Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[CH2:12]([NH:11][C:9]([C:4]1([C:1](=[O:3])[CH2:2][Br:26])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)C1(C(=O)NCc2ccccc2)CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C(CBr)C1(C(=O)NCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
To a solution of 1-acetyl-N-benzylcyclopentane carboxamide (44 g, 179.36 mmol) in EtOH (700 mL) were added NBS (70.22 g, 394.59 mmol) and PTSA (3.5 g, 17.94 mmol). After addition, the reaction mixture was stirred at rt for 48 h and concentrated in vacuo. To the residue was added water (500 mL) and the resulting mixture was extracted with EtOAc (500 mL×3). Then the combined organic phases were washed with saturated Na2S2O3 solution (500 mL×3) and brine (500 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the product as a white solid (39.5 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[S:30][C:29]([C:31]([NH2:33])=[O:32])=[N:28][N:27]=1>CN(C=O)C>[C:31]([C:29]1[S:30][C:26]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:27][N:28]=1)(=[O:32])[NH2:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: NC(=O)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(N)=O)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.2 mmol) in anhydrous DMF (8 mL) was added cesium carbonate (8 mmol) and 5-chloro-1,3,4-thiadiazole-2-carboxamide (3.2 mmol). The resulting mixture was stirred at room temperature overnight then quenched with crushed ice. The pH was adjusted to 2 with 6M HCl and the mixture extracted with EtOAc (2×200 mL). The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-75% EtOAc in hexane) to give ethyl 2-(6-(5-carbamoyl-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:19]>C(O)C.O>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1cccc(F)c1F
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cnccc1Nc1cccc(F)c1F
Yield: 77.9 %

Procedure:
To a solution of 4-chloro-3-nitropyridine (3.0 g, 18.9 mmol) in dry ethanol as added 2,3-difluorobenzenamine (3.66 g, 28.3 mmol). The reaction mixture was refluxed for 30 min. After cooling and concentration in vacuo to give a brown solid, the crude product was taken up in water and the aqueous solution adjusted to a pH of 8-9 and the solution extracted with EtOAc (3×100 mL). The combined organics were washed with water (3×100 mL) and brine solution (1×100 mL), respectively, dried over Na2SO4, and evaporated in vacuo to give a light brown solid. The crude product was triturated with petroleum ether (3×30 mL) to afford N-(2,3-difluorophenyl)-3-nitropyridin-4-amine (3.7 g, 79% yield) as light yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[C:12]([I:13])[C:5]=12.Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:15]3[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:11]=[C:12]([I:13])[C:5]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1-n1nc(I)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.825 mmol, 153 mg) was added to a suspension of 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 3.825 mmol) in DMF (5 mL). After 10 min, 2-chloro-3-cyanopyridine (531 mg) was added and the reaction was heated at 60° C. for 16 h. The resulting dark mixture was poured into ice-water (50 mL) and the solid collected by filtration to afford 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-pyridyl cyanide as a brown solid (1.1 g, 79%); 1H NMR (DMSO-d6, 400 MHz) δ 7.82 (1H, m), 8.29 (1H, s), 8.64 (1H, m) and 8.93 (1H, m); RP-HPLC (Pecosphere, C18, 3 μm, 33×4.6 mm column, 0% to 100% acetonitrile in 50 mM ammonium acetate, buffered to pH 4.5, at 3.5 mL/min) Rt 2.16 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=1)[O:11][CH2:12][C:13](=[CH2:16])[CH2:14][OH:15].[CH3:31]COCC>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=1)[O:11][CH2:12][C:13]1([CH2:14][OH:15])[CH2:31][CH2:16]1
Reactant: CCOCC
Reactant: C=C(CO)CO[C@H](CCc1ccccc1Br)c1cccc(COC2CCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: OCC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Yield: 59 %

