Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.[CH2:22](Br)[CH3:23]>C1(C)C=CC=CC=1>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:23]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Reactant: CCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2cc3c(cc2c1=O)OCO3
Temperature: 130 °C
Yield: 98.6 %

Procedure:
A mixture containing 25 ml of toluene, 5 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate and 5.67 g of ethyl bromide was placed in a sealed tube and heated at 130°C (bath temperature) for 30 hours. The reaction mixture was worked up as described in Example 9 and 4.93 g of ethyl 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylate was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][OH:34])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:35]1(C)[CH:40]=CC(S(O)(=O)=O)=C[CH:36]=1>C(O)(C)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][O:34][CH:35]([CH3:40])[CH3:36])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC(C)OCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Yield: 43.9 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (46 mg, 0.10 mmol) and para-toluenesulfonic acid (38 mg, 0.2 mmol) were dissolved in isopropanol (1.0 mL) and irradiated in the microwave at 140° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford the pure product (22 mg, 44%). ESI-MS m/z calc. 500.2, found 501.3 (M+1)+; retention time 3.30 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[N:21]=[C:22]([CH3:25])[NH:23][CH:24]=1>>[Br:19][C:20]1[N:21]=[C:22]([CH3:25])[N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Cc1nc(Br)c[nH]1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cc(Br)nc2C)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (0.4 g, 1.47 mmol) and commercially available 4-bromo-2-methyl-imidazole (0.35 g, 2.17 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.41 g, 70%). MS (ISP) 399.0 [(M+H)+]; mp 180° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.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.O>[N:22]1([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCNCC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCNCC2)c(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-(1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 145.1, 51 mg, 0.111 mmol), pyridin-3-ylboronic acid (13.6 mg, 0.111 mmol), and Na2CO3 (35 mg, 0.333 mmol) in a mixture of DME (2.4 mL), EtOH (0.32 mL) and water (0.48 mL) was flushed with argon. Pd(PPh3)2Cl2 (4 mg, 0.005 mmol) was added and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.7 min, m/z=458.1 [M+H]+, m/z=456.2 [M−H]−.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH:12]=O.[CH:14](=[O:18])[CH2:15][CH2:16][CH3:17].C(OC(C)C)(C)C>O.CCO>[CH2:16](/[C:15](=[CH:12]\[C:4]1[NH:3][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)/[CH:14]=[O:18])[CH3:17]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CCCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC/C(C=O)=C\c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
To a solution of KOH pellets (0.4 g, 7.1 mmol) in H2O (5 ml), indole-2-carboxaldehyde (0.5 g, 3.44 mmol) in EtOH (45 ml) was added. After cooling to 0° C. butyraldehyde (0.31 ml, 3.44 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The ethanol was removed under vacuum and the aqueous solution was adjusted to pH 5 and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash-chromatography (hexane/EtOAc 7:3) to afford, after trituration with isopropyl ether, 0.3 g (44%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:46])[CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:46])[CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CN(CCN1CCOCC1)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCOCC1)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
Trifluoroacetic acid (5.0 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(methyl(2-(morpholin-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0.074 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and water and chloroform were added to the residue. After adjusting the pH to 7.0 with a saturated aqueous solution of sodium bicarbonate, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resulting mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.024 g of 2-(2-hydroxy-5-(methyl(2-(morpholin-4-yl)ethyl)amino)benzamido)-4-phenylbenzoic acid as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl[CH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:23][C:20]([F:21])([F:22])[C:19]1[C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1cccnc1CCl
Product: O=Cc1ccc2c(cnn2Cc2ncccc2C(F)(F)F)c1

Procedure:
1-(3-Trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde was prepared from 1H-Indazole-5-carbaldehyde and 2-Chloromethyl-3-trifluoromethyl-pyridine following General Procedure A.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]1[C:24]2[CH:23]=[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]3=[C:20]([O:29]C)[C:19]=2[C:18]2[C:17]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][CH:15]=[CH:14][C:13]1=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([N:12]1[C:24]2[CH:23]=[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]3=[C:20]([OH:29])[C:19]=2[C:18]2[C:17]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][CH:15]=[CH:14][C:13]1=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(OC)c3ccccc3cc1n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.6 %

