Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH:7]([C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)[CH2:6]2.[CH2:32]([NH2:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:32]([NH:38][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH:7]1[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: COc1ccc(C2Cc3cc(OC)ccc3C2CCCCCCCCCC(=O)O)cc1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)CCCCCCCCCC1c2ccc(O)cc2CC1c1ccc(O)cc1

Procedure:
The process described in Example 1 was repeated using 10-[(1RS, 2RS)-5-methoxy-2-p-methoxyphenylindan-1-yl]decanoic acid and n-hexylamine as starting materials. There was thus obtained as an oil N-n-hexyl-10-[(1RS, 2RS)-5-hydroxy-2-p-hydroxyphenylindan-1-yl]decanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:22]2[CH2:24][CH2:23]2)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH:22]1([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)[N:8]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
The solutions of 3.6 g (10.7 mmol) of 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 27D]) in 40 ml of ethanol and of 1.07 g (26.7 mmol) of sodium hydroxide in 5 ml of H2O were mixed and then refluxed for 1 hour. After cooling to ambient temperature, 6.7 ml of 4N aqueous hydrochloric acid was added. The reaction mixture was extracted with three portions of ethyl acetate. The combined organic phases were washed with water and brine and dried over anhydrous sodium sulfate. The 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid crystallized upon concentrating the solution by evaporation. After cooling in an ice bath, 3.08 g of white crystals were obtained (84% of theory).
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([O:22][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(oc3cc(O)ccc13)C(=Cc1ccccc1)CC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3c(oc2c1)C(=Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one (1.5 g) was reacted with ethyl 2-bromo-acetate (1.67 g) in dimethylformamide (60 ml), in the presence of anhydrous K2CO3 (1.38 g), under stirring at room temperature for 3 hours. The reaction mixture was diluted with ice water containing NaH2PO4 and the precipitated product was filtered and washed with water: crystallization from CH2Cl2 /methanol gave (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)acetic acid, ethyl ester, m.p. 152°-154° C. (1.75 g), which was dissolved in dimethylformamide (22 ml) and treated with 2N NaOH (11.5 ml) at room temperature for 2 hours. The reaction mixture was acidified with 2N HCl and then diluted with ice water: the precipitated product was filtered and washed with water until neutral. Crystallization from CHCl3 /ethanol gave 1.4 g of (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1 ]benzopyran-6-yloxy)-acetic acid, m.p. 277°-279° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.C[C:17](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:18]>C(O)=O>[CH:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(C)ON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O=CO
Product: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhyddride (7.6 g.) and formic acid (3.4 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 3.75 g.), mp. 168° to 169° C. (dec.).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:16][C:17](CCl)=[CH2:18]>CO>[CH2:18]([S:14][CH2:11][CH:12]=[CH2:13])[CH:17]=[CH2:16].[C:5]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Oc1ccc(-c2ccc(S)cc2)cc1
Reactant: C=C(CCl)CCl
Solvent: CO
Product: C=CCSCC=C
