Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.CCN(CC)CC.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=C(NCc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
By the method described in Example 18, the title compound of Example 2 in CH2Cl2 with molecular sieves #5A and Et3N was reacted with 4-(aminomethyl)pyridine to generate the free base of the title product. This material was converted to the title compound by the method described in Example 40.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:8]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].[OH-].[K+]>CS(C)=O.CCOCC>[CH2:17]([N:7]1[CH:8]=[C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])[N:5]=[C:6]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: COC(OC)c1c[nH]c(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-dimethoxymethyl-2-phenyl-1H-imidazole 208 (2.18 g, 10 mmol) and n-butyl bromide (2.74 g, 20 mmol) in anhydrous DMSO (15 mL) is added to a suspension of powdered potassium hydroxide (0.96 mg, 15 mmol) in DMSO (20 mL) at room temperature over 3 h. The mixture is then stirred at rt for 16 h. The mixture is diluted with ether and washed with water (three times), brine, and dried over anhydrous sodium sulfate. Removal of the solvent and purification of the residue affords the desired product. Yield: 2.5 g; LC-MS (MH+): 275.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=[O:18])(C(C)(C)C)(C)C.I[CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+].O.[CH:31]1[CH:36]=CC=[CH:33][CH:32]=1>>[CH2:20]([C:12]1([CH2:36][CH2:31][CH2:32][CH3:33])[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[OH:8])[C:13]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCCCC1(CCCC)Cc2c(O)cccc2C1=O

Procedure:
A mixture of 4-(tert-butyldimethylsilyl)oxy-1-indanone (524 mg), 1-iodobutane (0.91 ml), and potassium tert-butoxide (896 mg) in dry benzene (15 ml) was refluxed for 2 hours under nitrogen. The reaction mixture was allowed to cool and poured into water. The separated oil was extracted with ethyl acetate. The organic layer was washed with brine, and concentrated in vacuo. The residue was subjected to column-chromatography on silica gel (elution by 10% n-hexane in dichloromethane and then dichloromethane) to yield 2,2-dibutyl-4-hydroxy-1-indanone (150 mg) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1>[Pd].C(Cl)Cl.CO.[H][H]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1
Reactant: Cc1cc(-c2cc3cc([N+](=O)[O-])ccc3n2C)ccc1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2cc3cc(N)ccc3n2C)ccc1C#N

Procedure:
Prepared analogously to Example 1c from 4-(1-methyl-5-nitro-1H-indol-2-yl)-methyl-benzonitrile, palladium on activated charcoal in methylene chloride/methanol and hydrogen.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:24])[C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=3)=[O:20])=[CH:17][CH:16]=2)=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Product: CCCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCCC)cc3)cc2)cc1

Procedure:
Propyl p-hydroxybenzoate and terephthalic dichloride are allowed to react in a similar procedure to Example 5. The reaction product is recrystallized from hexane-chloroform (1:1) to yield di(p-propoxycarbonylphenyl)terephthalate, m.p. 136°-139° C., as white crystals.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCCC1>[CH2:10]([O:17][C:18]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-aminobutyric acid (0.52 g), 2 mol/L aqueous sodium hydroxide solution (10 mL) and tetrahydrofuran (10 mL) was added benzyloxycarbonyl chloride (1.07 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue (solid) was treated with n-hexane. The crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-benzyloxycarbonylaminobutyric acid (0.59 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 1,1′-carbonylbis-1H-imidazole (0.59 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethylether. The insoluble material was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 3-benzyloxycarbonylaminobutyramide (0.54 g). The obtained 3-benzyloxycarbonylaminobutyramide (76 mg) was dissolved in methanol (3 mL). To the solution was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (32 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH:12]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH:12]1([N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(C2CCCCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C3CCCCCCC3)CC2)cc1

Procedure:
1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8 g, 183 mmol) dissolved in methanol (200 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.36 g (32%); white powder; mp 180° C.; MS: 410 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:11])[C:5]([CH3:10])=[CH:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>O.CCO>[CH3:10][C:5](=[CH:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:11])=[O:3]
Reactant: CCOC(=O)C(C)=CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=CC(C)C)C(=O)O
Yield: 99.1 %