Procedure:
At 0° C., Pd(OAc)2 (500 mg) and ~0.4M CH2N2 in ether (1.84) were added portionwise and simultaneously to a solution of the allylic alcohol of Step 4 (20.45 g, 43.0 mmol) in 80 mL of THF. When the reaction was complete, the mixture was filtered through a small pad of silica and concentrated. The residue was purified by flash chromatography on silica with EtOAc:toluene 15:85 to give 12.40 g (59%) of the title product.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1I
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1I
Temperature: 80 °C

Procedure:
2-Iodobenzoic acid (100 g) was dissolved in 400 mL of concentrated sulphuric acid and placed in a 2 liter 3 necked flask. The flask was fitted with reflux condenser, a thermometer and an addition funnel. Fuming nitric acid (400 ml) was added drop by drop. The addition was adjusted in such a way that the temperature was allowed to raise to 80° C. over a period of 2 hours. During the addition, the reaction mixture was stirred vigorously and maintained the temperature at 80° C. for an additional 2 hours. After the completion of the reaction, the reaction mixture was poured slowly into crushed ice (3 Kg). The contents were allowed to settle and were filtered. The yellow precipitate was collected and dried at 30° C. The yield was 9.0 grams.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[CH2:15][O:16][CH3:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH3:17][O:16][CH2:15][CH:3]1[CH:2]([NH:1][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCC1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1-dimethylethyl 4-amino-3-[(methyloxy)methyl]-1-piperidinecarboxylate D33 (0.7 g), and benzoyl chloride (490 mg, 3.5 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Fisher) were dissolved in dichloromethane (30 ml) and then triethylamine (1.3 ml, 8.7 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, then washed with water (2×), brine, dried with MgSO4, filtered and solvent removed to obtain a yellow oil of crude product which was purified by column chromatography on silica gel eluting with pet eth/EA (2/1) to give clean desired product D34 as a yellow oil in 0.8 g. LCMS [M-56+H] 293.1@1.62 min (5 min run)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[N:13]([C:15]4[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=4)[N:12]=[C:11]([C:25]([F:28])([F:27])[F:26])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:29]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C1(C=CC(O)=CC=1)O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:29]=1)=[CH:8][CH:9]=[C:10]1[C:14]=2[N:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:12]=[C:11]1[C:25]([F:28])([F:26])[F:27]
Reactant: COc1ccc2c(c1)CCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Product: COc1ccc2c(ccc3c(C(F)(F)F)nn(-c4ccc(S(N)(=O)=O)cc4)c32)c1
Yield: 87 %

Procedure:
4-[4,5-Dihydro-7-methoxy-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide from Step 2 (1.27 g, 3.0 mmol) was dissolved in 1,4-dioxane (200 ml), and DDQ (681 mg, 3.0 mmol) was added. The reaction was heated to reflux for 16 hours at which time a second equivalent of DDQ (681 mg, 3.0 mmol) was added and the reaction was heated to reflux for an additional 24 hours. At three successive 24 hour intervals, 3.0 mmol additional DDQ was added and heating continued until no starting material was left (as determined by thin layer chromatography). The reaction was cooled to room temperature at which time most of the hydroquinone by-product precipitated. The reaction was filtered and concentrated. The residue was chromatographed on silica gel eluting with 50% ethyl acetate in hexane to yield 4-[7-methoxy-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide (1.1 g, 87%): 1H NMR (acetone d6) δ=3.9 (s, 3H), 6.9 (broad s, 2H) 7.1 (m, 1H), 7.6 (m, 2H), 7.8 (m, 2H), 8.0 (d, 2H j=8.7 Hz), 8.2 (d, 2H j=8.7 Hz); 19F NMR (acetone d6) δ-61.8 ppm (s, 3F).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Cl[C:16]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]1[C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:16]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[N:17][CH:18]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described in example 108B], 4-(trifluoromethoxy)-phenylboronic acid was reacted with methyl 6-chloro-4-(trifluoromethyl)nicotinate in the presence of bis(triphenylphosphine)palladium(II)chloride and aqueous 2M K3PO4 solution to give the title compound as yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][CH3:24])[CH2:21][CH2:20]3)=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+].O.CC#N>C(O)C.O1CCCC1>[CH2:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=3)=[CH:14][C:15]=2[CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]1)[CH3:24]
Reactant: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc2C(C)C)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
Using General Procedure I; a solution of methyl{4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate (Compound 100, 130.0 mg, 0.35 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred at 50° C. for 4 h. Work-up and isolation by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded 88.0 mg (70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[Cl:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Br:11])[C:3]=1[Cl:10]
Reactant: Cc1c(Cl)ccc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(Cl)c1CBr
Temperature: 0 °C
Yield: 97.2 %