Procedure:
Boron tribromide (0.148 mL, 1.56 mM) was slowly added to a stirred solution of 5-benzyl-11-methoxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester, (0.474 g, 1.2 mM) in 8 mL methylene chloride at −10° C. After 1.5 h, the mixture was quenched with methanol (1.22 mL, 30.0 mM) and allowed to warm to room temperature with stirring over 2 h. The mixture was diluted with methylene chloride, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant orange-brown solid was purified by column chromatography on silica gel (elution with gradient hexane/ethyl acetate) to afford 0.245 g (47%) of the title compound 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester as an orange foam (MW 381.44).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2.[Br:14]Br.Cl>[OH-].[Na+]>[Br:14][C:8]1[C:7]2[C:11](=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: FC(F)(F)c1cccc2cn[nH]c12
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cccc2c(Br)n[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a mechanically stirred solution of 7-trifluoromethyl-indazole (3.5 g, 18.8 mmol) in 20% NaOH was added bromine (0.62 mL, 12.1 mmol) dropwise. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled and acidified to pH 6-7 by careful addition of concentrated HCl. The solids formed were filtered and dried to give the title compound (2.9 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[N:1]([C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[C:13]=[O:14]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(N=C=O)c1

Procedure:
To a vigorously stirred solution of 3-aminobenzenesulphonamide (1 g, 5.8 mmol) in dry 1,4-dioxane (25 ml) is added trichloromethyl chloroformate (1.72 g, 8.7 mmol) and the reaction mixture is heated to reflux for 3 hours. The solvent is removed in vacuo to yield the title compound which is used without further purification.
Reaction SMILES: [OH2:1].[C:2]([OH:5])(=O)[CH3:3]>>[O:1]=[CH:3][C@@H:2]([C@H:3]([C@@H:2]([C@@H:3]([CH2:2][OH:5])[OH:1])[OH:5])[OH:1])[OH:5]
Reactant: O
Reactant: CC(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The single bath process according to the invention was formed by adding 28 liters of water to the machine at 100° F., and subsequently raising and controlling the temperature of the bath by means of the integrated heating element to a temperature in the range of 135°-138° F. To the water was added 7 grams (0.25 grams/liter of bath) of a conventional non-ionic detergent which acts as a wetting agent and 14 grams (0.5 grams/liter of bath) of 56% acetic acid to adjust the pH to 4.5-5.5. Subsequently was added cellulase enzymes commercially available as "BACTOSOL® CA" (a cellulase enzyme containing preparation that hydrolyses cellulose to produce glucose and glucose polymers, available from Sandoz Chemical Inc., Charlotte, N.C.) which was indicated by the manufacturer to be optimally active at a temperature of approximately 130°-150° F., at a pH in the range of 3.8-5.5. Present in the machine was a cellulase enzyme concentration of 2940 CMC units per lb. of denim. Afterwards was added 560 grams (20 grams/liter of bath) of Glauber's salt and 1% by weight (based on the dry denim textile) of a direct dye solution Lumicrease® Orange 3LG (Colour Index Direct Orange 107) (available from Sandoz Chemical Inc.) which was prepared from a dry form according to the manufacturer's instructions. The machine was operated at the "wash" setting for 45 minutes, after which the liquid was removed from the machine. The treated denim was observed to have been effectively overdyed. It was also observed that good exhaustion of the dye was achieved by visual inspection of a sample of the liquid as it was removed from the machine.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2N(CC3C=CC(Cl)=CC=3)N=C(S(C(F)(F)F)(=O)=O)C=2CC1)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClC1C=CC(B(O)O)=CC=1>C1COCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2c(S(=O)(=O)C(F)(F)F)nn(Cc3ccc(Cl)cc3)c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Clc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1