Procedure:
A mixture of 2,4-dimethylpent-2-enoic acid ethyl ester (116 g, 742 mmol) and KOH 85% (147 g, 2.23 mol) in water/EtOH (1:1, 2.0 L) was refluxed for 1 d. The EtOH was stripped off on a rotary evaporator, and the remaining mixture was washed with Et2O. The combined ethereal washings were extracted with 2 N aq. NaOH (100 ml), and all aqueous solutions were combined. Under cooling with an ice/water bath, conc. aq. H3PO4 (200 ml) was added to adjust the combined aqueous solutions to pH 3, and the product was extracted with Et2O (200 ml). The ethereal solution was washed with water (200 ml) and brine (25 ml). After drying (Na2SO4), the solvent was evaporated in a rotary evaporator to furnish 94.2 g (99%) of 2,4-dimethyl-pent-2-enoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:21][C:22]([O-])=[O:23].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:27]([O:26][C:20](=[O:25])[CH2:21][C:22]([NH:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
The compound (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.8 g, 6.6 mmol, see procedure 4a) was dissolved in 32 mL of 2:1 CH2Cl2/DMF. The resultant solution was charged sequentially with mono-benzyl malonate (1.28 g, 6.6 mmol), N,N-diisopropylethylamine (5.8 mL, 33 mmol) and HATU (3.0 g, 7.9 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid benzyl ester (2.3 g, 77% yield). A portion (860 mg) of this material was dissolved in 10 mL of THF. The resultant solution was charged with 30 mL of acetic acid, heated at 65° C. for 3 h, and concentrated in vacuo. The residue was purified by flash chromatography to provide (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid benzyl ester (343 mg, 54% yield). MS found: (M+H)+=335.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>CC(O)CCC.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To the solution of (E)-1-chloro-4-(4-(2-nitrovinyl)phenoxy)-2-(trifluoromethyl)benzene (640 mg, 1.862 mmol) in 2-pentanol (5 mL) and chloroform (15.00 mL) was added silica-gel (2 g), and then NaBH4 (282 mg, 7.45 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was purified via a flash column affording the title compound (330 mg, 49.2% yield). LCMS: rt=4.62 min, [M+H+]=NA
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[NH2:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:19]=1[C:20]([NH2:22])=[O:21]>O1CCCC1.O>[C:8]([NH:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:12])[CH:9]([CH3:11])[CH3:10]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 119 %

Procedure:
0.260 cm3 (1.86 mmol) of triethylamine and 0.098 cm3 (0.93 mmol) of isobutyryl chloride are added, at a temperature close to 25° C., to a solution of 0.23 g (0.93 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 15 cm3 of tetrahydrofuran. After stirring for 16 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 60 cm3 of water and then extracted with twice 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.35 g of 2-isobutyrylamino-4-(4-nitro-phenyl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 15 (d, J=7.0 Hz, 6H); 2.64 (m, 1H); from 6.50 to 8.50 (very broad m, 2H); 6.79 (d, J=2.5 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 8.19 (d, J=9.0 Hz, 2H); 10.45 (broad s, 1H); 11.65 (broad s, 1H).
Reaction SMILES: [OH:1][C@:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH:22]=[C:21]([CH2:36]OS(C)(=O)=O)[CH:20]=3)=[CH:17][N:18]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[N-:42]=[N+:43]=[N-:44].[Na+]>CN1C(=O)CCC1>[N:42]([CH2:36][C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C@@:2]3([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:12])([CH3:13])[CH2:3]3)=[N:18][CH:17]=2)[CH:24]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:22]=1)=[N+:43]=[N-:44]
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN=[N+]=[N-])cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
A solution of the product of Step 1 (250 mg, 0.407 mmol) in anhydrous NMP (5 ml) was treated with sodium azide (132 mg, 2.034 mmol, 5.0 equiv) and stirred at 23° C. for 18 h. The reaction was partitioned between EtOAc (2×75 ml) and water (85 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl(1S,4R)-4-{5-[3-(azidomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (220 mg, 96%), as an orange oil. MS ESI: [M+H]+ m/z 562.1
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:16])[CH3:15]>>[CH2:14]([O:16][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH3:15]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCO
Agent: [Na]
Product: CCOc1nsnc1-c1cccnc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in ethanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (540 mg, 3.3 mmol). The mixture was stirred at 40° C. for 10 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 520 mg (76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)([CH3:12])[C:7](=[O:20])[C:6]([C:21](OCC)=[O:22])=[C:5]2[OH:26].Cl.[C:28]([O:32][C:33](=[O:36])[CH2:34][NH2:35])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:19][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[C:8]([C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:12])[C:7](=[O:20])[C:6]([C:5]([NH:35][CH2:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:36])=[O:26])=[C:21]2[OH:22]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(c2ccc(Cl)cc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(c2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A solution of ethyl 6-chloro-1-(4-chlorophenyl)-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (0.998 g, 2.55 mmol), glycine tert-butyl ester hydrochloride (0.513 g, 3.06 mmol), and DIPEA (0.889 mL, 5.10 mmol) in 1,4-dioxane (15 mL) in a 75 mL sealed vessel was stirred at 120° C. for 3 hours. The solution was diluted with deionized water (75 mL) and extracted with DCM (2×50 mL). The combined organic layers were then washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo to give 1.42 g crude product. The crude product was purified by flash column chromatography (silica, 0-25% DCM in hexane) to give the title compound (0.888 g). MS m/e=420 (M+H-tBu)+.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.[CH2:14]([O:16][C:17](=O)[O:18]CC)[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]([CH:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13])=[O:18])[CH3:15]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2ccccc2C1=O
Yield: 64 %

