Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH:6]1[C:23]2[C:22]3[CH:21]=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[CH:19]4)=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C1C(=O)N([Br:31])C(=O)C1.BrC1CC(=O)NC1=O>O>[Br:31][C:14]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:23]=3[C:22]=2[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cc3c(ccc4ccccc43)cc2c1
Agent: O=C1CC(Br)C(=O)N1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2cc2c1ccc1ccccc12
Yield: 91.6 %

Procedure:
Into 300 ml of DMF, N,N-dimethylformamide, 40 g of commercial benzanthracene was dispersed, and 35.6 g of NBS, bromosuccinimide, was added to the resultant suspension at the room temperature. After the resultant mixture was stirred for 3.5 hours, 600 ml of water was added, and the formed crystals were separated by filtration and washed with methanol. The obtained crude crystals were purified using a silica gel column with toluene and filtered with hexane, and 49.3 g of 7-bromobenzanthracene was obtained as cream crystals (the yield: 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)N1CCOCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCOCC4)nc3cc21

Procedure:
Morpholine-4-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and morpholine 4-carbonyl chloride. The title compound was obtained as light yellow powder (51 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C>C1COCC1>[C:26]([O:25][C:23]([N:18]1[C:19]2[C:15](=[C:14]([F:13])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[B:30]([OH:35])[OH:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2c(F)cccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0° C. was added n-BuLi (500 mL, 1.25 mol, 2.5 M in hexane) dropwise. The mixture was stirred at 0° C. for 40 min. Then the mixture was cooled to −78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at −78° C. for another 40 min. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH4Cl (sat. 500 mL). Then the mixture was adjusted to pH=6 with 1 N HCl. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE to give (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield: 64%, store in fridge). 1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:12]([NH:14][CH2:15][CH3:16])=O)[CH2:11][CH2:10]CC=1.[CH3:17][CH2:18]OCC>>[CH:16]1([CH2:15][NH:14][CH2:12][CH:7]2[CH2:11][CH2:10]2)[CH2:18][CH2:17]1
Reactant: CCOCC
Reactant: CCNC(=O)C1=CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C1CC1CNCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of lithium aluminum hydride (1.3 g, 9.35 mmol) in 10 mL dry ether, a solution of N-cyclopentenoyl-ethylamine (1.7 g, 13.3 mmol) in dry ether (10 mL) was added under a nitrogen atmosphere. This reaction was stirred at RT for 8 h and the reaction mixture was then quenched with saturated sodium sulfate solution, filtered, and the precipitate was washed with diethyl ether. The filtrate was concentrated to afford the title amine (0.8 g), yield: 69%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=2)[NH:7][N:6]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cc12
Temperature: 25 °C
Yield: 25.2 %

Procedure:
5-bromo-3-methyl-1H-indazole (30.7 mg, 0.145 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (110.3 mg, 0.291 mmol), Fibercat palladium catalyst (Johnson-Matthey, 59.3 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.6 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13% EtOAc/hexanes->100% EtOAc). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (14.0 mg, 25%). MS (ESI pos. ion) m/z: 384 (M+H). Calc'd Exact Mass for C23H17N3OS: 383.
Reaction SMILES: [O:1]1[C@H:10]2[C:5](=[CH:6][CH2:7][CH2:8][C@H:9]2[CH2:11][OH:12])[CH2:4][CH2:3][CH2:2]1.CN(C=O)C.N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>O>[C:23]([Si:27]([O:12][CH2:11][C@H:9]1[C@@H:10]2[C:5]([CH2:4][CH2:3][CH2:2][O:1]2)=[CH:6][CH2:7][CH2:8]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1CCC=C2CCCO[C@@H]21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1CCC=C2CCCO[C@@H]21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 360 mg (8S,8aR)-3,4,6,7,8,8a-hexahydro-2H-chromen-8-ylmethanol added 2.2 mL DMF, then 224 mg imidazole followed by 0.66 mL tert-butyl(chloro)diphenylsilane. The reaction was stirred overnight at RT, then added to water and extracted with diethyl ether. The crude extract was dried over Na2SO4, filtered, concentrated, then purified on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ=1.05 (s, 9H), 1.37-1.46 (m, 1H), 1.54-1.58 (m, 1H), 1.63-1.73 (m, 2H), 1.86-2.09 (m, 3H), 2.16-2.24 (m, 1H), 2.25-2.31 (m, 1H), 3.53 (m, 1H), 3.60 (dd, J1=9.8 Hz, J2=7.7 Hz, 1H), 3.80 (d, J=5.1 Hz, 1H), 3.90 (dd, 10.0 Hz, J2=7.4 Hz, 1H), 3.94-3.98 (m, 1H), 4.49-5.52 (m, 1H), 7.35-7.42 (m, 6H), 7.67-7.72 (m, 4H) ppm.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1>C(O)C.C(O)(=O)C>[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15]3[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[NH:7][C:16]=32)=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCc2ccc(F)cc21
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc2c(c1)-c1[nH]c3ccccc3c1C2
Temperature: 85 °C

