Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[C:13]([C:15]3[NH:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH:14]=2)[NH2:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.O>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[C:13]([C:15]3[NH:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH:14]=2)[NH:11][CH2:29][C:30]2[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CNc2cc(-c3nc4cccnc4[nH]3)cc(-c3ncccc3Cl)c2)cc1
Reaction time: 8 h
Yield: 47 %

Procedure:
NaCNBH4 (15.5 mg, 0.25 mmol) was added to a solution of Example 183 (32.1 mg, 0.1 mmol) in CH2Cl2-MeOH (2 mL) containing sodium acetate (12.3 mg, 0.15 mmol) and p-methyl benzaldehyde (14.4 mg, 0.12 mmol) at 0° C. The resulting suspension was stirred overnight and water (50 mL) was slowly added and the mixture extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by LCMS (acetonitrile-water gradient) to give the title compound (20 mg, 45%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 2.27 (s, 3H) 4.3 (s, 2H) 7.01 (t, J=5.21 Hz, 1 H) 7.08 (d, J=5.11 Hz, 2 H) 7.13 (dd, J=7.21, 4.42, Hz, 1 H) 7.25 (dd, J=5.27, 3.48 Hz, 1 H) 7.39 (t, J=5.11 Hz, 1 H) 7.46 (t, J=5.11 Hz, 1 H) 7.58 (d, J=5.11 Hz, 2 H) 7.68 (dd, J=9.21, 5.42, Hz, 1 H) 8.76 (d, J=5.91 Hz, 1 H) 8.82 (d, J=5.91 Hz, 1 H). MS (ES) [M+H] calculated for C25H21ClN5, 426.14; found 426.09.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:15][C:16]([OH:18])=O)[C:9](=[O:10])[C:8]2=[CH:33][CH:34]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:48][OH:49]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:15][C:16]([NH:48][OH:49])=[O:18])[C:9](=[O:10])[C:8]2=[CH:33][CH:34]=1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)cc1OC1CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)cc1OC1CCCC1
Yield: 59.8 %

Procedure:
3-(4-Acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(4-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (1.78 g, 3.82 mmol), carbonyldiimidazole (0.74 g, 4.6 mmol) and hydroxylamine hydrochloride (0.38 g, 5.3 mmol) in tetrahydrofuran (12 mL) to afford 3-(4-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.1 g, 60% yield): mp, 177–180° C.; 1H NMR (DMSO-d6) δ 1.87–1.56 (m, 8H, C5H8), 2.12 (s, 3H, CH3), 3.11 (d, J=7.5 Hz, 2H, CH2), 3.70 (s, 3H, CH3), 4.72 (m, 1H, OCH), 5.64 (t, J=7.5 Hz, 1H, NCH), 6.88 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.81 (m, 2H, Ar), 8.17 (br s, 1H, OH), 8.78 (s, 1H, Ar), 10.56 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 21.13, 21.81, 29.79, 31.89, 47.78, 53.15, 77.18, 109.68, 110.16, 111.75, 117.29, 120.85, 121.95, 122.40, 128.89, 131.50, 142.48, 144.33, 163.63, 165.20, 165.50, 166.92; Anal Calcd for C25H27N3O7+1.2 H2O: C, 59.68; H, 5.89; N, 8.35. Found: C, 59.69; H, 8.19; H2O, 6.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24](=S)[NH:23]1.[NH3:35]>C(OO)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24]([NH2:35])=[N:23]1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Reactant: N
Agent: CC(C)(C)OO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Yield: 31 %