Procedure:
To a stirred suspension of NaH (11 g, 274 mmol, 60% in oil) in toluene was added dropwise 1-tetralone (20 g, 137 mmol) in toluene (50 mL). After the complete addition, the mixture was heated at reflux for 1 h. Then at 60° C. diethylcarbonate was added (24 g, 137 mmol) dropwise and the mixture was again heated at reflux for 2 h. The reaction was quenched with aqueous HCl (4N, 100 mL) and dilute with H2O. Ether (200 mL) was added for the extraction, the organics were dried and concentrated to oil. Distillation (100° C. at 0.1 mm Hg) gave the title compound (19.1 g, 64%). 1H NMR (CDCl3, 200 MHz): δ 1.34 (t, 3H, J 7.0 Hz), 1.38 (t, 3H, J 7.0 Hz), 2.20-3.10 (m, 4H), 3.59 (1H, dd, J 7.0 Hz J 10.0 Hz), 4.24 (1H, q, J 7.0 Hz), 4.28 (q, 1H, J 7.0 Hz), 7.29 (m, 3H), 7.78 (m, 1H), 8.01 (m, 1H), 12.5 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ 14.1, 14.2, 20.5, 26.36, 27.5, 27.7, 54.5. 60.4; 61.1; 96.9. 124.2, 126.5, 126.7, 127.2, 127.6; 128.7, 130.0, 130.4. 131.8. 133.7, 139.3, 143.6. 165.0, 170.1, 172.6, 193.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:32])=[O:38])=[CH:27][CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)Cc1ccc(OCc2ccccc2)cc1)c1ccc(SC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)Cc1ccc(OCc2ccccc2)cc1)c1ccc(S(C)=O)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 1.34 g (2.98 mmols) of ethyl N-(2-(4-benzyloxyphenyl)acetyl)-N-(4-methylthiophenyl)glycinate (VIIq) in 25 mL dry dichloromethane (CH2Cl2) was added 1.05 equivalents of m-chloroperoxybenzoic acid at 0° C. After stirring for 30 min., the solution was poured into 200 mL of saturated NaHCO3 solution containing 10 mL of 10% NaHCO3 solution and was extracted with two 100 mL portions of CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated to give 1.40 g (ca. 100% yield) of the sulfoxide (VIIt) was an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Cc1ccc(O)c(N)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
2-Amino-4-methylphenol (1.15 g, 9.34 mmol) was added to a solution of 4-bromophenyl isothiocyanate (2.00 g, 9.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for 16 h. Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and then added to a silica pad and purified using 1:5 ethyl acetate:heptane (2 L) followed by diethyl ether as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a light brown solid (2.30 g, 81%);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S(OC1C2C(=CC=C(C(OCC[Si](C)(C)C)=O)C=2)C=NC=1)(=O)=O.C(N(CC)CC)C.[CH3:61][N:62]([CH3:66])[C:63](Cl)=[O:64]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:61][N:62]([CH3:66])[C:63]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:64]
Reactant: CN(C)C(=O)Cl
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(O)cc3)c2c1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(-c2cncc3ccc(C(=O)OCC[Si](C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Into dichloromethane (6.5 mL), 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)isoquinoline-6-carboxylate (234 mg, 0.64 mmol) synthesized from 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate by the same method as in Example 8 (8a) was dissolved, to which triethylamine (178 μL, 1.28 mmol), 4-dimethylaminopyridine (23 mg, 0.19 mmol) and N,N-dimethylcarbamoyl chloride (88 μL, 0.96 mmol) were added, followed by stirring at room temperature for three hours. The resulting reaction liquid was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (260 mg, yield 93%).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C>CO>[N:15]1([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), piperidine (5.84 g, 68.7 mmol) and acetic acid (2.75 g, 45.8 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (400 g) eluting with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the desired intermediate as a clear oil (2.48 g, 54%). MS (APCI+) m/z: 201 (M+H)+.