Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:23])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].FC1C=CC=C[C:26]=1[N:31]1C2C=CC=CC=2NS1(=O)=O.BrC[C@H](C)CO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][C@@H:3]([CH3:23])[CH2:2][NH:31][CH3:26])[S:6]1(=[O:22])=[O:21]
Reactant: C[C@@H](CBr)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: C[C@H](CO)CBr
Product: CNC[C@H](C)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 19, step 1, 1-[(2R)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and (R)-3-bromo-2-methylpropan-1-ol giving 0.27 g of the desired product.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Yield: 89.7 %

Procedure:
Methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate (3.7 g) in 40 ml of acetic acid was stirred at 60° C. for 24 hours while blowing air into the mixture in the presence of 0.4 g of cobalt acetate. After completion of the reaction, 3N sulfuric acid was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium carbonate solution and saturated aqueous sodium chloride solution in that order, and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2) to give 3.3 g (yield 90%) of 5-methoxycarbonylmethyl-3,4-bis(4-methoxyphenyl)isoxazole.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34]N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=435.3 (M+H)+
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]5[C:38]=4[CH:39]=[CH:40][CH:41]=[N:42]5)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: Oc1cccc2ncccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)Nc2c(C)cc(Cl)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1c2ncc(CCOc3cccc4ncccc34)cc2C(=O)Nc2c(C)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.7 %

Procedure:
Diethyl azodicarboxylate (DEAD) (77 μL, 0.49 mmol) was added drop wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)4methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (125 mg, 0.38 mmol), 5-hydroxyquinoline (70.9 mg, 0.49 mmol) and Ph3P (128 mg, 0.49 mmol) in THF (2.5 mL) at room temperature. After 1.5 h, additional amounts of DEAD (35 μL, 0.22 mmol) and PPh3 (59 mg, 0.22 mmol) were added to the mixture. The mixture was stirred at room temperature for 1 h then was diluted in EtOAc (50 mL) and the solution was successively washed with aqueous 1 N NaOH (4×10 mL) and brine (15 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:acetone, 85:15). The resulting solid was triturated with Et2O to give the title compound (38 mg, 22% yield) as a white solid: MS (ESI) m/z 460/462 (MH)+.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[CH2:17](Br)[CH:18]=[CH2:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:19]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1c2ccccc2-c2noc3c2C1CCC3
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In 20 ml dry dimethylformaldehyde (DMF) were combined 4.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 3.26 ml allyl bromide and 8 g milled K2CO3. The mixture was heated at 90° C. and mechanically stirred. Every hour 2 ml more allyl bromide was added. After 3 hours, the reaction was complete as observed by TLC. The mixture was partitioned between water and EtOAc. The EtOAc layer was concentrated to a solid which was purified by passing over a silica column (flash chromatography). The product obtained in this manner was recrystallized twice from 20% EtOAc/hexanes to yield 2.99 g solid which was dried in vacuo, m.p. 114°-117° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Fc1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4N hydrogen chloride in dioxane (200 ml) is added to a solution of 3-(4-fluoro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester 5 (39.43 g, 140 mmol) in ethanol (200 ml) and the mixture stirred at room temperature for 18 hours. The solvent is evaporated under vacuum and the residue basified using 4N sodium hydroxide solution (200 ml). The resulting product is extracted using DCM (3×100 ml). The organic extracts are dried (using MgSO4), filtered and evaporated to give the title compound as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCO.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.O>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1ccc(Br)cc1C(=O)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: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(F)c2)cc1C(=O)O
Temperature: 100 °C
Yield: 72.9 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (1 g, 5.12 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (720 mg, 4.65 mmol, 1.1 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and H2O (5 mL) were added Na2CO3 (1.98 g, 18.68 mmol, 4 eq) and Pd(PPh3)4 (270 mg, 0.23 mmol, 0.05 eq). The mixture was heated at 100° C. under N2 for 4 h and the reaction quenched by addition of 1M HCl. The aqueous phase was extracted with EtOAc and the combined organic extracts washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether:EtOAc, 20:1 to 1:1) to give the title compound as a white solid (780 mg, 68%).
Reaction SMILES: [C:1]([CH:6]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18](C(OCC)=O)[C:17]2=[O:30])=[CH:10][C:9]=1[Cl:31])([O:3]CC)=[O:2].[OH-].[Na+].Cl>CO.C(Cl)Cl>[C:1]([CH:6]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:7][C:8]1[C:9]([Cl:31])=[CH:10][C:11]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:30])=[CH:12][C:13]=1[Cl:14])([OH:3])=[O:2]
Reactant: CCOC(=O)C(Oc1c(Cl)cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc1Cl)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C(Oc1c(Cl)cc(Cn2c(=O)[nH]c3ccccc32)cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of 0.082 g (0.14 mmol) of the product of step C in 1.0 mL of methanol and 1.0 mL methylene chloride was added 250 gL of a 5.0 N solution of sodium hydroxide and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then adjusted to pH=5-6 with dropwise addition of 6 N hydrochloric acid, and then concentrated in vacuo. The residue was redissolved in methanol, filtered, and evaporated. The mixture was then purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH-NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.061 g (90%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.[Pd]>[CH3:1][CH:2]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)c1ccncc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccncc1
Reaction time: 18 h

