Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C#Cc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(C#Cc2ccccc2)ccc1C(=O)O)c1ccccc1
Reaction time: 0.5 h

Procedure:
0.24 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1 mL of methanol and 2 mL of tetrahydrofuran containing 0.13 g of methyl 2-(benzamido)-4-(phenylethynyl)benzoate at room temperature and stirred at the same temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 while ice-cooled with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 0.11 g of 2-(benzamido)-4-(phenylethynyl)benzoic acid as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:25][N:26]([CH3:53])[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=1)[CH2:31][CH2:30]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:25][N:26]([CH3:53])[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[CH:39]=1)[CH2:31][CH2:30]2
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CN(C)c1ccc2c(c1)CCN(c1cccc(B3OC(C)(C)C(C)(C)O3)c1)C2=O
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: COCCOC
Solvent: O
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(Nc4ccc(C(=O)N5CCOCC5)cn4)c(=O)n(C)c3)c1)C2=O
Yield: 40.6 %

Procedure:
5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (67 mg, 0.17 mmol), 6-Dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one (67 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), and sodium carbonate (54 mg, 0.51 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was heated to 170° C. for 12.5 minutes in the microwave. The resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.069 mmol). MS (ESI) 579.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:21]=O)[C:15]=2[N:14]=[CH:13][CH:12]=1>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][CH:12]=[N:11]2)[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)N
Reactant: O=Cc1cccc2nccnc12
Product: CCOC(OCC)[C@H](C)NCc1cccc2nccnc12
Yield: 78.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 1.57 g (10.0 mmol) was reacted with quinoxaline-5-carbaldehyde 1.34 g (8.5 mmol) to obtain the title compound 1.93 g (78%).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][C@H:38]([C:56]([OH:58])=[O:57])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:55])[NH:44][S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46].[S:59]1[CH:63]=[CH:62][N:61]=[CH:60]1>>[CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([NH:37][C@H:38]([C:56]([OH:58])=[O:57])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:55])[NH:44][S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46])=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:20])=[O:21])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:59]1[CH:63]=[CH:62][N:61]=[CH:60]1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)cc1
Agent: c1cscn1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)NS(=O)(=O)Cc2ccccc2)C(=O)O)cc1
Yield: 63 %

Procedure:
A 100 mg portion of the compound of Example 11 was coupled with 0.19 mmol of H-Arg(Tos)-thiazole (prepared following the procedure of Example 5) following the procedure as described in Example 6. RP-HPLC purification gave the title compound (110 mg, 63% yield). FAB-MS (M+H)+917.8
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[N:24](C)[C:23](=O)O[C:20](=[O:21])[C:19]=12>C(O)(=O)C>[CH3:12][C:9]1[O:8][C:7]2[C:2]([NH:1][C:20](=[O:21])[C:19]3[C:18]([NH:24][CH3:23])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:13])=[CH:3][CH:4]=[CH:5][C:6]=2[C:10]=1[CH3:11]
Reactant: Cc1oc2c(N)cccc2c1C
Reactant: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Solvent: CC(=O)O
Product: CNc1cccc(Cl)c1C(=O)Nc1cccc2c(C)c(C)oc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A mixture of 7-amino-2,3-dimethylbenzo[b]furan (100 mg) and 6-chloro-N-methylisatoic anhydride (147 mg) in acetic acid (2 ml) was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was crystallized from a mixture of ethanol and water to give 2,3-dimethyl-7-(2-chloro-6-methylaminobenzoylamino)benzo[b]furan (210 mg)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12](Cl)=[O:13])=[CH:3]1.Cl.C([O:20][C:21](=[NH:34])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[CH:24]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:33][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[C:23]([C:22]2[C:21](=[O:34])[NH:20][C:12](=[O:13])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:24]1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Reactant: Cc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of the known (1-methyl-1H-indol-3-yl)-oxo-acetyl chloride (183 mg, 0.83 mm) and 2-(1,6-dimethyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (233 mg, 0.83 mm) in CH2Cl2 (6 mL) which had been cooled to 0° C., was added Et3N (0.46 mL, 3.3 mm). The reaction was allowed to warm to room temperature overnight, then diluted with CH2Cl2 (20 mL), and extracted with H2O(15 mL) and 0.5N HCl(15 mL). The organic fraction was dried over MgSO4, filtered and evaporated, and the residue combined with toluene (3 mL). After cooling to 0° C., para-toluene sulfonic acid (pTsOH) (174 mg, 0.91 mm) was added, and the mixture was stirred at room temperature for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL) and H2O(25 mL). The organic fraction was washed with saturated NaHCO3 (25 mL) solution, then dried over MgSO4, filtered and evaporated. The residue was washed with cold CH2Cl2 to yield 3-(1,6-dimethyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3yl)-pyrrole-2,5-dione; mp=264°-266° C.
Reaction SMILES: [C:1]([O:21][CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:13].[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:27]([O:13][C@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:21][CH3:22])=[O:20])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:29]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:28]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCC[C@H](C/C=C\CCCCCCCC(=O)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 148.6 %

