Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH3:33])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:29]C(=O)C)=[C:17]([CH:28]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH3:33])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:29])=[C:17]([CH:28]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Yield: 48.6 %

Procedure:
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-fluoroaniline (0.068 g, 0.145 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.030 g, 0.0705 mmol, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([OH:17])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([O:17][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of Intermediate 63a (204 mg, 0.864 mmol) and Et3N (180 μL, 1.3 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (279 μL, 1.04 mmol) and the mixture stirred at RT for 1 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give the title compound as a pale brown gum (290 mg, 86%). LCMS (Method 3): Rt 4.99 min, m/z 393 [MH+].
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].C[O:35][C:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37]>COCCOC.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>[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:2]2[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:10])=[CH:5][CH:6]=2)=[CH:40][CH:39]=1)([OH:37])=[O:35]
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: COCCOC
Product: O=C(CSc1ccc(-c2ccc(C(=O)O)cc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 130 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
The resultant product (200 mg) of Example 31, tetrakistriphenylphosphinepalladium (25 mg), sodium carbonate (200 mg) and 4-methoxycarbonylphenylboronic acid (105 mg) were dissolved in a mixed solution of ethylene glycol dimethylether (4 mL) and water (250 μL), and the mixture was heated under reflux at 130° C. for 6 hrs. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure, and the residue was purified by column chromatography using chloroform as an eluent. The eluent was evaporated and the obtained yellow oil was dissolved in ethanol (2 mL). A 1N aqueous sodium hydroxide solution (50 μL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was adjusted to pH=5 with 1N hydrochloric acid, and the mixture was extracted with chloroform. The extract was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (90 mg) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([O:12][C:6]1[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a suspension of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol) and potassium carbonate (0.43 g, 3.1 mmol) in 1.6 mL of acetone was added benzyl bromide (300 mg, 1.55 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was filtered to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to obtain the title compound as a yellow oil (292 mg, 67%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13](CO)([N+:15]([O-:17])=[O:16])[CH2:12][N:11]([CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CO>[CH2:1]([N:8]1[CH2:14][CH:13]([N+:15]([O-:17])=[O:16])[CH2:12][N:11]([CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccccc2)CC(CO)([N+](=O)[O-])C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCN(Cc2ccccc2)CC([N+](=O)[O-])C1
Temperature: 40 °C

Procedure:
To a solution of 1-benzyl-6-hydroxymethyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine in methanol (800 ml), potassium tert-butoxide (97 g) is added, and the solution is heated at about 40° C. for 30 minutes. The solvent is evaporated under reduced pressure, and the residue is diluted in a solution of hydroxylamine hydrochloride (60 g) in water (500 ml) and extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of ethyl acetate. Fractions containing the object compound are pooled and evaporated under reduced pressure to give 1-benzyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine (45 g) as a pale yellow oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[C:24]([CH3:29])[CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37]C(=O)[O:35][C:33]1=[O:34]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[I:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:31][C:32]([CH3:39])([CH3:37])[C:33]([OH:35])=[O:34])[CH2:13][CH2:12]3)=[N:15][CH:16]=2)=[O:30])=[CH:23][C:24]=1[CH3:29]
Reactant: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)ccc1I
Reactant: CC1(C)CC(=O)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)ccc1I
Reaction time: 0.5 h

Procedure:
4-[5-(4-Iodo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (35 mg, 0.07 mmol) was dissolved in 30% TFA in CH2Cl2 solution at room temperature. The mixture was stirred for 30 min and then partitioned between EtOAc and H2O. The water layer was made basic by the addition of Na2CO3. The organic layer was then collected washed with water dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2 and treated with 2,2-dimethysuccinic anhydride (13 mg, 0.10 mmol). After stirring at room temperature for 4 h the mixture was concentrated to a residue and washed with excess of hexanes to afford the product. HRMS m/z calcd for C23H27N4O4I [M+H]+: 551.1150. Found: 551.1152.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][C:25](O)=[O:26])[N:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:25](=[O:26])[CH2:24][N:21]4[CH:22]=[CH:23][C:19]([C:18]([F:28])([F:17])[F:29])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1ccc(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.026 g, 0.12 mmol), 2-(3-(trifluoromethyl)-pyrazol-1-yl)acetic acid (0.024 g, 0.12 mmol) and NEt3 (0.060 mL, 0.43 mmol) in DMF (0.5 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.035 g, 74%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.64 (m, 1H), 7.43 (m, 2H), 7.15 (dd, J=8.8, 8.4 Hz, 2H), 6.62 (d, J=2.4 Hz, 1H), 5.23 (s, 2H), 3.82 (m, 2H), 2.84 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CCCCCCCBr
Solvent: CC#N
Solvent: O
Product: CCCCCCCOC(=O)c1cc(O)ccc1O

