Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(OCC)(=O)C>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(F)c1)c1ccccc1
Reactant: CC(C)(C)C(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(C(=O)c1ccccc1)c1ccnc(F)c1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
To a solution of 2-(2-fluoropyridin-4-yl)-1-phenylethanone (450 mg, 2.1 mmol) in dry THF (10 mL) at 0° C. was added a solution of sodium bis(trimethylsilyl)amide (2.1 mL, 1M). After 10 min. 1-bromopinacolone (309 μL, 2.3 mmol) was added dropwise and the solution stirred for 2 h. The solution was poured into ethyl acetate (25 mL) and H2O (25 mL) and the layers allowed to separate. The organic layer was collected and the aqueous layer extracted with ethyl acetate (30 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography using EtOAc-Pet. spirit (20:80) as eluant to give the pure product as a pale yellow oil (574 mg, 87%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:23]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)[CH:27]=[CH:26][CH:25]=[N:24]1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccccc1-n1cccn1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccccc4-n4cccn4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-(pyrazol-1-yl)benzeneboronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[2-fluoro-2′-(pyrazol-1-yl)biphenyl-5-yl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 431 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br.[CH3:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1.[C:29](#[N:31])[CH3:30]>>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:31][CH:29]([C:21]2[N:20]([CH3:19])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[CH3:30])[N:7]=1
Reactant: CC#N
Reactant: Cn1cnc2ccccc21
Reactant: CC(C)c1nc(N)nc(Cl)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1nc(N)nc(NC(C)c2nc3ccccc3n2C)n1

Procedure:
2.6 g (0.015 mol) of 2-amino-4-chloro-6-isopropyl-1,3,5-triazine and 4.2 g (0.03 mol) of K2CO3 are introduced into 50 ml of acetonitrile. 3.8 g (0.015 mol) of 1-methylbenzimidazole hydrobromide are added to this solution, and the mixture is subsequently refluxed for 3 hours. Then, all solid constituents are filtered off with suction and the filtrate is evaporated on a rotary evaporator. The residue is purified by means of column chromatography (eluent: ethyl acetate). This gives 4.1 g (88% of theory) of 2-amino-4-isopropyl-6-[1-(1-methylbenzimidazol-2-yl)-1-ethylamino]-1,3,5-triazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=O.N1CCCCC1.Cl>C(O)C>[C:9]([C:8](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]([OH:20])=[C:12]([OH:11])[CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)c(O)c1)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
To a mixture of 758 mg (5.00 mmole) of 4-chlorophenylacetonitriie (purchased from Tokyo Kasei), 691 mg (5.00 mmole) of 3,4-dihydroxybenzaldehyde (purchased from Tokyo Kasei) and 10 ml of ethanol (purchased from Kokusan Kagaku) were added 0.54 ml of piperidine (purchased from Wako Junyaku Kogyo), the mixture was refluxed with heating for 6 hours and air-cooled, the reaction product was added to 100 ml of 1N hydrochloric acid, and deposits were filtered, washed with water, dissolved in ethyl acetate, washed with a 20% sodium hydrogensulfite solution twice and subsequently with saturated saline once and dried over sodium anhydrous sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified according to silica gel column chromatography (effluent with a ratio of hexane to ethyl acetate of 5:1 to 5:2 used) to obtain 919 mg (yield: 67.6%) of α-cyano-4-chloro-3',4'-dihydroxystilbene (yellow crystal) represented by the following formula: ##STR147##
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=2)=[O:22])=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:31](=[O:32])[CH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:14]2[CH:15]=[N:16][N:17]([CH3:18])[C:13]=2[C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1)[CH3:2]
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.9 %

Procedure:
A mixture of diethylamine (0.17 g), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ((2E)-N-{4-[2-(diethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.48 g, yield 62%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1ccc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.5 %

Procedure:
2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenol (20a) (357.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (21d) (546 mg, 80% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH:3]1[O:5][CH2:4]1.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[OH:5][CH:3]([C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:4][O:8][N:9]1[C:13](=[O:14])[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:19]
Reactant: CC(C)(C)C1CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)CON1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Yield: 13.9 %