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of MeOH at 0 C under N2 was added Na metal (1.03 g, 45 mmol). The reaction was slowly allowed to warm to room temperature. 4-hydroxy-4′mercaptobiphenyl (8.0 g, 40 mmol) was added to the reaction, and the reaction was heated to reflux. 3-chloro-2-chloromethyl propene (2.25 g, 18 mmol) was added dropwise over an hour, and the reaction was allowed to reflux overnight. The solution was reduced in vacuo and purified by flash chromatography 20:80 acetone/hexanes to yield 3.92 g of the pure allyl sulfide. Yield 47.7%. 1H NMR (400 MHz, DMSO-d6, δ): 9.56 (s, 2H, Ar—OH), 7.46 (m, 8H, Ar—H), 7.33 (m, 4H, Ar—H), 6.82 (m, 4H, Ar—H), 5.06 (s, 2H, C═CH2), 3.8 (s, 4H); 13C NMR (400 MHz, DMSO-d6, δ): 157.13 (C1), 139.57 (C10), 137.92 (C5), 133.15 (C8), 129.97 (C4), 129.52 (C7), 127.43 (C3), 126.24 (C6), 116.55 (C11), 115.71 (C2) 36.89 (C9); MS (ESI, m/z): [M−H]− calcd for C28H24O2S2, 455.1; found, 455.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:25][O:26][C:27]1[CH:49]=[CH:48][C:30]([CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][O:32][C:33]2[CH:38]=[C:37]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:36]=[N:35][CH:34]=2)=[CH:48][CH:49]=1
Reactant: COc1ccc(COc2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ccc(COc2cncc(-c3nc(N4CCOCC4)c4sc(CN5CCN(C)CC5)cc4n3)c2)cc1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-(4-methoxy-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 2-[5-(4-methoxy-benzyloxy)-pyridin-3-yl]-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then reacted with trifluoroacetic acid in dichloromethane to give the desired compound.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15]4=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]4[CH:17]=[CH:18][N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nccnc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CN=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of 3-[4-(cyclohexyloxy)phenyl]pyrazin-2-amine (470 mg) in THF (dry) (25.00 mL) was added to a mixture of NaH (60%, 349 mg) and 2-chloroethanesulfonyl chloride (853 mg) in THF (dry) (25 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and THF was removed in vacuo. A precipitate was collected by filtration and washed with water-Et2O to give the title compound (522 mg) as a yellow solid. The solid was crystallized from CH3CN-IPE to give a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:35])N(C(OCC)=O)[C:24]2=[O:29])([O-:19])=[O:18]>O>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:35])[N:1]([CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:24]2=[O:29])([O-:19])=[O:18]
Reactant: CCOC(=O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reaction time: 3 h

Procedure:
To a stirred solution of glutamic acid (10 mmol) and sodium carbonate (10.5 mmol) in water (50 mL) is added ethyl 4-nitro-1,3-dioxoisoindoline-2-carboxylate (10 mmol). The resulting mixture is stirred for 3 hours. The mixture is filtered. The filtrate is then acidified to pH 1 with 4 N hydrochloric acid to afford the 1-(4-nitro-1,3-dioxoisoindolin-2-yl)propane-1,3-dicarboxylic acid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:15]3([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:19][CH2:20]3)[C:30](=[O:35])[CH2:31]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Triethylamine (400 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (440 mg) obtained in Reference Example 11 in dichloromethane (15 ml), 4-bromobenzenesulfonyl chloride (255 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, the material was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (403 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12](C(C)=C)[C:11]3=[O:22])[C:4]=2[CH:3]=1.CO.O.Cl>C(Cl)Cl.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:22])[C:4]=2[CH:3]=1
Reactant: C=C(C)n1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1Cc1csc2ccc(Cl)cc12
Temperature: 80 °C
Yield: 89.6 %

Procedure:
1-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (0.53 g, 1.56 mmol) was treated with MeOH (5 mL) followed by water (5 mL). To this heterogeneous reaction mixture was added 37% hydrochloric acid (4 mL). This heterogeneous reaction mixture was heated to 80° C. for 30 min. A white solid was precipitated out. TLC indicated that reaction was complete (starting material Rf 0.8, product Rf 0.4, CH2Cl2:MeOH 95:5). The reaction mixture was diluted with CH2Cl2 (at this point a white precipitate was completely soluble in CH2Cl2) and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.44 g (89%) of the desired product as a white solid. This product was used for the next reaction without further purification. LCMS (ESMS): m/z 315.79 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([CH3:41])(=[O:40])=[O:39]>>[F:16][C:17]1[C:18]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3S(C)(=O)=O)c2)OC1(C)C
