Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([NH:15][CH3:16])=[C:11]([C:17](N(OC)C)=[O:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([NH:15][CH3:16])=[C:11]([CH:17]=[O:18])[CH:10]=[N:9]2)=[CH:23][CH:24]=1
Reactant: CNc1c(C(=O)N(C)OC)cnn(Cc2ccc(OC)cc2)c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1c(C=O)cnn(Cc2ccc(OC)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-methoxybenzyl)-N-methoxy-N-methyl-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carboxamide (3) (4.60 g, 13.8 mmol) in THF (50.0 mL) was treated with 1.0 M LAH in THF (15 mL, 15 mmol) at −78° C. The mixture was stirred at 0° C. for 1 h then quenched carefully at 0° C. with MeOH (1.0 mL), followed by water (1.0 mL) and 1 M aq HCl (1.0 mL). The resulting suspension was filtered and the filtrate was concentrated in vacuo to give 1-(4-methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehyde as a pale yellow solid. MS (ESI, pos. ion) m/z: 274 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Product: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].[CH3:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:27].[CH2:35]([OH:39])[C:36](=[CH2:38])[CH3:37].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:27].[CH3:37][CH:36]([CH3:38])[CH:35]=[O:39]
Reactant: C=C(C)CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(=O)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)C=O
Temperature: 130 °C
Reaction time: 2 h

Procedure:
0.2 palladium acetate and 0.48 g triphenyl-phosphine were dissolved in 40 ml dimethylacetamide. Sodium bicarbonate (10 g), 4-bromoacetophenone (19.9g), methallyl alcohol (10.8 g), and diisopropylethylamine (1.0 g) were added and the mixture was heated to 130° C with stirring. After 2 hours, a 100% conversion of 4-bromoacetophenone to 3-Cp-acetylphenyl)-2-methylpropanal was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[NH:35](C(OC(C)(C)C)=O)[C@H:36]([C:42]([O:44]C(C)(C)C)=[O:43])[CH2:37][CH2:38][C:39](=O)[OH:40].Cl.C(N(CC)CC)C.[CH3:64][O:65][C:66]1[C:75]([NH2:76])=[CH:74][CH:73]=[CH:72][C:67]=1[C:68]([O:70]C)=[O:69]>ClCCl>[CH3:64][O:65][C:66]1[C:75]([NH:76][C:39](=[O:40])[CH2:38][CH2:37][C@@H:36]([C:42]([OH:44])=[O:43])[NH2:35])=[CH:74][CH:73]=[CH:72][C:67]=1[C:68]([OH:70])=[O:69]
Reactant: COC(=O)c1cccc(N)c1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)CC[C@H](N)C(=O)O)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
84 mg (0.2 mmol) of HATU, 30 mg (0.2 mmol) of HOAt, 61 mg (0.2 mmol) of Boc-Glu-OtBu hydrochloride, 0.084 mL (0.6 mmol) of triethylamine and 1 mL of dichloromethane were added to 36 mg (0.2 mmol) of methyl 2-methoxy-3-aminobenzoate, and stirred at room temperature overnight.
Reaction SMILES: [N+](=[C:3]([C:9]([O:11][CH:12]([C:17]([Cl:20])([Cl:19])[Cl:18])[CH:13]=[C:14]([CH3:16])[CH3:15])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-]>CCCCCCCC.[Cu]>[Cl:18][C:17]([Cl:20])([Cl:19])[CH:12]1[CH:13]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:14]2([CH3:16])[CH3:15])[C:9](=[O:10])[O:11]1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CCCCCCCC
Product: CCOC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C

Procedure:
To a refluxing suspension of copper powder (5.0 g, 0.079 mole) in 240 ml of n-octane was added dropwise in one hour a solution of ethyl (±)-3-methyl-1-trichloromethyl-2-butenyl diazomalonate (5.0 g, 0.0146 mole) in 60 ml of n-octane. The reaction mixture was then heated under reflux for 21/2 hours and filtered. The n-octane was removed from the filtrate by evaporation under vacuum, yielding a residue which was distilled under vacuum to give ethyl (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo-[3.1.0]hexane-1-carboxylate as a highly viscous oil (2.47 g, 54% yield); bp, 123°-125°/0.3 mm.
Reaction SMILES: Br[CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][C:2]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(Br)Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1nc(N)sc1Cc1ccccc1
Yield: 15.1 %

