt (compound 4, 0.50 g, 2.25 mmol) was reacted with acetyl chloride (0.20 g, 2.55 mmol) and triethylamine (0.45 g, 4.45 mmol) in tetrahydrofuran following the procedure described in Example 1, Step 4. Purification by chromatography on silica eluting with ethyl acetate gave the required product as a crystalline solid (0.35 g, 69%); mp 68-70° C.