Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C[O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([Cl:39])[CH:33]=1.C([O-])(O)=O.[Na+].ClCCl>S(Cl)(Cl)=O>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[NH:38][C:14](=[O:15])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:31]([OH:40])=[O:30]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)nc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)nc3)nc3cc(F)c(F)cc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by heating [2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexylacetic acid (200 mg, 0.46 mmol) in 5 ml thionylchloride to 80° C. for 4 h. The solvent was evaporated and the residue taken up in dichloromethane. 4-Amino-3-chloro-benzoic acid methyl ester (85 mg, 0.46 mmol) were added and the reaction mixture stirred at rt overnight. The crude product was worked up by addition of a solution of 1 M NaHCO3 and extraction of the aqueous layer with dichloromethane. Organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was taken up in methanol (3 ml) and 1N NaOH (1 ml) added. The mixture was stirred at rt overnight, the solvent evaporated and the product isolated via preparative HPLC. MS (ES+): 560 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][C:13]([CH3:18])([CH3:16])[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(COCc2ccccc2)OC1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 2,2-dimethyl-1,3-propanediol (4.16 g, 40 mmol) and toluene (70 ml), p-toluenesulfonic acid monohydrate (287 mg, 1.51 mmol) was added and refluxed for 4 hours while removing water by the Dean-Stark apparatus. After the reaction mixture was cooled to room temperature, triethylamine (4 ml) was added to the reaction mixture and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/9) to obtain the title compound (7.6 g, yield: 96.6%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:16][N:15]([C:17](OC(C)(C)C)=O)[CH2:14]1.ClC1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>>[Cl:35][C:32]1[CH:33]=[N:34][C:17]([N:15]2[CH2:14][CH:13]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[CH3:1])[CH2:16]2)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: Cc1cc(C(F)(F)F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(C(F)(F)F)cc2C)C1
Yield: 30.3 %

Procedure:
The title compound (D86) (44 mg) was prepared according to the experimental procedure described in Description 85 starting from tert-butyl 3-((2-methyl-4-(trifluoromethyl)phenyl)amino)azetidine-1-carboxylate (D32) (150 mg, 0.454 mmol) and methyl 2,5-dichloronicotinate (74.92 mg, 0.363 mmol)
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][CH:12]([F:23])[O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:11][CH:12]([F:23])[O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(OC(F)F)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2cccc(OC(F)F)c2)cc1F
Yield: 55.3 %

Procedure:
The title compound (144 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and 3-(difluoromethoxy)phenylboronic acid (234 mg, 1.25 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.49 (d, J 7.9, 1H), 7.43-7.39 (m, 2H), 7.38-7.30 (m, 2H), 7.32 (t, J 74, 1H), 7.06 (dd, J 1.8, 7.9, 1H), 5.42 (s, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O.O>[C:29]([O:28][C:26]([N:11]1[C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:14][CH2:13][C@H:12]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a stirred solution of the title compound from Step D (2.5 g, 4.6 mmol) in methanol/water 4:1 (30 mL) was added lithium hydroxide (533 mg, 23.1 mmol). The resulting mixture was stirred at RT overnight. The mixture was diluted with water and extracted with ether. The aqueous layer was acidified with 1N citric acid to PH 4.5, and then extracted with ethyl acetate. The organic layer was separated and washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by reverse phase HPLC (Luna10u, 250×50 mm I.D.; 45-65% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford 1.31 g (74%) of the title compound (i-3) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 2H), 7.93 (d, J=7.8 Hz, 2H), 7.80 (s, 1H), 7.44-7.38 (m, 1H), 7.03 (s, 2H), 5.66-5.33 (m, 1H), 4.16 (s, 1H), 4.00-3.88 (m, 1H), 3.01-2.95 (m, 1H), 2.68-1.58 (m, 1H), 2.04-1.83 (m, 2H), 1.60 (s, 9H), 1.31-1.20 (m, 2H), 0.96 (s, 9H), 0.17 (s, 3H), 0.00 (s, 3H). MS: m/z (ESI) 527 (M+1).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].Br[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[I-].[K+]>C(N(C(C)C)CC)(C)C>[F:1][CH:2]([F:5])[CH2:3][NH:4][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NCC(F)F
Reactant: CCOC(=O)CCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNCC(F)F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 62.7 %

Procedure:
2,2-difluoroethylamine (0.50 g) was added to a suspension of ethyl 3-bromopropanoate (1.1 g), potassium iodide (0.10 g) in diisopropylethylamine (1.2 mL) and the mixture was stirred at 100° C. for 3.5 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the sub-title compound (0.69 g) as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 5.81 (1H, tt), 4.13 (2H, q), 2.95 (2H, dt), 2.93 (2H, t), 2.48 (2H, t), 1.24 (3H, t).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 110 °C