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (28 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (27.6 g), 1-bromo-heptane (39 g) and acetonitrile (380 ml) was heated, under reflux for 18 h. The cooled reaction mixture was added to water (1000 ml) and extracted with ethyl acetate (3×400 ml). The combined organic layers were washed with 1N-hydrochloric acid (300 ml) and water (2×400 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (40 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent, to give heptyl 2,5-dihydroxybenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7](Br)[CH:8]=1.[Li]CCCC.[CH2:16](Br)/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])\[CH3:19].[NH4+].[Cl-].[NH4+].[OH-]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:16]/[CH:17]=[C:18](\[CH3:19])/[CH2:20][CH2:21]/[CH:22]=[C:23](\[CH3:24])/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH:6]=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1cc(C)cc(Br)c1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C)cc(C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of 3-methoxy-5-bromotoluene (0.50 g, 2.49 mmol) in dry THF (8 mL) was added n-BuLi (1.71 mL, 2.74 mmol, 1.6 M in Hexane) dropwise at −78° C. After the reaction mixture was stirred for 15 min, Li2CuCl4 (0.1 mL, 0.1 mmol, 0.1 M in THF) was added, and the mixture was stirred for another 10 min at the same temperature. Then, a solution of (E,E)-farnesyl bromide (0.70 mL, 2.58 mmol) in THF (3 ml) was added over 0.5 hour and stirring was continued for 2 hours at −78° C. After the reaction was complete, the mixture was warmed to room temperature and saturated aqueous NH4Cl (20 mL) was added, followed by 10% NH4OH (40 mL) and Et2O (3×50 mL). The combined organic layer was washed with water, brine, and dried with Na2SO4. The crude product was purified by flash silica gel chromatography (hexanes/EtOAc 60:1, 30:1, 20:1 and 10:1) to yield compound 24 (658.1 mg, 78%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: CC#N
Reactant: Cc1ccc(Br)cc1C=O
Product: Cc1ccc(Br)cc1C(O)CC#N

Procedure:
Addition of 5-bromo-2-methylbenzaldehyde to acetonitrile gave 3-(5-bromo-2-methylphenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (3.33 g, 86%): 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.0, 2.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.96 (d, J=4.4 Hz, 1H), 5.04-5.00 (m, 1H), 2.88 (ABd, J=16.8, 4.4 Hz, 1H), 2.77 (ABd, J=16.8, 6.4 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:59]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:59][C:58]5[CH:61]=[CH:62][C:63]([Cl:64])=[C:56]([Cl:55])[CH:57]=5)=[CH:42][CH:43]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (27 mg, 0.078 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.39 mmol) and potassium carbonate (0.39 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (21 mg, LC/MS: m/z 889).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5](=[O:18])/[CH:6]=[CH:7]/[C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:1]=[CH:2][CH:5]([OH:18])/[CH:6]=[CH:7]/[C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C=C[Mg]Cl
Reactant: CCCCCC#CCC#C/C=C/C=O
Solvent: C1CCOC1
Product: C=CC(O)/C=C/C#CCC#CCCCCC
Temperature: 0 °C

Procedure:
A solution of vinyl magnesium chloride (2.2 Molar in tetrahydrofuran 35 mL) was added to tetrahydrofuran (150 mL) and cooled to -60°. The compound (E)-2-tridecen-4,7-diyn-1-al (12.6 g) dissolved in tetrahydrofuran (50 mL) was added to the above solution over 5-10 min and the cooling bath was removed and the temperature of the reaction mixture was allowed to warm to 0° C. (20 min). Ether (200 mL) was then added followed by a saturated aqueous solution of ammonium chloride (10 mL). After the contents of the flask had been stirred for a further 15 L min, magnesium sulfate was added and after a further 30 min, the solids were filtered off and washed with ether. Removal of the solvents from the combined filtrates and purification of the residue by liquid chromatography (two columns, 10% by volume ethyl acetate in 90% by volume hexane) yielded the pure (E)-1,4-pentadecadien-6,9-diyn-3-ol (13.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH2:16])=[O:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: NC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Cl
Yield: 99.3 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (150 mg, 0.862 mmol), (R)-2-amino-2-phenylacetamide hydrochloride (160 mg, 0.858 mmol) and DIEA (0.400 mL, 2.30 mmol) in DMF (5 mL) was stirred at room temperature for 6 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-2-phenylacetamide (245 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-n1ccnc1
Yield: 84.2 %