Procedure:
Treat a mixture of 1-bromo-2,4-dichloro-3-methyl-benzene (76.01 g, 0.316 mol) and N-bromosuccinimide (59.2 g, 0.332 mol) in CCl4 (500 mL) with benzoyl peroxide (0.77 g, 3.18 mmol) and is heat to reflux for 6 hours under N2. Cool the reaction mixture to 0° C. and filter using hexanes to rinse the solids. Extract the filtrate with water and saturated NaHCO3. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 97.89 g (97%) of the titled product. Rf=0.34 (100% hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:10][Br:11].ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl>[Br:11][CH2:10][C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccccc1/C=C(\CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccccc1C1OC1(CBr)c1ccccc1
Yield: 70.2 %

Procedure:
30 g of Z-1-(2-chlorophenyl)-2-phenyl-3-bromoprop-1-ene were refluxed with 23 of 3-chloroperoxybenzoic acid in 500 ml of chloroform. When the reaction was complete, the chloroform phase was washed acid-free with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. The residue gave 41.3 g (70.2%) of 2-bromomethyl-2-phenyl--(2-chlorophenyl)-oxirane, which was then further processed with triazole according to the Example below. II. Preparation of the end products
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(Cl)ccc(Br)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1c(Cl)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (20.0 g, 0.084 mol) in ethanol (250 mL) was added sodium borohydride (6.4 g, 0.168 mol) and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×200 mL), dried (sodium sulfate) and concentrated. The crude solid was recrystallized from hexanes to give (3-bromo-6-chloro-2-fluorophenyl) methanol (10.4 g, 0.043 mol): 1H NMR (CDCl3): δ 7.50 (m, 1H), 7.15 (dt, 1H), 4.90 (s, 2H), 2.10 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CS(C)=O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])[C:12]=1[C:13]#[N:14]
Reactant: Nc1c(F)cccc1F
Reactant: N#Cc1c(F)cccc1F
Solvent: CS(C)=O
Product: N#Cc1c(F)cccc1Nc1c(F)cccc1F
Temperature: 25 °C

Procedure:
2,6-Difluoroaniline (1.29 g, 10 mmol) was dissolved in dimethyl sulfoxide (10 mL) and stirred under argon at room temperature. Sodium hydride, dry, 95%, (0.24 g, 10 mmol) was added in portions and the mixture was stirred at room temperature for 1 hour. 2,6-Difluorobenzonitrile (0.463 g, 3.3 mmol) dissolved in dimethyl sulfoxide (5 mL) was added and the mixture stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water (5×), brine (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–25% CH2Cl2 in hexane to give the title compound as a white amorphous solid. mp 145–146° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][O:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([NH:25]C(=O)OC(C)(C)C)=[C:20]([CH3:33])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(NC1C(C)=NC(OCC(O)=O)=NC=1C)=O)(C)(C)C.Cl>C(Cl)(Cl)Cl>[NH2:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([O:17][CH2:16][C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[CH3:35])=[O:34])=[N:19][C:20]=1[CH3:33]
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.9 %