Procedure:
In a manner analogous to that described in Example 2c), the ammonolysis of (R)-5-[2,4-difluoro-5-(6-trifluoromethyl-benzooxazol-2-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (110 mg, 217 μmol) with ammonia (7M in methanol; 2.14 ml) and tert-butylhydroperoxide (70% in water; 260 μl) yielded the title compound (33 mg, 31% yield). MS (ISP): m/z=490.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:26])[CH2:21][S:22][CH:23]([CH3:25])[CH3:24])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:26])[CH2:21][S:22]([CH:23]([CH3:24])[CH3:25])=[O:41])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)SCC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)CC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(isopropylthio)ethyl]pyrrolidine (1.61 g) was subjected to oxidation as in Example 2-A) in dichloromethane using 1.1 equivalent of m-chloroperbenzoic acid to give 1.40 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]([C:31]1[N:32]=[C:33]([NH:36][C:37](=[O:48])[C@@H:38]([NH2:47])[C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[S:34][CH:35]=1)=[O:30].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:27][O:28][C:29]([C:31]1[N:32]=[C:33]([NH:36][C:37](=[O:48])[C@@H:38]([NH:47][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:17][CH:18]=2)[C@H:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[S:34][CH:35]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of (R)-tert-butoxycarbonylamino-(4-tert-butoxycarbonylamino-phenyl)-acetic acid (420 mg, 1.13 mmol) and (2S,3S)-2-(2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (300 mg, 0.94 mmol) (prepared as described in Example 7) in dichloromethane (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (220 mg, 1.13 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature slowly, stirred overnight and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography over silica gel gradient eluted between 0 and 60% ethyl acetate in hexanes followed by a precipitation of the product from dichloromethane with excess hexanes gave 2-{(2S,3S)-2-[(R)-2-tert-butoxycarbonylamino-2-(4-tert-butoxycarbonylamino-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester as a white solid (520 mg, 82%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](OC)(OC)[C:13]1=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[O:34])=[CH:28][CH:27]=1.C(O[CH2:41][CH3:42])(=O)C>O1CCCC1>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:35][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:41]([CH3:42])=[CH:27][CH:28]=2)=[O:34])([NH:35][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)=[O:34])[C:13]1=[O:25])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(NC(N)=O)cc1
Reactant: COC1(OC)C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(Cc3ccccc3)c3ccccc32)cc1
Yield: 23 %

Procedure:
To a solution of 0.80 g of anhydrous aluminum chloride in 20 ml of dry tetrahydrofuran were added successively a solution of 0.57 g of 1-benzyl-3,3-dimethoxyindolin-2-one in 10 ml of dry tetrahydrofuran and 0.60 g of p-tolylurea at 0° C. under a nitrogen atmosphere, and the mixture was heated under reflux for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=4/1) to obtain 0.24 g (23%) of 1-benzyl-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:24])[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:16][C:17]1([CH3:24])[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CC1(C)CCN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(C)CCn2c(nc(-c3ccncc3)cc2=O)N1
Yield: 33 %

Procedure:
A mixture of 7.68 g (39.8 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 7.9 g (37.9 mmol) of 6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide (prepared according to Bull. Soc. Chim. Belg., 1950, 59, 573-587) and 11 g (79.5 mmol) of potassium carbonate in 80 ml of ethanol were heated at reflux temperature during 18 h. The reaction mixture was cooled and the solvent removed by evaporation. The residue obtained was treated with water and the precipitate recovered by filtration to give 3.21 g (33%) of product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([C:12](=[O:13])[C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)c2cc(C(C)(C)C)ccc2C(=O)O)cc1
Temperature: 0 °C
Yield: 54 %