Procedure:
A solution of 350 mg (1.6 mmol) 1-(2-methoxy-4-nitro-phenyl)-1H-imidazole and 1873 mg (8.3 mmol) stannous dichloride in ethyl acetate (5 ml) and ethanol (2.5 ml) were heated to 70° for 35 minutes. The reaction was poured onto water/ice and neutralized with an aqueous solution of sodium hydrogen carbonate. It was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 255 mg (84%) 3-methoxy-4-(imidazol-1-yl)-phenylamine as a brown solid. MS ISP (m/e): 190.0 (100) (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1>CCO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCOCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCO
Solvent: O
Product: O=C1CC(C2CCOCC2)Oc2ccc(Br)cc21
Yield: 19.8 %

Procedure:
To a stirred solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (943.9 mg, 4.39 mmol) in EtOH (5.6 mL) and H2O (9.4 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 4.39 mmol) and borax (1.67 g, 4.39 mmol). The mixture was refluxed overnight. Then the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in CR2Cl2 and filtrated. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography to give 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (270 mg, 20%). 1H-NMR (CDCl3, 400 MHz): 1.54 (m, 2H), 1.78 (m, 1H), 1.95 (m, 1H), 2.75 (m, 2H), 3.44 (m, 3H), 4.09 (m, 2H), 4.15 (m, 1H), 6.89 (m, 1H), 7.56 (m, 1H), 8.01 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([N:39]([CH3:41])[CH3:40])[CH:37]=2)[N:32]=[CH:31][CH:30]=1.O=[O+][O-]>O.CCO>[ClH:28].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([N:39]([CH3:41])[CH3:40])[CH:37]=5)[N:32]=[CH:31][CH:30]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Agent: Cl
Agent: O=[O+][O-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc(N(C)C)cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amide E5 (228 mg, 0.62 mmol) in 1:2 EtOH:H2O (20 mL) were sequentially added c.HCl (0.17 mL, 5.61 mmol) and 4-chloro-6-dimethylaminoquinoline (O3) (140 mg, 0.68 mmol), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) after this time showed some starting material still present in the reaction mixture, thus more O3 (140 mg, 0.68 mmol) was added. After a further few hours refluxing, TLC showed the reaction was complete, and thus solvent was removed under reduced pressure. The residue was crystallized from MeOH:EtOAc to afford Cpd. P as an (extremely fine) amorphous yellow solid (170 mg, 51%). 1H NMR [(CD3)2SO] δ 2.28 [s, 3H], 3.15 [s, 6H, ArN(CH3)2], 6.21 [br s, 1H, ArH], 6.89 [d, J=6.71 Hz, 1H, ArH], 7.65 [m, 5H, ArH], 7.82 [m, 4H, ArH & ArNH2], 7.96 [d, J=9.39 Hz, 1H, ArH], 8.18 [d, J=8.57 Hz, 2H, ArH], 8.35 [t, J=12.38, 6.19 Hz, 1H, ArH], 10.44 [br s, 1H, ArH], 10.65 [br s, 1H, ArNHAr], 10.71 [s, 1H, ArNHAr], 12.75 [br s, 1H, ArC(O)NH], 14.56 [d, J=4.10
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>COCCOC.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl malonate (7.8 mL, 68.2 mmol) in DME (100 mL) at 0° C. was added K2CO3 (12.6 g, 91.0 mmol). The reaction mixture was stirred for 30 min, and then 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.5 mmol) was added. The reaction mixture stirred at 40° C. overnight. The reaction was cooled, diluted with water (200 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated. The residue was triturated with PE:EtOAc=8:1 (30 mL) to 13.0 g (86%) of the title compound as a yellow solid. [M+H] Calc'd for C11H10BrNO6, 332, 334. Found, 332, 334.