Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].N[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOCC>[Br:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 48% aqueous HBr (2.31 ml, 20 mmol) dissolved in DMSO (25 ml) was added dropwise to a solution of 4-aminobenzophenone (0.986 g, 5 mmol) in a mixture of 25 ml of DMSO and KNO2 (0.851 g, 10 mmol) at 35° C. with agitation. The added mixture was stirred at 35° C. for 10 minutes, and then transferred to a solution containing K2CO3 (5 g) in 100 ml ice-water. The reaction mixture was then taken up in ether, and then the ethereal extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude 4-bromobenzophenone. The crude product was further purified by column chromatography to obtain 4-bromobenzophenone. The yield determined by gas chromatography was 72% (based on decane as an internal standard).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.[Cl:17][C:18]1[S:22][N:21]=[N:20][C:19]=1CCl>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][C:19]3[N:20]=[N:21][S:22][C:18]=3[Cl:17])=[N:6][C:5]=2[N:16]=1
Reactant: ClCc1nnsc1Cl
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: C[C@H](CO)Nc1nc(Sc2nnsc2Cl)nc2nc(N)sc12

Procedure:
Prepared by the method of example 32 step c), using the product of example 32 step b) and 5-chloro-4-(chloromethyl)-1,2,3-thiadiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:20])[CH:11]([C:13]2[N:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH3:12])=[N:6][CH:7]=1.N([C:23]1C=CC=CN=1)N>>[Cl:19][C:16]1[N:15]=[N:14][C:13]([C:11]([CH3:23])([CH3:12])[C:10]([NH:9][NH:8][C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=2)=[O:20])=[CH:18][CH:17]=1
Reactant: NNc1ccccn1
Reactant: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Product: CC(C)(C(=O)NNc1ccccn1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized using an analogous procedure to that described in the preparation of Compound 48C using 2-hydrazinylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([O:25][CH2:26][CH3:27])=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:23][CH3:24])=[C:11]([CH:22]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:23][CH3:24])=[C:11]([CH:22]=1)[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)OCc2ccccc2)c1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)O)c1)OCC
Yield: 97.3 %

Procedure:
1.6 g of benzyl 5-(3-ethoxy-2-ethoxy-3-oxo-1-propenyl)-2-methoxybenzoate was dissolved in 30 ml ethanol, 0.35 g of 10% palladium-carbon was added, and the mixture was stirred for 16 hours in a hydrogen atmosphere. The catalyst was filtered through Celite and the solvent was evaporated. Then, the residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 1.2 g of 5-(3-ethoxy-2-ethoxy-3-oxopropyl)-2-methoxybenzoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[BrH:30].[S:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:30].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][S:31][CH2:36][CH2:35]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCSCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCSCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C

Procedure:
Equimolar amounts of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4,-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-thiomorpholinobutyric acid hydrobromide and dicyclohexylcarbodiimide are reacted to form the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.C(OC)(OC)OC.[CH:21]([NH2:24])([CH3:23])[CH3:22].[BH4-].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:24][CH:21]([CH3:23])[CH3:22]
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: CC(C)NCc1cccc(-c2nccs2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of 3-(1,3-thiazol-2-yl)benzaldehyde (15 g, 81 mmol, 1.0 eq) in THF (100 mL) was added trimethyl orthoformate (9.0 mL, 8.6 g, 81 mmol, 1.0 eq) followed by isopropyl amine (11 mL, 7.3 g, 120 mmol, 1.5 eq) and the resulting reaction was stirred at 23° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methanol (100 mL). Sodium borohydride (6.1 g, 160 mmol, 2.0 eq) was added portionwise over 30 minutes and after addition was complete the reaction was stirred for an additional 30 minutes at 23° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200 mL) and 1M aqueous potassium carbonate solution. The aqueous layer was separated and extracted with ethyl acetate (50 mL×2) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield N-[3-(1,3-thiazol-2-yl)benzyl]propan-2-amine (15 g, 80%) as a white solid. 1H NMR (400 MHz, DMSO): δ 7.91-7.86 (m, 2 H); 7.77-7.72 (m, 2 H); 7.39 (d, J=5.4 Hz, 2 H); 3.72 (s, 2 H); 2.73-2.63 (m, 1 H); 0.98 (d, J=6.2 Hz, 6 H). LRMS m/z (M+H) 233.2 found, 233.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-bromophenol (50 g, 289 mmol) in 340 mL DMF was added Et3N (35 g, 347 mmol) and tert-butyldimethylsilyl chloride (52 g, 347 mmol). The mixture was stirred for 0.5 h, and then diluted with ET2O (2 L). The organic phase was washed with 5% aqueous HCl and brine, and dried over MgSO4. Flash chromatography using hexane:EtOAc (95:5) gave 80.1 g (96%) of product.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>S(=O)(=O)(O)O>[CH2:19]([O:5][C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CC(O)CC(=O)O
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCOC(=O)CC(C)O
Yield: 62.6 %