Procedure:
To a solution of ethyl 3-methyl-3-pyridin-4-ylprop-2-enoate (Method 9; 8.4 g, 44 mmol) in ethanol (150 ml) was added 5% palladium on charcoal. The mixture was stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through diatomaceous earth and the filtrate evaporated to leave a colourless oil. The crude product was purified by chromatography eluting with 30-50% EtOAc in hexane to give the product as a colourless oil. M/z 194.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:3]=1.C([Li])CCC.[C:30](=[O:32])=[O:31].Cl>C(OCC)C.C(OCC)(=O)C.O>[F:11][C:10]([F:13])([F:12])[CH2:9][O:8][C:6]1[CH:5]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:3]=[C:2]([C:30]([OH:32])=[O:31])[CH:7]=1
Reactant: FC(F)(F)COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(OCC(F)(F)F)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
2-bromo-4-(2,2,2-trifluoroethoxy)-6-[3-(trifluoromethyl)phenoxy] pyridine (9.81 g, 0.0236 mol) was dissolved in about 200 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [16 ml (ca. 1.63 M in hexane solution), 0.0236×1.1 mol]. The obtained mixture was stirred for about 10 minutes. After replacing an interior of the reactor with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 15 ml of a 4 N aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane). The purified product was recrystallized by adding hexane thereto, thereby obtaining an aimed product.
Reaction SMILES: [C:1]([NH:5]/[CH:6]=[C:7](\[C:14]([O:16][CH3:17])=[O:15])/[CH:8]=[CH:9]/[C:10]([O:12]C)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O-].[Na+]>CO>[C:1]([N:5]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[O-]
Reactant: COC(=O)/C=C/C(=C/NC(C)(C)C)C(=O)OC
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(=O)n(C(C)(C)C)c1

Procedure:
To a solution of dimethyl (2E,4Z)-4-[(tert-butylamino)methylene]-2-pentenedioate (1.2 g) in MeOH (10 mL) was added 28% sodium methoxide in MeOH (1.9 mL), and the mixture was heated to reflux for 8 hr under a nitrogen atmosphere. The solvent was evaporated in vacuo, and the residue was diluted with EtOAc (20 mL). The resulting mixture was washed successively with 1 M HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine, dried over MgSO4 and evaporated in vacuo to give ethyl 1-(tert-butyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (657 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:21](O)=O.C=O>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:21])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:20])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Agent: C=O
Solvent: O
Product: CCOC(=O)c1ccc(N(C)Cc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
To ethyl-4-(4-chlorobenzylamino)-benzoate (5.8 g; 0.02 mole) was added 80% formic acid (30 ml) and 40% formaldehyde solution (10 ml) and the mixture was heated at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, water (60 ml) added and the product filtered, dried under vacuum at 60° C. and was crystallised from ethanol to give N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-methylamine (4.86 g; 80%). M.p. 106°-7° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>CO.O>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cc2)c2cc(CC)oc2c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A suspension of ethyl 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylate (400 mg, 1.0 mmol) and LiOH.H2O (200 mg, 4.7 mmol) in MeOH (20 mL) and water (2 mL) was stir for 4 hr at room temperature. TLC (petroleum ether/EtOAc 4:1) indicated the reaction was complete. The reaction mixture was concentrated to dryness and poured into water (30 mL). The aqueous layer was acidified to pH˜2 with conc. HCl and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (25 mL×2), dried over Na2SO4 and concentrated to afford the desired product (350 mg, 99%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:2].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[NH2:10])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 36.6 %