Procedure:
Into a 500 ml three-necked flask, 36 g (176 mmole) of 4-t-butyl-phthalic anhydride, 27 g (200 mmole) of t-butylbenzene and 100 ml of dichloroethane were placed under a stream of argon and cooled to 0° C. To the obtained mixture, 56 g (420 mmole) of aluminum chloride was slowly added. After the addition was completed, the resultant mixture was stirred at the room temperature for one night. After the reaction was completed, ice was added slowly, and then concentrated hydrochloric acid was added. The formed precipitates were separated by filtration and washed well with water, and 32 g of the benzoic acid compound of the object compound was-obtained (the yield: 54%; a white powder).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([CH:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4].[CH3:35][NH:36][CH3:37].O1CCCC1>C(#N)C.C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([CH:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4]
Reactant: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 3-[4-(2-chloroacetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (1.1 g, 2.3 mmol) in acetonitrile (15 mL) was added dimethylamine in tetrahydrofuran (3.3 mL, 2 N, 6.6 mmol) at room temperature and kept for overnight. The solvent was removed in vacuo to give a solid. The solid was diluted with methylene chloride (50 mL) and sodium hydrogen carbonate (25 mL). The separated organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was purified with chromatography to give 3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (640 mg, 57% yield). To a stirred solution of 3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide in ethyl acetate (4 mL) was added hydrogen chloride in ether (2 mL, 1 N, 2 mmol) at room temperature. The resulting suspension was filtered and washed ethyl acetate to give 3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide hydrogen chloride as a white solid (580 mg, 84% yield): mp, 92-94° C.; 1H NMR (DMSO-d6) δ 1.30 (t, J=6.9 Hz, 3H, CH3), 2.75 (s, 3H, CH3), 2.87 (s, 6H, 2CH3), 2.98 (s, 3H, CH3), 3.21 (dd, J=5.7, 16.6 Hz, 1H, CHH), 3.61 (dd, J=9.3, 16.5 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 3.98 (q, J=6.9 Hz, 2H, CH2), 4.26 (s, 2H, CH2), 5.62 (dd, J=5.6, 9.1 Hz, 1H, NCH), 6.90-6.91 (m, 2H, Ar), 7.01 (s, 1H, Ar), 7.65 (d, J=7.2 Hz, 1H, Ar), 7.85 (t, J=7.7 Hz, 1H, Ar), 8.21(d, J=8.2 Hz, 1H, Ar), 10.25 (brs, 1H, HCl), 10.56 (s, 1H, NH); 13C NMR (DMSO-d6) δ14.72, 26.37, 34.41; 34.81, 36.59, 43.34, 50.43, 55.52, 58.02, 63.78, 11.79, 112.38, 119.52, 127.79, 131.88, 131.94, 134.19, 135.79, 147.76, 148.47, 164.52, 167.25, 167.40, 169.16; Anal Calcd for C26H32N4O6+HCl+0.48 H2O: C, 57.65; H, 6.32; N, 10.34; Cl, 6.55; H2O, 1.60. Found: C, 57.70; H, 6.28; N, 10.28, Cl, 6.81; H2O, 1.61.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:34])[C@H:21]([CH2:23][C:24](OCC1C=CC=CC=1)=[O:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.C(Cl)Cl>C(OCC)C>[CH2:12]([O:19][C:20]([C@H:21]1[NH:22][C:24](=[O:25])[CH2:23]1)=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
1 was synthesized according to a procedure similar to that reported by Salzmann.20 A modified procedure31 was adopted to achieve higher yields of 1. Commercially available L-aspartic acid dibenzyl ester p-toluenesulfonate salt (25 g 0.052 mol) was charged to a dry schlenk flask. The substrate in the flask was dried under high vacuum for 2 h. Dry CH2Cl2 (450 mL) was transferred to the flask under N2 and then the solution was cooled to 0° C. using an ice bath. Triethyl amine (15.8 mL, 0.1133 mol, 2.2 eq) was added and followed by addition of TMSCI (6.588 mL, 0.052 mol). The solution was slowly warmed to room temperature and stirred for an additional 12 h. The solution was then cooled again to 0° C. and tert-BuMgCl (77 mL of a 2.0 M solution in diethyl ether, 3.0 eq) was slowly added to the mixture. The solution was kept at 0° C. for 2 h and then slowly warmed to room temperature. The reaction was stopped 10 h later by addition of 200 mL wet CH2Cl2. The organic phase was washed with 1 N HCl (2×400 mL), saturated NaHCO3 (2×400 mL) and brine (2×400 mL). The organic phase was dried over MgSO4. After the solvent was removed, a yellow solid was obtained. The solid was purified by crystallization from CH3OH and then sublimation at 110° C. under high vacuum to give 1 as white crystals (6.1 g, 55%). FTIR (THF): 1779 cm−1 (νCO, lactam, s), 1747 cm−1 (νCO, ester, s). 1H NMR (CDCl3, 500 MHz) δ 7.25 (s, 5H, CH2C(O)NHCH(CO2CH2C6H5)), 6.0 (br, 1H, CH2C(O)NHCH(CO2CH2C6H5)), 5.15 (s, 2H, CH2C(O)NHCH(CO2CH2C6H5)), 4.24 (dd, 1H, CH2C(O)NHCH(CO2CH2C6H5)), 3.36 (ddd, 1H, CH2C(O)NHCH(CO2CH2C6H5), 3.15 (ddd, 1H, CH2C(O)NHCH(CO2CH2C6H5)). 13C NMR (CDCl3, 200 MHz) δ 171.0, 166.5, 135.1, 128.9, 128.7, 67.7, 47.5, 43.8. FTIR, 1H NMR and 13C NMR spectra of this compound were identical to literature data for 1.12
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][C:20]([F:19])([F:31])[F:32])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccccc3OC(F)(F)F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2-Trifluoromethoxybenzoyl chloride (1.64 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][C:13]1C=CC(S(O)(=O)=O)=CC=1>C(OCC)(OCC)(OCC)C>[CH3:12][C:13]1[O:11][C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccc(C(=O)O)c1O
Agent: CCOC(C)(OCC)OCC
Product: Cc1nc2cccc(C(=O)O)c2o1