Procedure:
A 500 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 72.0 g (0.69 moles) 3- hydroxybutyric acid, 268.5 g (1.45 moles) dodecyl alcohol, and 0.36 g sulfuric acid (based on 0.5 g/mole 3-hydroxybutyric acid). The mixture was heated to 115 degrees for 48 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 100 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Excess dodecyl alcohol was removed by high vacuum distillation to yield 117.65 g (60% yield) of clear oil (91% pure by GC).
Reaction SMILES: [F:1][C:2]([F:13])([S:9](Cl)(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(=O)([O-])O.[Na+].[OH:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>C(#N)C>[F:1][C:2]([F:13])([S:9]([O:19][N:20]1[C:24](=[O:25])[C:23]2[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]1=[O:30])(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)CCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)C(F)(F)CCO
Temperature: 0 °C
Yield: 69.7 %

Procedure:
In 100 mL of acetonitrile, 25 g of a liquid of 1,1,2,2-tetrafluoro-4-hydroxybutanesulfonyl chloride (purity: 99%, equivalent to 0.102 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 10.3 g (0.123 mol) of sodium hydrogencarbonate and 18.3 g (0.112 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. With this, 26.4 g of the target compound was obtained as a pale yellow solid (yield: 57%, purity: 82%, pure content: 21.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[N:14]1.[H-].[Na+].[CH3:22]I.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][O:19][CH3:22])[CH:15]=[N:14]1
Reactant: OCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]methanol (1.5 g), sodium hydride (0.15 g) and methyl iodide (0.7 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 2 hours and left over the weekend. The mixture was added to water and extracted with ether. The extract was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methoxymethyl-2H-1,2,3-triazole, m.p. 32°-33°. (Compound 20)
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]3[N:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:14][C:15]=3[CH3:16])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (549 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetate (618 mg, yield: 74%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(CC([N:6]1[CH2:9][CH:8]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:13]([CH3:40])[CH:12]=2)[CH2:7]1)=O)#N.[OH-].[Li+]>O1CCCC1.CO>[NH:6]1[CH2:9][CH:8]([O:10][C:11]2[CH:12]=[C:13]([CH3:40])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:15]([CH3:17])[CH:16]=2)[CH2:7]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)CC#N)C5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OC2CNC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
(S)-Methyl 2-(6-((4′-((1-(2-cyanoacetyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 16c (80 mg, 0.15 mmol) was dissolved in 2 mL of a mixture of the solvents of tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (1 mL, 1 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 16 (65 mg, yield 95.6%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.C(O)(=O)C.[BrH:25].CC(O)=O>C(OCC)C>[BrH:25].[Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH2:6][NH2:7]
Reactant: O=C(CNC(=O)OCc1ccccc1)OCC(Cl)(Cl)Cl
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A well stirred solution of 45.0 g. (0.13 mole) of carbobenzyloxyglycine 2,2,2-trichloroethyl ester in 100 ml. of glacial acetic acid is cooled to 20° and 100 ml. of 5N HBr-CH3CO2H is added. After 10 minutes, a vigorous evolution of gas occurs. The reaction mixture is stirred at room temperature for two hours. The mixture is then diluted with dry ethyl ether and the precipitate is filtered. The product is crystallized from acetonitrile to give aminoacetic acid 2,2,2-trichloroethyl ester, hydrobromide as white crystals; m.p. 238°-240° (d); 29.5 g. (78.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)OCc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3CCCC[C@H]3C(=O)OCc3ccccc3)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 57.3 %

Procedure:
With 2.00 g of the compound obtained in Step 113-1 and 1.42 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 1.74 g of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl.[Cl:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:21][CH2:20][Cl:19])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NCCCl
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NCCCl
Yield: 41.8 %