Procedure:
To a solution of methyl ricinoleate (8.0 g, 32 mmol) in anhydrous pyridine (90 mL) and anhydrous THF (45 mL) was added t-butylchlorodimethyl silane (8.5 mL, 33.3 mmol) and silver nitrate (5.65 g, 33.3 mmol). The solution was stirred at room temperature for 90 minutes under nitrogen. The solution was filtered through celite and the filter cake was rinsed with THF (400 mL). The filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane (300 mL) and washed with 5% HCl (150 mL). The aqueous layer was separated and washed with dichloromethane (2×200 mL). The combined dichloromethane extracts were washed with brine (350 mL), dried on magnesium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (gradient: 100% hexanes to 10% ethyl acetate in hexanes) to afford the title compound as a colourless oil (13.1 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[Si](C)(C)[CH3:17]>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:17])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(C(=O)O)c2n1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cccc2ccc(C)nc12
Yield: 32.5 %

Procedure:
To a stirred solution of 2-methylquinoline-8-carboxylic acid (0.830 g, 4.43 mmol) in MeOH (20 mL) was added dropwise chlorotrimethylsilane (2.41 g, 22.2 mmol). The reaction mixture was heated at reflux overnight. After cooling, the reaction was concentrated under reduced pressure. The residue was dissolved in water and basified by dropwise addition of saturated aqueous NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to give methyl 2-methylquinoline-8-carboxylate (0.290 g, 33%).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([CH:11]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([S:32]([CH3:35])(=[O:34])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:7][NH:8][C:9]([CH:11]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([S:32]([CH3:35])(=[O:34])=[O:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)C(C/C=C/c1cccnc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)C(C/C=C/c1cccnc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.4 %

Procedure:
A solution of 0.21 g of (E)-2(R)-[1(RS)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-(3-pyridyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in 5 ml of methanol was treated with 0.097 g of 4-toluenesulphonic acid. The mixture was stirred for 2.5 hours at room temperature and then diluted with water. The solid was filtered off, washed with water and diethyl ether and dried in vacuum to yield 0.138 g of (E)-2(R)-[1(RS)-(hydroxycarbamoyl)-4-(3-pyridyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:23]1[CH2:24][CH2:25][C:26]([F:30])([F:29])[CH2:27][CH2:28]1)[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: COc1ccc(C(CN)N2CCC(F)(F)CC2)cc1
Product: COc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cc1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: C1COCCN1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCOCC3)s2)c(C)[nH]c1=O
Yield: 57.4 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with morpholine as described in Step 5, Example 24 to give the title compound as a solid (57.4% yield). LC/MS: RT 2.72 min; m/e 369 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, d); 7.3 (1H, d), 3.7 (4H, m), 2.95 (4H, s), 2.4 (2H, q), 2.36 (3H, s), 1.05 (3H, t).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C(=O)N([Br:39])C(=O)C1>C(O)(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([Br:39])=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)N1CCC(Oc2cc(Oc3ccc(S(C)(=O)=O)cc3F)ncn2)CC1
Solvent: CC(=O)O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2Br)CC1
Yield: 57.2 %

Procedure:
4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (1.02 g, 2.25 mmol) and NBS (601 mg, 3.38 mmol) in acetic acid (10 mL) was stirred at 40° C. for three days. The mixture was purified through HPLC to provide compound C155 as a solid (685 mg, 50%). 1H NMR (CDCl3, 400 MHz) δ 1.24 (d, 6H), 1.82-1.86 (m, 2H), 1.94-1.98 (m, 2H), 3.08 (s, 3H), 3.46-3.52 (m, 2H), 3.68-3.74 (m, 2H), 4.92 (hept, 1H), 5.38-5.42 (m, 1H), 7.42-7.46 (m, 1H), 7.77-7.81 (m, 2H), 8.18 (s, 1H). Exact mass calculated for C20H23FBrN3O6S 531.1, found 532.4/534.4 (MH+).
Reaction SMILES: [Na].[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][C:9]#[N:10])[CH:4]=1.[N:11]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O)=[N+:12]=[N-:13]>CCO>[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:13]=[N:12][N:11]3[C:14]4[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:16](=[O:18])[NH:10][C:9]=23)[CH:4]=1
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)O
Reactant: Cc1cc(CC#N)no1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(-c2nnn3c2[nH]c(=O)c2ccccc23)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
Sodium (0.2 g, 8.6 mmol) was dissolved in EtOH (9 mL) and (5-methylisoxazol-3-yl)acetonitrile (0.65 g, 5.3 mmol) was added. The solution was stirred for 15 min then a solution of 2-azidobenzoic acid (0.7 g, 4.3 mmol) in EtOH (7 mL) was added and the mixture stirred for 1 h. After this time the mixture was heated at reflux for 5 h. The suspension was then allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up in water and 1N citric acid was added to pH4. The resultant precipitate was collected by filtration, washed with water then dried in vacuo at 60° C. The title compound (0.92 g, 80%) was isolated as a colourless solid. 1HNMR (360 MHz, d6-DMSO) δ 2.51 (3H, s), 6.83 (1H, q, J=0.8 Hz), 7.72 (1H, d of t, J=8.1 and 1.0 Hz), 8.01 (1H, d of t, J=7.5 and 1.4 Hz), 8.24 (1H, dd, J=8.0 and 1.3 Hz), 8.36 (1H, d, J=8.0 Hz), 12.16 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[CH3:12][S:13]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: OCCOc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(F)cc1