Procedure:
1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of 142.7 mg of 1-(4-chloro-benzyl)-3-trifluoromethanesulfonyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, prepared as in Example 43, Steps A through C, in 3 mL of THF was added 0.17 g of K3PO4, 54.9 mg of 4-chlorophenylboronic acid, and 22.1 mg of PdCl2dppf. The mixture was heated at reflux for 48 h. The mixture was filtered through diatomaceous earth, rinsing with toluene, and the filtrate was concentrated in vacuo. Chromatography on SiO2 (hexanes to 75% EtOAc/hexanes) afforded 6.7 mg of the desired compound. MS (ESI): exact mass calculated for C25H27Cl2N3O2, 471.15; found, m/z 472.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)[CH2:17][C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19].O>CS(C)=O>[CH3:19][C@@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16][N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC[C@H](C)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
This example illustrates a synthesis of 1-(3-(S)-methyl-7-methyl-6,7-oxidooctyl)-3,7-dimethylxanthine (inventive compound no. 1588S). Sodium hydride (95%) (631 mg, 25 mmol) was added to a solution of theobromine (4.14 g, 23 mmol) in dimethylsulfoxide (75 mL). After 20 minutes of stirring, (S)(-)Citronellyl bromide (5.0 g, 22.8 mmol) was added. After 16 hours of stirring at room temperature, the reaction mixture was poured into a separatory funnel containing 500 mL water and extracted with dichloromethane (3×100 mL). The organic portions were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% petroleum ether/ethyl acetate eluant to yield 5.7 g (80% yield) 1-(3-(S)-methyl-7-methyloct-6-enyl)-3,7-dimethylxanthine (inventive compound no. 1596S) as an yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH3:19])[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=O)[CH3:2].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([CH:3]([CH2:18][CH3:19])[CH:4]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])[CH3:2]
Reactant: CCC(CC)C(=O)c1oc2ccc(OC)cc2c1C
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a mixture of 2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butan-1-one (800 mg) synthesized above, methyl 4-aminobenzoate (464 mg), triethylamine (3.43 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (404 μL), and the mixture was stirred overnight at room temperature under argon atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (882 μL) and sodium cyanoborohydride (386 mg), and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (718 mg, 59%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([CH3:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:33]=[C:34]([CH3:36])[CH:35]=[C:30]([CH3:29])[CH:31]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 84 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-dimethylphenyl boronic acid instead of phenyl boronic acid to obtain the title compound (84%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:31])[CH:9]([C:17]1[CH:30]=[CH:29][C:20]2[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:23][C:19]=2[CH:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.[B-](F)(F)(F)[F:38].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1>[C:3]([O:7][C:8](=[O:31])[C:9]([C:17]1[CH:30]=[CH:29][C:20]2[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:23][C:19]=2[CH:18]=1)([F:38])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(F)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (0.96 g, 24.0 mmol) in THF (75 mL) cooled to 0° C. was added a solution of di-tert-butyl[2-(ethoxycarbonyl)-1-benzothien-6-yl]malonate (described above) (9.66 g, 23.0 mmol) in THF (150 mL) under nitrogen. The resulting orange solution was stirred at 4° C. for 15 minutes. DMF (225 mL) was added followed by Selectfluor (8.15 g, 23.0 mmol). The reaction was warmed to ambient temperature and stirred for 4 hours under nitrogen. The reaction was quenched with ammonium chloride solution and partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by flash column chromatography (2-20% ethyl acetate/hexanes) gave a mixture of starting material and product. This was resubjected to above reaction conditions and purified in a similar manner to give a pale yellow solid. 1H NMR (DMSO-d6) δ 8.21 (s, 1H), 8.17 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 4.33 (q, J=7.3 Hz, 2H), 1.44 (s, 18H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)=[O:10])=[CH:6][CH:5]=[C:4]([CH2:21][C:22]([O:24]CC)=[O:23])[N:3]=1.[OH-].[Na+].CO.O.Cl>C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)=[O:10])=[CH:6][CH:5]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[N:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cn(C)c3ccccc23)c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)Nc2ccc(CC(=O)O)nc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetate (859 mg, 2.31 mmol) was dissolved in THF (25 ml). To the resulting solution was added 0.25N NaOH (13.9 ml, 3.47 mmol), followed by stirring at room temperature for 4 hours. Methanol-water (1:1, v/v, 10 ml) was added, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was acidified with 1N HCl (5.0 ml). The crystals thus precipitated were collected by filtration, washed with water, and dried under reduced pressure to give 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetyl acid (702 mg, 88%) as a colorless solid.
Reaction SMILES: [CH2:1]([CH:18]1[CH:24]2[O:25][CH:21]([CH2:22][O:23]2)[CH2:20][O:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-]>C(OCC)C>[CH2:1]([CH:18]1[CH2:24][O:25][CH:21]([CH2:22][OH:23])[CH2:20][O:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCC1OCC2COC1O2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC1COC(CO)CO1
Temperature: 0 °C

Procedure:
For each diastereomer of (4-heptadecyl-3,6,8-trioxabicyclo[3.2.1]octane, 260 mg of the diastereomer (0.73 mmol) was mixed with 48 mg of LiAlH4, in 5 mL of diethyl ether, and then refluxed gently. Dropwise, 15 mg (1.1 mmol) of AlCl3, in 5 mL of diethyl ether was added to the refluxing solution over a 5 minute period. The resulting reaction mixture was then refluxed vigorously over a period of about several hours. The reaction mixture was subsequently cooled to 0° C., quenched by the dropwise addition of ethylacetyl ether, and then mixed with 10 mL of water to form the associated diastereomers of 5-heptadecyl-2-hydroxy methyl-1,4-dioxane. This product was then extracted from the reaction mixture with diethyl ether and the product extract was subsequently dried and evaporated.