Procedure:
Compound 30 (calculated assuming that Compound 9 in the previous process was 74.74 g and the yield of amidation was 80%) was dissolved in chloroform (140 mL). The solution was added to a 6N aqueous HCl solution (530 mL) at room temperature (20 to 30° C.). The equipment used to add compound 30 was thoroughly washed with chloroform (240 mL) and was then stirred at room temperature (20 to 30° C.) for 2.5 hours. After the chloroform layer was separated, chloroform (300 mL) was added to the aqueous layer. While ice (740.7 g in total) was added as necessary, a 4N aqueous sodium hydroxide solution (805 mL) was added portionwise. An additional amount of 4N aqueous sodium hydroxide solution (25 mL to adjust the pH of the aqueous layer to 8.5) was added, followed by the addition of chloroform (80 mL), and separation was performed. After the chloroform layer was separated, chloroform (200 ml) was added to the aqueous layer and separation was performed again. The chloroform layer collected in the two extraction processes was dried over magnesium sulfate and suction-filtered. The filtrate was then evaporated under reduced pressure to give 100.15 g (103.9% yield, in 2 steps) of the crude desired product as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=1)[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Reactant: BrCCCCCBr
Product: CCOC(=O)CCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Yield: 80.6 %

Procedure:
Starting with 0.458 g (1.42 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxy-γ-oxobenzenebutanoic acid ethyl ester, and 1.65 g (7.29 mmol) of 1,5-dibromopentane, the title compound was obtained in 80.6% yield as a white solid, mp 40°-41° C., using the procedure of example 21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C.ClCCl>CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:15][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([NH:10][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:11][CH3:12])[CH3:9])[CH:18]=1
Reactant: COc1c(C)cc(F)cc1C(C)N
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)cc(F)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Yield: 15 %

Procedure:
A solution of 1-(5-Fluoro-2-methoxy-3-methylphenyl)ethanamine (0.34 g, 1.87 mmol), 2,4-difluoro-1-methanesulfonyl-benzene (0.3 g, 1.56 mmol) and diisopropylethylamine (1.4 mL, 7.81 mmol) in N,N-dimethylformamide (10 mL) was stirred at 110° C. for 18 h. Dichloromethane was added (20 mL) and washed with water (2×20 mL), brine (20 mL), dried, and concentrated under reduced pressure to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 5-fluoro-N-(1-(5-fluoro-2-methoxy-3-methylphenyl)ethyl)-2-(methylsulfonyl)benzenamine (83 mg, 14%): 1H NMR (400 MHz, CDCl3): δ 7.78 (dd, 1H), 7.07 (dd, 1H), 7.03 (dd, 1H), 6.53 (dd, 1H), 6.32 (dd, 1H), 4.82 (bs, 1H), 4.45 (m, 1H), 3.75 (s 3H), 3.07 (s, 3H), 2.41 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24](F)[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.CN1C=CC(NC(C2C=C(OC3C=CC(C#N)=CC=3)C3CC(C)(C)OC=3C=2)=O)=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[CH:24][CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Agent: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (187b) (212 mg, 0.321 mmol) and used without further purification for the next step.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[CH3:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1.II>[CH3:5][C:6]1[O:10][C:9]([CH:11]([OH:12])[CH2:2][CH3:3])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C)o1
Reaction time: 1 h
Yield: 151.7 %

Procedure:
Under an atmosphere of nitrogen, 10 ml of tetrahydrofuran and 10 mg of iodine were mixed with 3.974 g of magnesium flakes. With stirring, 3 ml of a solution prepared by dissolving 22.28 g of ethyl bromide in 25 ml of tetrahydrofuran was added dropwise to the mixture. The residual tetrahydrofuran solution of ethyl bromide was added dropwise to the reaction vessel placed in a water bath over one hour. After stirring for thirty minutes, a solution prepared by dissolving 15 g of 5-methyl-2-furaldehyde in 5 ml of tetrahydrofuran was added dropwise to the reaction solution over five minutes under ice-water cooling. After one hour, the reaction solution was added to a cooled 10% ammonium chloride solution and stirred for five minutes. The mixed solution was extracted twice with diethyl ether. The combined ether layer was washed twice with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was distilled, and a distillate fraction of 95° to 98° C. at 22 mmHg was collected to yield 28.977 g of 1-(5-methyl-2-furyl)propanol. Yield 91% b.p.: 95°-98° C. (22 mmHg)