Procedure:
To a solution of 3,3-dimethyl-1,2-epoxybutane (5.0 mL, 41.0 mmol) in DMF (100 mL) was added N-hydroxyphthalimide (8.03 g, 49.2 mmol) and triethylamine (6.90 mL, 49.2 mmol). The solution was heated at 75° C. for two days. The solution was cooled to room temperature, diluted with ethyl acetate and washed with water (2×), saturated potassium carbonate (3×), brine (2×), dried over Na2SO4 and concentrated to an orange solid. Purification using flash column chromatography (dichloromethane) provided the desired product as a white solid (1.50 g, 14%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[CH2:45]([CH2:49][C:50](=O)[CH3:51])[C:46]([CH3:48])=O>CO>[CH3:51][C:50]1[N:8]([CH:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:13][CH2:14]2)[C:46]([CH3:48])=[CH:45][CH:49]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(C)n1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide trifluoroacetic acid salt (as prepared in Example 35 Step B, 0.24 g, 0.4 mmol) in methanol (2 mL) was added DIEA (Aldrich, 0.21 mL, 1.2 mmol) and acetonylacetone (Aldrich, 0.06 mL, 0.5 mmol). The resulting mixture was stirred at rt overnight and the volatile organics were removed by evaporation. The residue was dissolved in water, extracted with EtOAc, dried over Na2SO4. Filtration and evaporation gave a crude product, which was purified by column chromatography (eluent: EtOAc) to give the cis isomer as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH:43]([CH3:47])[C:44](Cl)=[O:45].C(=O)(O)[O-].[Na+]>C1COCC1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:5]3[C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:2]4[NH:1][C:44](=[O:45])[CH:43]([CH3:47])[O:8][C:7]=4[N:6]=3)=[CH:14][CH:13]=2)[CH2:18][CH2:17][CH2:16]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c(N)cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of tert-butyl 1-(4-(5-amino-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutylcarbamate (0.5 g, 1.159 mmol) in THF (Volume: 20 ml) was added DIPEA (1.01 ml) followed by the addition of 2-chloropropanoyl chloride (0.235 g, 1.854 mmol) in THF (5 ml) in dropwise at 0 degree over 1 h. The resulted mixture was stirred at r.t. over night. Sodium bicarbonate saturated solution (30 ml) was added. The resulted mixture was heated to reflux for 16 h. The reaction mixture was cooled down to room temperature. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 ml). The organic phase was combined and washed with water (30 mlX2), brine (25 ml) then concentrated at reduced pressure. The residue was suspended in DCM (10 ml). The precipitate was collected by filtration and washed with DCM (5 ml) to afford product (439 mg). 1H NMR (500 MHz, CD3OD): 7.20-7.29 (m, 8H), 7.13-7.15 (m, 2H), 4.98 (q, 1H), 2.41-2.47 (m, 4H), 2.05 (m, 1H), 1.86 (m, 1H), 1.64 (d, 3H), 1.21-1.36 (br, 9H).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4](#[N:7])[CH:5]=[CH2:6].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[Na])CCC>O.C(O)C>[C:9]1([CH2:8][N:2]2[C:4]([NH2:7])=[CH:5][CH:6]=[N:3]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC#N
Reactant: NN
Agent: CCCCO[Na]
Solvent: CCO
Solvent: O
Product: Nc1ccnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydrazine hydrate (14.55 mL, 300 mmol) and ethanol (75 mL) was cooled in an ice water bath and then 2-propenenitrile (15.3 g, 288 mmol) was added dropwise. After stirring at room temperature for 2 h, benzaldehyde (31.8 g, 300 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 2 d. The solvent was removed under reduced pressure. The crude oil was cooled in an ice/water bath followed by dropwise addition of a n-BuONa solution (Na 6.9 g, (300 mmol) in n-Butanol (300 mL)). The reaction mixture was heated at reflux for 1 h, and then cooled to room temperature. The contents were poured onto 300 mL of water and then extracted with Et2O (2×200 mL). The ether phase was extracted with 1N HCl (3×100 mL). The combined HCl extracts were combined and cooled in a ice/water bath, followed by addition of 6N NaOH until basic (pH>12). The mixture was extracted with Et2O (4×100 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (eluent: 0 to 50% EtOAc:Hex). The final product was collected as 6.96 g (14%). LCMS E-S (M+H)=174.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.39 (br. s., 2 H), 5.23 (s, 2 H), 5.59 (d, J=1.77 Hz, 1 H), 7.17 (d, J=6.82 Hz, 2 H), 7.28-7.37 (m, 4 H)
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[S:14][CH3:15].N(CCO)CCO>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[S:14][CH3:15]
Reactant: COc1ccc(Cl)c(SC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: OCCNCCO
Product: CSc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.9 %

Procedure:
Boron tribromide (1M in dichloromethane, 31 ml, 31 mmol) was added dropwise to a solution of 1-chloro-4-methoxy-2-(methylsulfanyl)benzene (2.88 g, 15 mmol) in dichloromethane (80 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 72 h then cooled to 0° C. A solution of diethanolamine (10 ml) in dichloromethane (20 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then partitioned between dichloromethane and 2N hydrochloric acid. The organic phase was washed with water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 85:15) as eluant to give 4-chloro-3-(methylsulfanyl)phenol (2.12 g) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([C@@H:14]4[CH2:17][C@H:16]([N:18]5[CH2:25][C@@H:24]6[C@@H:20]([N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23]6)[CH2:19]5)[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:21]1[CH2:22][CH2:23][C@@H:24]2[CH2:25][N:18]([C@@H:16]3[CH2:17][C@H:14]([C:12]4[S:13][C:9]5[CH:8]=[C:7]([C:5]6[CH:4]=[N:3][CH:2]=[N:1][CH:6]=6)[CH:34]=[CH:33][C:10]=5[N:11]=4)[CH2:15]3)[CH2:19][C@H:20]12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN([C@H]3C[C@@H](c4nc5ccc(-c6cncnc6)cc5s4)C3)C[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ncc(-c2ccc3nc([C@H]4C[C@@H](N5C[C@H]6CCN[C@H]6C5)C4)sc3c2)cn1
Reaction time: 2 h