Procedure:
A solution of 3-amino-2-hydroxy-benzoic acid (9.40 mmol) and PTSA (0.34 mmol) in triethyl orthoacetate (5.77 mL) is heated to reflux for 5 h and concentrated in vacuo. The residue is washed with ether and dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.67 min; [M+H]+=178.0.
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[H-].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]2[CH2:21][O:20]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C1C[O:25]CC1>>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]([OH:25])[CH2:21][O:20][CH:1]([CH3:3])[CH3:2])[CH2:15]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Reactant: CC(C)O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Isopropyl alcohol (215 μL, 2.8 mmol) was dissolved in THF (428 μL), and the mixture was cooled at 0° C. NaH (33.8 mg, 1.4 mmol) was added in 4 portions, and the mixture stirred for 10 minutes at room temperature. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (200 mg, 938 μmol) was added. The resulting solution was placed in a microwave reactor for 10 minutes at 100° C., then cooled to room temperature. The mixture was extracted with Hexanes (10 mL) and washed with water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to give the title compound as a clear oil (162 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>CC(C)=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:21]
Reactant: CN1Cc2ccnc(N)c2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: CN1Cc2cc[n+]([O-])c(N)c2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
A mixture of 4-amino-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Compound 310B, 62.5 mg, 0.383 mmol) and m-Chloroperbenzoic acid (145 mg, 0.843 mmol) in Acetone (10.0 mL) was stirred at rt for 90 minutes. The reaction mixture was concentrated under reduced pressure to an off white solid. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/7 N NH3 in MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (68.3 mg, 99.5%). 1H NMR (DMSO-d6, 400 MHz): δ=8.19 (d, J=6.57 Hz, 1H), 7.02 (br. s., 2H), 6.82 (d, J=6.57 Hz, 1H), 4.41 (s, 2H), 3.01 (s, 3H). MS (ES+): m/z 180.07 [MH+] (TOF, polar).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O>[CH3:3][CH:4]1[CH2:8][CH2:7][C:6](=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]1=[O:9]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A solution of 16.8 g of 85% strength aqueous potassium hydroxide solution and 1,500 ml of water was charged to a 31 stainless-steel autoclave, 294 g of 2-methylcyclopentanone and 421.8 g of 4-chlorobenzaldehyde were added, and the mixture was then heated to 120° C. under the intrinsic pressure. Stirring was subsequently carried out at this temperature for 3 hours. After cooling to room temperature, the finely particulate yellow product was filtered off with suction, washed to neutrality with water and then dried in a vacuum oven at 60° C. In this way 658.5 g of 2-methyl-5-(4-chlorobenzylidene)-cyclopentanone (93.1% pure) were obtained. This corresponds to a yield of 93% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccc(F)cc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.36 mmol) and pyridine (114 mg, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added 4-fluorobenzene-1-sulfonyl chloride (70.1 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous Sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 478.9.