Procedure:
A stirred mixture of 9.2 g (0.03 mole) of 2-(2-ethoxy-4-nitrophenyl)-1H-isoindol-1,3(2H)-dione and 12.8 g (0.23 mole) of iron powder in 50 ml of water was heated at 100° C. During a two hour period 35.1 g (0.58 mole) of glacial acetic acid was added to the hot reaction mixture. After complete addition the mixture was heated at reflux for four hours. The reaction mixture was cooled then made basic by the addition of potassium carbonate. The basic mixture was extracted with 500 ml of methylene chloride. The extract was filtered, and the filtrate extracted with 300 ml of 2N hydrochloric acid. The acidic extract was made basic with cold concentrated ammonium hydroxide. The basic solution was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under the reduced pressure to produce 3.1 g of 3-ethoxy-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)aniline as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCBr)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 12.4 g (60.4 mmol) of 1,3-dibromopropane, 8.3 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. in an argon gas atmosphere for 8 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 15.1 g (isolated yield: 88.8%, purity: 98% in terms of area percentage by high performance liquid chromatography) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate as a white crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:21]([CH3:27])[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N)cc1
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
In a 10 mL round-bottomed flask 5-[3-(4-amino-phenyl)-3-(4-chloro-2-methyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (88 mg) and methanesulfonyl chloride (40.1 mg) were combined with pyridine (0.87 mL) to give a brown solution. The reaction mixture was stirred at room temperature for 3 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was extracted 3× with ethyl acetate, the organic layers were washed 3× with water and dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 10% methanol in dichloromethane) to give the title compound (68 mg) as a colourless foam, MS (ESI+): m/z=459.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:9]2[O:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2]>O1CCCC1>[CH3:14][C:11]1[O:10][C:9]2[C:4]([CH2:1][OH:2])=[CH:5][CH:6]=[CH:7][C:8]=2[C:12]=1[CH3:13]
Reactant: Cc1oc2c(C(=O)O)cccc2c1C
Solvent: C1CCOC1
Product: Cc1oc2c(CO)cccc2c1C
Temperature: 25 °C
Reaction time: 40 h
Yield: 86.9 %

Procedure:
A mixture of 7-carboxy-2,3-dimethylbenzo[b]furan (400 mg) and borane-dimethyl sulfide complex (0.4 ml) in tetrahydrofuran (6 ml) was stirred at ambient temperature for 40 hours. The mixture was quenched with 1N-hydrochloric acid and extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from n-hexane to give 2,3-dimethyl-7-hydroxymethylbenzo[b]furan (322 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1>[OH-].[Na+].O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][C:20]1[N:21]=[C:16]([Cl:15])[N:17]=[C:18]([CH3:23])[N:19]=1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1O
Reactant: Cc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)n1
Reaction time: 1 h

Procedure:
3-bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol (1.16 g) was dissolved in 10% NaOH (1.78 g) and 5 mL of water. The solvent was stripped under reduced pressure. The salt was taken up in 50 mL acetonitrile and cooled to 0°-5° C. 2,4-dichloro-6-methyl-1,3,5-triazine (0.61 g) was added and the mixture was stirred at 0°-5° C. for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with methylene chloride. The extracts were combined and stripped under reduced pressure to yield 3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH3:39])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH2:38]([O:37][C:33]1[C:30]2[C:31]([CH3:32])=[C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:40])=[O:2])(=[O:10])=[O:11])=[CH:13][CH:14]=4)=[CH:23][CH:22]=3)=[O:26])[O:28][C:29]=2[CH:36]=[CH:35][CH:34]=1)[CH3:39]
Reactant: CCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.3 %

Procedure:
To 100 mg of (S)-2-{4′-[(4-ethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum and triturated with acetonitrile to give 89 mg (91% yield) of (S)-2-{4′-[(4-ethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.6, 6.6 Hz, 6 H) 1.4 (t, J=6.9 Hz, 3 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (m, 1 H) 4.2 (q, J=6.9 Hz, 2 H) 6.8 (d, J=8.3 Hz, 1 H) 7.2 (d, J=8.3 Hz, 1 H) 7.4 (t, J=8.2 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.1 Hz, 1 H) 10.5 (s, 1 H) 12.6 (s, 1 H).