Procedure:
The title compound was prepared by mixing the product of Example 38B with 1:1 mixture of TFA and dichloromethane. After 2 hours, the solvent was removed under reduced pressure, the residue was basified with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 9.19-9.26 (s, 1H) 9.01 (s, 2H) 8.09 (d, J=8.54 Hz, 1H) 8.05 (d, J=1.53 Hz, 1H) 7.65 (dd, J=8.54, 1.83 Hz, 1H) 3.81-3.92 (m, 1H) 3.60-3.71 (m, 1H) 3.03-3.12 (m, 1H) 2.95-3.03 (m, 1H) 2.87-2.95 (m, 1H) 2.72-2.79 (m, 1H) 2.64-2.71 (m, 2H) 2.50-2.62 (m, 3H) 2.32-2.46 (m, 3H) 1.91-2.00 (m, 1H) 1.57-1.67 (m, 1H). MS: (M+H)+=378.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1nncc2ccc(Br)nc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2nc(Br)ccc2cnn1Cc1cccc(Cl)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-3,8-diazaisoquinoline (1.00 g, 4.46 mmol) using 3-Chlorobenzyl bromide (1.37 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Trituration with hexanes/ethyl acetate 10:1 will afford the desired product. Step 2): 2-(3-chlorobenzyl)-7-(3-phenylprop-1-ynyl)-2H-3,8-diazaisoquinolin-1-one
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:14]Br>C(O)(=O)C>[Br:14][CH:10]1[CH2:11][CH2:12][N:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:7][CH2:8][C:9]1=[O:13]
Reactant: O=C1CCCN(C(=O)C2CC2)CC1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CCN(C(=O)C2CC2)CCC1Br
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A solution of 1-Cyclopropanecarbonyl-azepan-4-one (2.7 grams, 14.9 mmol, obtained in above step) in acetic acid (30 mL) was cooled to 10° C. and treated with bromine (0.71 mL, 14.9 mmol) over a period of 15 minutes. The resulting slurry was stirred for 18 hours under nitrogen atmosphere. After completion of reaction, mass was concentrated to dryness to obtain the title compound (3.87 grams).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44](O)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.CN(C)C1C=CN=CC=1>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44]([O:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)CCCCCCCCCCCC(CC(=O)OCc1ccccc1)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of benzyl 3-hydroxy-15-methylhexadecanoate (1.77 g) and N-tertiarybutoxycarbonyl-L-phenylalanine (1.25 g) in dichloromethane (50 ml) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.08 g) and 4-dimethylaminopyridine (1.22 g). The mixture was stirred at room temperature for 14 hours and evaporated. The residue was poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give almost pure benzyl 3-(N-tertiary butoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoate, which can be used for next step without further purification (2.87 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]1([NH:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CC(O)C.C1COCC1>[C:15]1([NH:21][CH2:22][CH2:23][NH:24][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCNc1ccccc1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Oc1ccc([C@H]2CC[C@H](NCCNc3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(4-hydroxyphenyl)cyclohexanone (1.0 g, 5.3 mmol) in a mixture of 2-propanol (40 mL) and THF (20 mL) was added N-phenylethylenediamine (0.72 g, 5.3 mmol) and 3 Å molecular sieves. After 3 hours, sodium borohydride (0.27 g, 7.3 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with MeOH, filtered through celite, and the filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (silica, 95:5 CH2Cl2:MeOH) and converted to a maleate salt. Recrystallization from MeOH/Et2O gave trans-4-[4-(2-phenylamino-ethylamino)cyclohexyl]phenol (0.31 g, 14%), as yellow solid: mp 180-184° C.; IR (KBr): 3368, 2945, 2863, 1516 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.40 (br s, 2H), 7.15-7.00 (m, 4H), 6.70-6.55 (m, 5H), 6.02 (s, 2H), 5.65 (br s, 1H), 3.40-3.25 (m, 2H), 3.20-3.10 (m, 3H), 2.45-2.40 (m, 1H), 2.20-2.10 (m, 2H), 1.90-1.80 (m, 2H), 1.50-1.35 (m, 4H); API-MS (m/z): 311 [M+H]+; HPLC: method A, 7.38 minutes (99.1%); method B, 13.29 minutes (99.1%); Anal. Calcd for C20H26N2O.C4H4O4: C, 67.59; H, 7.09; N, 6.57. Found: C, 67.38; H, 7.01; N 6.55.