Procedure:
Ethyl 3-bromo-2-oxo-4-phenylbutanoate (5.8 g) was dissolved in EtOH (110 ml), and then thiourea (3.1 g) was added to the solution. The reaction mixture was refluxed for 2 hours under N2 atmosphere. The cooled reaction mixture was evaporated in vacuo. The residual solid was suspended (pH=8) in saturated NaHCO3 and water. The solid was collected by filtration, and purified by flash column chromatography over silica gel with CHCl3/MeOH (10:1) as an eluent to give ethyl 2-amino-5-benzyl-1,3-thiazole-4-carboxylate (808.2 mg) as a yellow wax.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:42])(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([F:42])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(F)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (135 mg, 0.361 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., and N-fluorobenzenesulfonimide (1.5 equiv) was added in one portion. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl fluoride, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (31 mg, 22%): 1H NMR (CDCl3, 500 MHz) 7.37-7.34 (m, 2H), 7.27-7.24 (m, 3H), 6.36 (d, 1H, J=9.0 Hz), 4.71 (t, 1H, J=7.2 Hz), 2.68 (t, 2H, J=7.8 Hz), 1.94-1.86 (m, 2H), 1.71-1.66 (m, 2H), 1.51-1.43 (m, 6H), 0.96 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.6 (d, J=292 Hz), 143.2, 128.8, 128.7, 126.0, 99.1 (d, J=12.8 Hz), 69.2, 36.4, 36.3, 31.8, 29.5, 29.5, 26.1, 25.4, 18.6, −4.7, −4.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[Br:15][C:10]1[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:7]2[NH:6][C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: O=[N+]([O-])O
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)cc2c1[nH]c1ccc(Br)cc12
Temperature: 0 °C

Procedure:
Acetic acid (600 ml) and 3,6-dibromocarbazole (45 g) was placed into a one liter three-necked RB flask equipped with a reflux condenser, mechanical stirrer, and heating mantle. The stirred solution was heated to reflux at which time a solution of nitric acid (10 ml, density 1.4 g/cc, 0.156 mole in 100 ml of acetic acid) was added over a period of 30 minutes. After 2/3 of the nitrating mixture was added, a flocculent yellow precipitate deposited. The remainder of the nitrating mixture was added and the whole refluxed gently for one hour, cooled to 0° C. in an ice bath and filtered. The crude yellow precipitate softens at 232° C. and melts at 243°-246° C. The crude product was recrystallized from boiling acetonitrile to give yellow crystals with m.p. 252°-256° C. (uncovered), 256°-260° C. (covered). [H. Lindemann & F. Muhlhaus, Ber., 58, 2371 (1925) report a m.p. of 260° C. for the product].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([F:26])[CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH3:23])[N:12]=[CH:11][C:10]([C:24]#[N:25])=[C:9]2[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:26]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1N
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A mixture of 500 mg (1.34 mmol) 4-[(4-chloro-2-fluorophenyl)amino]-7-methoxy-6-nitro-3-quinolinecarbonitrile, 20 ml ethanol and 1.52 ml (6.71 mmol) tin chloride dihydrate was heated to reflux under N2. At 3 hours, removed heat, added ice water and made basic with sodium bicarbonate. Stirred for several hours and extracted with chloroform. Dried organic layer with sodium sulfate, stripped solvent and dried in vacuo, giving 350 mg of green solid: mass spectrum (electrospray m/e): M+H=342.9, 344.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13]O)[S:10][N:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: OCc1nc(-c2ccc(Cl)cc2)ns1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 75.3 %