Procedure:
To a solution of phenyl hydrazine (1.32 mL, 13.32 mmol) and 6-fluoro-1-indanone (2.02 g, 13.46 mmol) in ethanol (7.6 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 17 minutes and cooled to room temperature. Upon cooling, white crystals precipitated out of solution. These crystals were collected by vacuum filtration and dissolved in isopropanol (23 mL). Sulfuric acid (36N, 1.51 mL) was added via syringe and the resulting solution was stirred at reflux (90° C.) for 18 hours and subsequently cooled to room temperature. The solution was then basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of precipitate. The solid was collected by vacuum filtration to yield 37b as a brown solid in 46% crude yield (1.38 g, 6.17 mmol). Crude product was brought on to the next step without further purification. For purposes of characterization, the product was purified by flash column chromatography (20:1 to 20:1.5 hexanes-ethyl acetate). 1H NMR (600 MHz, CDCl3): δ 8.26 (s, 1H), 7.64-7.65 (d, 1H, J=7.8 Hz), 7.42-7.44 (m, 2H), 7.20-7.23 (td, 1H, J=7.2, 1.2 Hz), 7.16-7.19 (td, J=7.2, 1.2 Hz) 7.12-7.14 (dd, 1H, J=8.4, 2.4 Hz), 6.88-6.91 (m, 1H), 3.68 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 161.5-163.1 (d, J=242 Hz), 142.9 (d, J=2.4 Hz), 142.3 (d, J=2.9 Hz), 140.7, 136.5 (d, J=9.6 Hz), 126.0 (d, J=9.0 Hz), 124.5, 123.9, 122.3, 120.4, 119.2, 112.2, 111.0 (d, J=22.7 Hz), 104.8 (d, J=24.3 Hz), 29.8; FTIR: cm−1 3398, 1589, 1528, 1462, 1268, 1187, 744, 665. ESI-HRMS: Calcd. for C15H10FN+ [M]+: 223.0792. found 223.0792.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]=[O:9])[CH2:4][CH:3]=1.[CH2:10]([Mg]Br)[CH3:11].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8](=[O:9])[CH2:10][CH3:11])[CH2:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CC1=CC[C@H](C=O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CCC(=O)[C@H]1CC=C(C)CC1

Procedure:
(1R)-4-Methyl-3-cyclohexene-1-carboxaldehyde was treated with ethylmagnesium bromide followed by tetrapropylammonium perruthenate and 4-methylmorpholine N-oxide to afford 1-[(1R)-4-methylcyclohex-3-en-1-yl]-propan-1-one; [α]D=+41.3 (c=1.0, CHCl3). The product was identical in all respects to the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42].CCCCCC>C(CC(C)(C)C)(C)C>[C:41]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18])(=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=[CH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: CCCCCC
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of phytol and 600 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 94 mg of phytyl eicosapentaenoate.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>ClCCl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:6]2)[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.040 mmol, racemic intermediate from Example 139, Step 6) and triethylamine (20 μL, 0.14 mmol) in dichloromethane (0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.048 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated under reduced pressure and the crude mixture purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.8 mg, 19%). The product was isolated as a racemic mixture. LCMS calculated for C21H24ClF4N6O (M+H)+: m/z=487.2; Found: 487.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[C:13]([N:17]([CH3:19])[CH3:18])(OC)[CH3:14]>>[CH3:18][N:17]([CH3:19])/[C:13](/[CH3:14])=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: COC(C)(OC)N(C)C
Product: C/C(=C\C(=O)c1ccc(C)cc1)N(C)C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 1-(4-methylphenyl)ethanone (2.0 g, 15 mmol) in (1,1-dimethoxy-ethyl)-dimethyl-amine was heated to 120° C. and stirred overnight. The reaction mixture was cooled and concentrated to dryness. The residue was stirred with 25 mL hexane for 1 h and filtered. The solids were washed with hexane and then dried to give the title compound (1.8 g, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.37 (3H, s), 2.65 (3H, s), 3.07 (6H, s), 5.68 (1H, s), 7.19 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=8.0 Hz). [M+H] Calc'd for C13H17NO, 204; Found, 204.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:33][CH:32]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1Nc1ccc(Oc2ccccc2)cc1