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 4-fluorobenzeneboronic acid (0.119 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid after recrystallisation from ethyl acetate:hexane (1:1) (0.18 g).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>CN(C=O)C>[N:28]1([CH2:22][CH2:21][CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[C:11](=[C:10]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]2=[O:1])[O:12][CH2:13]3)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)OCCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C1=C1OCc2cc(CCCN3CCOCC3)ccc21
Temperature: 90 °C
Yield: 98.3 %

Procedure:
A mixture of methanesulfonic acid 3-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-propyl ester (400 mg, 1.04 mmol) and morpholine (1.5 ml, 17.2 mmol) in DMF (5 ml) was heated at 90° C. for 1.5 hours. The mixture was cooled, and poured into water (125 ml) with stirring. The solid was filtered, washed with water and dried under vacuum to give 3-[5-(3-morpholin-4-yl-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (385 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(NC(=O)C(=C2C(=O)Nc3ccccc32)c2[nH]c(C)cc2C)cc1OC
Yield: 37.6 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydro-indol-3-ylidene)-acetic acid (90 mg) was reacted with 3,4-dimethoxyaniline (110 mg) using method B to give 50 mg (37%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(CCCCO)cc1
Product: COc1ccc(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure O and Scheme W using 4-(4-methoxyphenyl)-1-butanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([O:11]C)[O:9]C)[CH:3]=1.O[Li].O.[CH2:16]1[CH2:20]OC[CH2:17]1.CO>O>[NH:5]1[C:6]2[C:7](=[CH:2][CH:17]=[CH:16][CH:20]=2)[CH:3]=[C:4]1[C:8]([OH:9])=[O:11]
Reactant: COC(OC)c1cc(Cl)ccn1
Reactant: C1CCOC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of the above ether (770 mg, 2.1 mmol) in THF/MeOH (25 mL/10 mL) was added LiOH.H2O (218.1 mg, 2.50 eq) dissolved in 3 mL of water. The clear reaction solution was stirred at room temperature for 5 h, then concentrated in vacuo. The residual aqueous solution was diluted with water (15 mL), and extracted with ether. The organic layer was disgarded. The aqueous layer was acidified to pH 5 with 1.4 N HCl (˜2.5 mL). A large amount of white precipitates were extracted with 200 mL of EtOAc and washed with brine. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the desired indole-2-carboxylic acid intermediate (644 mg, 90.5%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cn1ccc(N)n1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccn(C)n2)cn1
Yield: 87 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of 2-aminoethyl isopropylether, to the title compound (110 mg, 87%) which was obtained as a colourless oil. MS: m/e=390.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CON
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 50.2 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl 2-((aminooxy)methyl)pyrrolidine-1-carboxylate (796 mg) described in Reference Example 22, 336 mg of the title compound was afforded (yield 50%).
Reaction SMILES: C(SC[C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])/C=C/C1C=C(OC)C(O)=C(OC)C=1.[NH2:22][C@H:23]([C:49]([OH:51])=[O:50])[CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:46]([OH:48])=O)[CH2:30][S:31][CH2:32]/[CH:33]=[CH:34]/[C:35]1[CH:45]=[C:42]([O:43][CH3:44])[C:40]([OH:41])=[C:37]([O:38][CH3:39])[CH:36]=1)=[O:27]>>[CH2:32]([S:31][CH2:30][C@@H:29]([C:46]([NH:18][CH2:17][C:19]([OH:21])=[O:20])=[O:48])[NH:28][C:26](=[O:27])[CH2:25][CH2:24][C@@H:23]([C:49]([OH:51])=[O:50])[NH2:22])/[CH:33]=[CH:34]/[C:35]1[CH:36]=[C:37]([O:38][CH3:39])[C:40]([OH:41])=[C:42]([O:43][CH3:44])[CH:45]=1
Reactant: COc1cc(/C=C/CSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O)cc(OC)c1O
Reactant: COc1cc(/C=C/CSC[C@H](N)C(=O)O)cc(OC)c1O
Product: COc1cc(/C=C/CSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)cc(OC)c1O