Procedure:
To a solution of [3-(4-chlorophenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.25 g, 1.10 mmol) in toluene (8 ml) was added PBr3 (0.17 ml, 1.65 mmol). The resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 2% EtOAc-Hexane) to get the desired product (0.24 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C.Br[C:33]1[CH:41]=[CH:40][CH:39]=[C:35]([C:36]([O-:38])=O)[C:34]=1[C:42]([O-:44])=O.[I-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH:42]4[C:34]5[C:35](=[CH:39][CH:40]=[CH:41][CH:33]=5)[C:36](=[O:38])[O:44]4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: O=C([O-])c1cccc(Br)c1C(=O)[O-]
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC1=C(C(=O)OC2OC(=O)c3ccccc32)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) in N,N-dimethylformamide (15 ml) were added triethylamine (0.55 g), 3-bromophthalate (1.2 g) and sodium iodide (0.82 g) in turn in a stream of nitrogen, and the mixture was stirred at ambient temperature for half an hour. After the reaction mixture was poured into a mixture of ethyl acetate (300 ml) and water (200 ml), the organic layer was separated out, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, followed by treating with charcoal. After the filtrate was concentrated and thereto was added diethyl ether. The precipitated substance was collected by filtration to obtain phthalid-3-yl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: [C:1]([C:9]1([OH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22]O.OS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][O:16][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:18])=[O:17]
Reactant: CC(C)CCO
Reactant: O=C(O)C1CCCCC1(O)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)CCOC(=O)C1CCCCC1(O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
10 g (0.04 mol) of 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid (of example 1), 7.05 mol 3-methyl-butan-1-ol and 0.5 g H2SO4 are dissolved in 200 ml CHCl3 and heated to reflux during 18 hours using a water separator to remove the water formed during the reaction. The reaction mixture is then cooled to room temperature, washed with sodium bicarbonate and water and dried over Mg2SO4. After distillation of the solvent, the crude reaction product is purified by flash chromatography (silica gel, eluant petroleum ether/ethyl acetate 1:1) to give 3 g 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid 3-methyl-butyl ester as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([CH3:28])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:40])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(F)ccc1C(c1ccc(F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65 mg (0.17 mmol) of the compound from Example 101 were introduced into 8 ml of dichloromethane at 0° C., 41 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 67 mg (99% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:15]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (12 g, 0.3 mol, 60% in mineral oil) in 600 ml toluene and 400 ml dimethyl formamide was added 2,6-dihydroxynaphthalene (80 g, 0.5 mol) and the mixture was heated to reflux over a thirty minute period. Benzyl chloride (65 ml, 71.5 g, 0.56 mol) was added dropwise and the mixture was refluxed for 10 hours. After cooling to room temperature, the mixture was washed 6 times with water to remove the dimethyl formamide. The resulting toluene solution was washed twice with 150 ml 0.5N Sodium hydroxide to remove unreacted starting material and then with water and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated to 150 ml. The solid which had crystallized was collected by vacuum filtration and washed with a small amount of toluene to yield 2-benzyloxy-6-hydroxynaphthalene.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([CH2:19][C:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][C:22]([OH:24])=O)=[CH:11][C:10]=1[Cl:35].[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44][C:43]2=[O:52])[CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([CH2:19][C:20]([CH2:21][C:22](=[O:24])[N:36]2[CH2:37][CH2:38][CH:39]([N:42]3[CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[NH:44][C:43]3=[O:52])[CH2:40][CH2:41]2)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][C:10]=1[Cl:35]
Reactant: CCOC(=O)C(CC(=O)O)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 mL (23.0 mmol) of triethylamine were added dropwise to a solution of 8.00 g (19.0 mmol) of 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid, 4.39 g (19.0 mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, 6.00 g (18.0 mmol) of TBTU and 2.75 g (18.0 mmol) of HOBT in 100 mL of THF and the mixture was stirred for 16 h at RT. The solid formed was filtered off, washed with diethyl ether and dried i. vac.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C:8]([N:19]1[C:27]2[C:22](=[C:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[BH4-].[Na+]>COCCOC>[C:32]([O:31][C:29]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:8]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH2:9][OH:10])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a mixture of the product of step B (1.5 g, 2.9 mmol) and NMM (590 mg, 5.83 mmol) in DME (15 mL) was added isobutyl carbonochloridate (793 mg, 5.83 mmol) dropwise at 0° C. After stirring for 30 min. NaBH4 was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for another 1 h, and then quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE:EA=3:1) to afford the title compound as colorless oil. LC/MS m/z=501.2[M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:29][CH3:30])[C:11]=2[CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[CH:6]=1)=[O:4].[OH-].[K+].CO.Cl>C1COCC1.O>[CH3:30][O:29][C:10]1[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2c(CNCc3ccc(OC(F)(F)F)cc3)c(OC)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(OC(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a stirred solution of 6-methoxy-5-({[4-(trifluoromethoxy)-benzyl]amino}methyl)-2-naphthoic acid methyl ester (0.286 g, 0.682 mmol) in THF (1.00 mL) at rt was added 1 N KOH (0.682 mL, 0.682 mmol) dropwise. Enough MeOH (˜0.500 mL) was added to make reaction homogeneous. After 1 h at this temperature, the reaction was heated to 45° C. for 2 h. The solution was diluted with H2O (˜2-3 mL) and then acidified to pH 1 with 2 N HCl. The resulting solid was filtered off, washed with H2O and hexane, and dried on the high vacuum for 18 h to afford the product (0.207 g, 69%) as a white solid, mp 235-237° C.; 1H NMR (DMSO-d6) δ3.94 (s, 3H), 4.33 (s, 2H), 4.52 (s, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.59 (d, J=9.2 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.99 (d, J=9.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.60 (s, 1H), 9.14-9.37 (bs, 2H), 12.71-13.25 (bs, 1H); IR (neat) 2520-3100, 1715, 1685, 1630, 1600, 1575, 1510, 1485, 1455, 1295, 1270, 1265, 1210, 1200, 1165, 1110, and 1100 cm−1; mass spectrum [(+) ESI], m/z406 (M +H)+ and [(−) ESI], m/z 404 (M−H)−; Anal. Calcd. for C21H18F3NO4.HCl.0.1H2O: C, 56.86; H, 4.36; N, 3.16, Found: C, 56.45; H, 4.18; N, 3.09.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:2]1.[CH2:29]([Zn])C.ICI.Cl.N>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@@H:10]2[CH2:29][C@H:11]2[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:26])([F:28])[F:27])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:2]1
Reactant: C[C@@H](NC(=O)/C=C/c1c[nH]c2ccccc12)c1ccc(OCC(F)(F)F)cn1
Reactant: CC[Zn]
Agent: Cl
Agent: N
Solvent: ICI
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]1c1c[nH]c2ccccc12)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 3 %

Procedure:
To a solution of (R,E)-3-(1H-indol-3-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide (600 mg, 1.3 mmol) in dichloromethane (10 mL) was added ethylzinc (4.1 mL, 4.1 mmol, 1.0 M) at room temperature. After being stirred at room temperature for 3 min, diiodomethane (1.8 g, 6.7 mmol) was added to the mixture. The mixture was refluxed at 55° C. with stirring for 18 hours. sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=1/1 (v/v) and preparative LC-MS to give 14 mg, (3% yield) of the title compound as a white solid (2:1 mixture of the diastereomers).