Procedure:
The compound prepared in Example 3 was reacted with 4-phenoxyaniline according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[C:22]([Br:27])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[C:22]([Br:27])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 5) (480 mg, 0.913 mmol) in DCM (8 mL) at 0° C. was added TFA (1.9 mL) dropwise. The mixture was stirred for 2 h at RT and evaporated. The residue was triturated with hexane to afford (S)-3-amino-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (260 mg) as brown solid. LC-MS: 428 (M+H).
Reaction SMILES: [CH2:1]([C:3]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O)([CH:6]=[CH:7][CH2:8][CH3:9])[CH:4]=O)[CH3:2].Cl.C(Cl)Cl>COCCOC.[Zn]>[CH2:6]([C:3]1([CH2:1][CH3:2])[CH:4]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC=CC(C=O)(CC)CSc1ccccc1C=O
Agent: Cl
Agent: [Zn]
Solvent: COCCOC
Solvent: ClCCl
Product: CCCCC1(CC)C=Cc2ccccc2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 141.6 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 3.0 g of residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][NH2:11].Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:11][CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
4-Bromobenzyl bromide (200 mg, 0.800 mmol) was added slowly to a 2 M solution (4 ml) of methanamine in tetrahydrofuran, and the solution was stirred at room temperature for 24 hr. The reaction solution was adjusted to pH 3 by the addition of 1 N hydrochloric acid and was then washed twice with diethyl ether. A saturated aqueous sodium hydrogencarbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure to give 136.1 mg (yield 85%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CC(O)=O.[BH4-].[Na+]>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C@@H:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-methyl 2-amino-2-phenylacetate (1.0 g, 6.06 mmol) in anhydrous MeOH (20 mL) was added 4-methoxy benzaldehyde (0.82 g, 6.06 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., NaBH4 (0.69 g, 12.12 mmol) was added and the contents were stirred at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), MeOH was removed under reduced pressure and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was taken directly for step 2. MS ES+APCI calc'd. for C17H19NO3 [M+H]+ 286. Found 286.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Using General Procedure I; a solution of ethyl [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) of the title compound as a colorless solid.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.CCN(CC)CC.[CH3:26][CH2:27][O:28][C:29]([CH3:31])=O>CC#N>[O:28]1[CH2:29][CH2:31][C@H:26]([O:8][C:9](=[O:10])[O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])[CH2:27]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Yield: 92 %

Procedure:
Compound 21 (250 mg, 2.84 mmol), N,N′-disuccinimidyl carbonate (799 mg, 3.12 mmol), and Et3N (431 mg, 4.27 mmol) in CH3CN (5 mL) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL), washed with brine, then concentrated under reduced pressure to obtain compound 22 (595 mg, 92%) as a solid. M.P.: 97-99° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[N+](=[CH2:17])=[N-]>C(Cl)Cl>[CH3:17][O:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)c1sc2ccccc2c1O
Solvent: ClCCl
Product: COC(=O)c1sc2ccccc2c1OC

Procedure:
A stirred, ice-bath cooled mixture of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate (J. Org. Chem. 32, 2678 (1967) (2.1 g, 0.01 m) and dry methylene chloride (25 ml) was treated with ethereal diazomethane in portions until the yellow color of the diazomethane persists, and nitrogen was no longer evolved. Concentration in vacuo yielded methyl 3-methoxybenzo[b]-thiophene-2-carboxylate as a pale tan solid; m/z 324 (M+.). The material was used without further purification in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O>CS(C)=O.C(O)C.[Pd]>[O:15]=[C:13]1[NH:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:11]2[CH2:18][CH2:17][CH2:16][CH:12]12
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Pd]
Solvent: CCO
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2N2CCCC12

Procedure:
1.5 ml of o-fluoro-nitrobenzene and 8.2 g of L-proline were stirred at 60° C. for 3 hours in 50 ml DMSO. The mixture was then evaporated in vacuo to give a yellow oil. This oil was dissolved in 250 ml 96% ethanol and was hydrogenated at normal pressure at room temperature using 2 g 5% Pd/C as catalyst. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo to give the title compound. M.p. 169°-172° C.