Procedure:
2.54 g (10 mmol) of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (J. Med. Chem. 2001, 44, 1025) and 1.28 g (11 mmol) 2-chloroethylamine hydrochloride were added to 40 ml of anhydrous ethanol. Then 7 ml (50 mmol) of triethylamine were added. The mixture was heated at reflux until the reaction was completed (4 hours). The reaction mixture was concentrated under reduced pressure and 20 ml of saturated aqueous sodium carbonate solution was added. The mixture was extracted with 3×20 ml ethyl acetate. The combined organic layers were washed with 15 ml of water and 15 ml of brine, dried over Na2SO4 and evaporated in vacuo. The crude product (2.88 g) was first purified by flash chromatography on silica gel (petrol ether/ethyl acetate 5:1) and then crystallized from 20 ml of hexane/ethyl acetate=1/1 to afford 1.24 g (42%) of the desired product as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C)C=O.O>[CH2:11]([O:10][C:8]([C:7]1[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4][N:5]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:6]=1)=[O:9])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (6.24 g, 30.0 mmol) in N,N-dimethylformamide (60 ml) was added under ice-cooling 60% sodium hydride (1.80 g, 45.0 mmol) by a small amount and the mixture was stirred for 30 min. tert-Butyl bromoacetate (5.32 mL, 36.0 mmol) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give tert-butyl [4-(ethoxycarbonyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (7.33 g, 75%) as a colorless oil. Trifluoroacetic acid (30 mL) was added to the present compound (3.22 g, 10.0 mmol), and the mixture was stirred under ice-cooling for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (2.03 g, 76%) as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3-dihydrobenzofuran (5.0 g) in dichloromethane (30 ml) at -10° C. was slowly added a solution of acetyl chloride (5.9 ml) and anhydrous aluminum chloride (5.5 g) in dichloromethane (30 ml) while keeping the temperature below -6° C. After addition of the 2,3-dihydrobenzofuran was completed, the reaction mixture was stirred for 10 minutes at -10° C. The reaction mixture was then added to an ice/hydrochloric acid mixture which was extracted with dichloromethane. The combined dichloromethane extracts were washed with water and dilute sodium hydroxide, the organic layer dried over sodium sulfate and evaporated. The resulting residue was recrystallized from hexane to give 5-acetyl-2,3-dihydrobenzofuran, m.p.--56°-57° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19])C(OCC)=O)[CH3:2].[Cl-].[Li+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(N)c(C)cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(N)c(C)cc1Cl
Temperature: 170 °C
Yield: 50.6 %

Procedure:
To a solution of 2-(5-amino-2-chloro-4-methyl-phenyl)-malonic acid diethyl ester (0.50 g, 2.17 mmol) in DMSO (3 ml) and water (0.078 ml) was added, followed by lithium chloride (0.138 g, 3.26 mmol). The mixture was heated to 170° C. for three hours, then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 8:2) gave 0.250 g (50%) of (5-amino-2-chloro-4-methyl-phenyl)-acetic acid ethyl ester as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCN
Product: CCNCc1ccc(Br)cc1
Yield: 75.9 %

Procedure:
Following the procedure outlined for Example 488, 1-bromo-4-(bromomethyl)benzene (2.0 g, 8.0 mmol) was reacted with ethanamine (720 mg, 16 mmol) to afford the desired product (1.3 g, 75%) as a brown solid: ESI MS m/z 215 [C9H12BrN+H]+.
Reaction SMILES: N1C=CC([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])=CC=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:24][O:23][C:13]1[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[C:18]=2[C:10]([C:8]([NH2:7]=[O:33])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccncc2)c2c1oc1ccccc12
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)[NH2+][O-])c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of N-(pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide (150 mg, 0.47 mmol) (example 3) and m-chloroperbenzoic acid (50-55%) (406 mg, 2.3 mmol) in chloroform (2.5 ml) was stirred at room temperature for 16 h. Chloroform was evaporated and the resulting solid was washed with saturated sodium bicarbonate solution, water, dried and then purified by column chromatography using 20% acetone-chloroform as the eluent to give 70 mg of N-pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; nip: 246-251° C.; IR (KBr): 3207, 3116, 3056, 2931, 2840, 2797, 1678, 1626, 1603, 1530, 1485, 1458, 1439, 1391, 1330, 1277, 1214, 1174, 1122, 1099, 1023, 851, 829, 791, 749 cm−1.