Procedure:
As for Example 56, 12.5 g of 2-(p-fluorophenoxy) ethanol is reacted with 7 ml of methanesulfonyl chloride in 100 ml of dichloromethane in the presence of 23 ml of triethylamine. The product (18 g) is obtained as a colorless liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)C>O>[CH:34]1([N:33]([CH2:2][C:3]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=2)[CH3:32])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CNC1CCCCC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(CN(C)C2CCCCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 79.6 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), N-methyl-N-cyclohexylamine (2.28 g) and ethanol (45 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave ethyl 2-(N-cyclohexyl-N-methylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (2.80 g, 80%). This compound was recrystallized from ethanol. Colorless prisms, mp. 172°-174° C.
Reaction SMILES: CN1CCOCC1.[OH:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C:10]1=[O:19].[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>O1CCCC1>[CH3:20][Si:21]([CH3:24])([CH3:23])[O:8][C@@H:9]1[C@@H:14]([O:15][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@H:13]([O:16][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@@H:12]([CH2:17][O:18][Si:21]([CH3:24])([CH3:23])[CH3:20])[O:11][C:10]1=[O:19]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of N-methylmorpholine (246.8 mL, 2.24 mol) and (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-one 1a (50 g, 0.28 mol, bought from Aladdin) in anhydrous tetrahydrofuran (500 mL) was added dropwise trimethylchlorosilane (213 mL, 1.68 mol) over a period of 2 hours. The mixture was stirred at room temperature (rt) for 8 hours and quenched with 1 L of water. The resulting mixture was partitioned. The organic layer was washed with saturated aqueous dipotassium hydrogen phosphate (100 mL×8.3) and saturated aqueous sodium chloride (100 mL×8.3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=40/1 to give the title compound 1b as colorless oil (125.2 g, 100%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 4.17 (m, 1H), 3.99 (d, 1H), 3.89 (t, 1H), 3.81 (m, 3H), 0.18 (s, 9H), 0.17 (s, 9H), 0.15 (s, 9H), 0.11 (s, 9H).
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[C:18](Cl)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>N1C=CC=CC=1>[C:18]([O:4][C:3]1[CH:2]=[C:1]([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([O:15][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=2)[CH:8]=[C:6]([O:7][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:5]=1)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C=Cc2cc(OC(=O)CCCCCCCCCCCCCCC)cc(OC(=O)CCCCCCCCCCCCCCC)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.4 %

Procedure:
Resveratrol (100 mg; 0.44 mmol) was dissolved in 1 mL of pyridine. Palmitoyl chloride (425 μL; 1.40 mmol; 3.2 equiv) was added with immediate solid formation noted. This mixture was stirred at ambient temperature for 12 h at which point HPLC analysis indicated no resveratrol present. The mixture was partitioned into ethyl acetate and water and the water layer was decanted. The top organic layer was washed sequentially with 1.5 M HCl (10 mL) and 5% sodium bicarbonate (10 mL), dried (MgSO4), and concentrated to afford 0.45 g (99%) of resveratrol tripalmitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:27]=[CH:26]/[C:25]([OH:29])=[O:28])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C=CC(=O)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 100 °C

Procedure:
A mixture of the title compound of Example 5 (0.913 g), acrylic acid (0.17 mL), palladium acetate (4 mg) and triethylamine (0.70 mL) in 5 mL DMF is heated to 100° C. for 24 h in a pressure-safe tube. The reaction is cooled and diluted with 50 mL of a 10% aqueous HCl solution. The resulting solid is collected, dried and recrystallized from EtOH to yield 0.564 g of the desired product as a tan solid.