Procedure:
The composition of claim 5, wherein the mixture of S-sinapyl-L-cysteine, N-L-γ-glutamyl-S-sinapyl-L-cysteine, and S-sinapyl glutathione is isolated from pineapple juice.
Reaction SMILES: N[C:2]1[CH:3]=C(C=C([N+]([O-])=O)[C:10]=1C1C=CC=CC=1)C(O)=O.C(Br)C1C=CC=CC=1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([S:44](=[O:47])(=[O:46])[NH2:45])[C:37]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]([OH:34])=[O:33].C(Br)C=C>>[CH2:3]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([S:44](=[O:47])(=[O:46])[NH2:45])[C:37]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]([OH:34])=[O:33])[CH:2]=[CH2:10]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: BrCc1ccccc1
Solvent: C=CCBr
Product: C=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step D, 3-amino-5-nitro-4-phenylbenzoic acid and benzyl bromide with equimolar amounts of 3-amino-4-phenyl-5-sulfamylbenzoic acid and allyl bromide respectively, and following the procedure described, 3-allylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a melting point of 169°-172.5° C.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11]1[CH:20]=[C:19]2[C:21]([O:23][C:24](=O)[C:17]3=[C:18]2[C:13](=[CH:14][C:15]([Br:26])=[CH:16]3)[CH:12]=1)=[O:22]>N1C=CC=CC=1>[CH2:2]([O:9][N:10]1[C:24](=[O:23])[C:17]2[CH:16]=[C:15]([Br:26])[CH:14]=[C:13]3[C:18]=2[C:19](=[CH:20][CH:11]=[CH:12]3)[C:21]1=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cc(Br)cc(c23)C(=O)N1OCc1ccccc1
Yield: 89.1 %

Procedure:
O-Benzyl hydroxylamine hydrochloride (0.9 g, 5.6 mmol) and 3-bromo-1,8-naphthalic anhydride (1.3 g, 4.7 mmol, from Example N) were reacted in pyridine (30 mL) following the procedure of Example D to give 1.6 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:24][CH3:25])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-bromobenzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)C(=O)C(F)(F)F

Procedure:
Under a blanket of nitrogen, 2020.9 g (14.22 moles) of ethyl trifluoroacetate was charged to a 12-liter flask equipped with an overhead stirrer, an addition funnel, thermometer, and a condenser. To the stirred ethyl trifluoroacetate, 2015.0 g (15.59 moles) of dibutyl amine was added over a two hour period, during which the temperature of the stirred reaction mixture rose from 20° to 40° C. At the end of the addition period, the reaction flask was equipped with an 8 inch packed column and distillation head. The ethanol by-product was then removed by distillation with a maximum pot temperature of 135° C. The reaction mixture was then cooled and the product was isolated by distillation, boiling range 79°-87° C. at 2.2-3.2 mmHg. Yield 2850 g (89.0%).
Reaction SMILES: [CH:1]1([C@@H:7]([N:9]2[CH2:14][CH2:13][C@@:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:15][CH2:16][CH2:17][OH:18])[O:11][C:10]2=[O:26])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:18][CH2:17][CH2:16][CH2:15][C@@:12]1([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:11][C:10](=[O:26])[N:9]([C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:8])[CH2:14][CH2:13]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of (R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-6-(3-hydroxy propyl)-1,3-oxazinan-2-one (200 mg, 0.55 mmol) in CH2Cl2 (10 mL) was added Et3N (290 mg, 2.87 mmol) and MsCl (196 mg, 1.72 mmol) at 0° C. The reaction solution was stirred at rt for 2 h. The reaction was quenched by H2O and extracted with CH2Cl2. The organic phase was concentrated to give the 3-((R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophen-yl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (240 mg, 92%).
Reaction SMILES: Br[C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Br)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[C:32]3[S:31][CH:30]=[CH:34][CH:33]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1Sc1c(Br)cccc1S2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1csc(-c2cccc3c2Sc2c(cccc2-c2cccs2)S3)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 103 %

Procedure:
An airfree tube containing 1,9-dibromothianthrene (187 mg, 0.5 mmole) and Pd(PPh3)2Cl2 (35 mg, 0.05 mmole) was flame dried and filled with Ar. DMF (5 mL) was added to the tube and the tube was heated to 70° C. Tributylstannylthiophene (580 mg, 1.5 mmole) was added and the solution turned black. The reaction mixture was stirred for 2 days and then cooled down to room temperature. It was poured into dichloromethane (50 mL) and the organic layer was washed by water twice, dried by MgSO4. The solvent was removed in vacao. The crude product was further purified by column chromatography (hexane/dichloromethane 6/1) and yield white crystal (196 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:1]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2cccc(C)c2)c1-c1ccccc1

Procedure:
m-Toluidine (5 mmol, 0.5 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4 (sodium sulfate), the solids were separated, and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 92.5° C.-94.0° C.).