Product: CS(=O)(=O)c1ccccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 32.6 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-(2-fluoro-2′-(methanesulfonyl)biphenyl-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (105 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(6-fluoro-2′-methanesulfonylbiphenyl-3-yl)-2-trifluoromethyl[1,8]-naphthyridine (32 mg, 33%). δH (360 MHz, CDCl3) 2.97 (3H, s), 7.38-7.46 (2H, m), 7.54-7.74 (5H, m), 7.87 (1H, d, J 8.4), 8.26 (1H, dd, J 1.2 and 7.9), 8.79 (1H, d, J 8.4), 9.27 (1H, d, J 4.2). m/z (ES+) 447 [MH]+.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@@H]1[C@@H](C2C=CC=CC=2Cl)OC(CC)(CC)O1)(=O)C(C)(C)C>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:14]1[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11][C@@H:10]1[CH2:9][CH2:8][OH:7]
Reactant: CC(C)(C)C(=O)OCC[C@H]1OC2(CCCC2)O[C@@H]1c1ccccc1Cl
Agent: CCC1(CC)O[C@H](c2ccccc2Cl)[C@@H](CCOC(=O)C(C)(C)C)O1
Product: OCC[C@H]1OC2(CCCC2)O[C@@H]1c1ccccc1Cl
Yield: 80 %

Procedure:
The substantially same method as described in Example 358 was conducted, except that 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 359) was used instead of that 2-((4R,5R)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 357), to obtain the title compound (0.5 g, 80˜95%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][N:24]1[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccccc1NC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.4 %

Procedure:
A mixture of 15.5 g of 2-(tert-butoxycarbonylaminomethyl)aniline, 15 g of N-t-butyloxycarbonyl-4-piperidone, 250 mL of 1,2-dichloroethane, 4.2 mL of glacial acetic acid and 25 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Drying overnight under vacuum gave 30.1 g of tert-butyl (2-(tert-butoxycarbonylaminomethyl)anilino)piperidine carboxylate as a solid: 1H NMR (400 MHz, CDCl3) 7.19 (t, 1H), 7.0 (d, 1H), 6.6 (dd, 2H), 4.94 (br s, 1H), 4.75 (br s, 1H), 4.23 (br m, 2H), 4.0 (br m, 2H), 3.45 (br m, 1H), 3.0 (br m, 2H), 2.0 (br m, 2H), 1.82 (br m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C:6]1=[O:17])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.CCOCC>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C@H:6]1[OH:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(=O)C(NC(C)=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)[C@@H](O)[C@H](NC(C)=O)CC2
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred solution of 2-acetamido-7-methoxy-3,4-dihydronaphthalen 1(2H)-one in absolute ethanol (100 ml) was added sodium borohydride (1.6 gms, 0.04 m) in portions. After stirring for 1/2 hour, acetic acid was added to decompose any excess sodium borohydride. The reaction mixture was poured onto water (150 ml) and this was extracted with ethyl acetate (3×150). The ethyl acetate was washed with aqueous saturated sodium chloride, and was dried over anhydrous sodium sulfate. After filtration, the ethyl acetate was removed under reduced pressure (20 mm) to give a semisolid. The solid was slurried with ether and filtered to yield 3.3 gms (35%) of product as a white solid, m.p. 135°-140° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(=O)=O.[Co:8]>O>[OH2:3].[Co:8].[C:1]([O-:4])(=[O:3])[CH3:2].[Co+2:8].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Agent: [Co]
Agent: O=C=O
Solvent: O
Product: CC(=O)[O-]
Product: [Co+2]

Procedure:
The oxidation zone consisted of a vertical, glass tube oxidizer 60 inches (152.4 cm) in length and 2 inches (5.1 cm) in diameter having a capacity of 3.7L and equipped with inlets at the base for feeding air and the hydrolysis zone effluent. The top of the oxidizer was equipped with, in order, a heater exchanger for condensing acetic acid and water from the oxidizer vapor effluent, a vapor/liquid separator, a pressure-regulating valve, a trap cooled to -67° C. by dry ice (solid carbon dioxide) and a scrubber. The oxidizer is charged initially with an acetic acid solution containing 5 weight percent water and 0.3 weight percent cobalt, provided as cobalt hydrate or cobalt acetate. The oxidizer is heated to 130° C. by means of an electric heating cable and pressurized with air which was sparged to the bottom of the oxidation vessel while feeding either acetaldehyde or the EDA hydrolysis product.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1COCC1>[O:16]([CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: C=C(CBr)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(COc1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of ethyl 2-bromomethylacrylate (2.00 g, 10.4 mmol, ref: Villieras, J. and Rambaud, M. Synthesis, 1982, 914) and phenol(975 mg, 1.0 eq) in dry THF (20 mL) under N2 at 0° C. was treated with anhydrous K2CO3 (1.43 g, 1.0 mol eq). No reaction was observed for 1 h. Anhydrous DMF (20 mL) was added and stirred for 2 h at 0° C. and for 1 h at room temperature. After evaporation of DMF, water(100 mL) was added, and the reaction was extracted with ethyl acetate (100 mL×2). The organic extract was washed with brine (100 mL), dried (anh. Na2SO4), filtered and concentrated. Flash chromatography (40% CH2Cl2/hexanes) gave 1.712 g (80%) of the title compound.
Reaction SMILES: N[C:2]1[C:11]2C(=CC=C(OCCNC(=O)OC(C)(C)C)C=2)C=CN=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>Cl.O1CCOCC1.ClCCl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]([O:43][CH2:2][CH3:11])=[O:42])=[CH:44][CH:45]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2ccnc(N)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
648 mg (2.15 mmol) of t-butyl [2-(1-aminoisoquinoline-7-yloxy)ethyl]carbamate was dissolved in a mixture of 2.5 ml of 4 N solution of hydrogen chloride in dioxane and 5 ml of dioxane. The obtained solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 10 ml of DMF. 752 mg (2.36 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 451 mg (2.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 319 mg (2.36 mmol) of 1-hydroxybenzotriazole and 0.99 ml (7.08 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was treated with dichloromethane as the extracting solvent in an ordinary manner, and the obtained crude product was dissolved in a mixture of 2 ml of 4 N solution of hydrogen chloride in dioxane and 1 ml of dioxane. The obtained solution was stirred at room temperature overnight. The title compound was obtained in the same manner as that in step 4 in Example 1.
Reaction SMILES: Cl.CCN([CH:8]([CH3:10])[CH3:9])C(C)C.[NH:11](C(OC(C)(C)C)=O)[C@H](C(ON1C(=O)CCC1=O)=O)CC(=O)OCC1C=CC=CC=1.[C:41](O)(=O)[CH2:42][C:43]([CH2:48][C:49]([OH:51])=[O:50])(C(O)=O)O>CN(C=O)C.[Au]>[NH2:11][CH2:41][C:42]1[CH:43]=[C:48]([CH:10]=[CH:8][CH:9]=1)[C:49]([OH:51])=[O:50]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: [Au]
Agent: Cl
Solvent: CN(C)C=O
Product: NCc1cccc(C(=O)O)c1
Temperature: 5 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
circle-solid.HCl (Mamb; 13.08 g, 70.0 mmol) was dissolved in 120 ml DMF and DIEA (24.32 ml, 140 mmol) was added, changing the pH from 4 to 7.5. The white suspension was stirred for 30 min at room temperature before a solution of Boc-Asp(OBzl)-OSu (29.40 g, 70.0 mmol) in DMF (50 ml) was added. The mixture was allowed to stir 24 hr, during which time it turned to a gold solution. The solution was added to 5% citric acid (2000 ml) and cooled to 5° C. for 3 hr. The solids were then collected by filtration, washed with ice cold water (200 ml) and ice cold ethyl ether (100 ml), and dried under reduced pressure to give the title compound as a colorless solid (29.62 g, 92%); MP=149-151° C.; DCI-MS: [M+NH4 ]=474.