Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[C:10]([NH2:24])[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]N.CO>O>[C:2]1([CH:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)=[C:10]([NH:24][CH3:25])[O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reaction time: 48 h
Yield: 93 %

Procedure:
In this example, 2.5 ml of aqueous 2N hydrochloric acid was added at room temperature to a stirred slurry containing 10 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 60 ml of aqueous 40 wt % methyl amine followed by the addition of 50 ml of methanol. The resulting suspension was heated to reflux and refluxed for about 24 hours and then allowed to cool and stand at room temperature for about 2 days. The mixture was then added to a dilute acid solution containing 58 ml of aqueous 12N hydrochloric acid in 300 ml of water and then extracted twice with methylene chloride. The methylene chloride extracts were combined and successively washed once with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and evaporated under vacuum affording 9.7 g of the title compound as a pale yellow foam (yield=93%).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@:21]3([N:25]([CH3:26])[C:24](=[O:27])[N:23]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:22]3=[O:36])[CH2:20][N:19]([CH2:37][C:38](O)=[O:39])[CH2:18]2)=[CH:13][CH:12]=1)#[N:10].C[N:42]1CCOCC1.N>C(Cl)Cl.O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@:21]3([N:25]([CH3:26])[C:24](=[O:27])[N:23]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:22]3=[O:36])[CH2:20][N:19]([CH2:37][C:38]([NH2:42])=[O:39])[CH2:18]2)=[CH:15][CH:16]=1)#[N:10]
Reactant: CN1CCOCC1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)O)C[C@H]2c1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(N)=O)C[C@H]2c1ccc(C#N)cc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Isobutyl chloroformate (27 μl, 0.21 mmol) was added to a cooled (5° C.) suspension of Example 64 (90 mg, 0.19 mmol) and N-methyl morpholine (23 μl, 0.2 mmol) in DCM (4 ml). After 1 h, ammonia (420 μl, 0.5 M in dioxane, 0.21 mmol) was added. After 1 h at 5° C. and 3 h at RT, water (2 ml) was added. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic layers were concentrated in vacuo and the resulting material was purified by chromatography over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound as a solid (49.6 mg). 1H NMR (CDCl3): 7.64 (2H, d, J=8.2 Hz), 7.25–7.30 (3H, m), 6.84 (1H, br s), 6.65 (2H, d, J=1.5 Hz), 6.18 (1H, br s), 3.87 (1H, t), 3.4–3.5 (5H, m), 3.24 (3H, s), 3.15 (1H, d, J=10.9 Hz).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:33][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N3CCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
Lithium hydroxide monohydrate (0.02 g, 0.68 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(pyrrolidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.075 g, 0.17 mmol) in a 3:1 mixture of THF—H2O mixture (8 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-3-methyl-4-[4-(pyrrolidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.064 g, 88%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s, 1 H), 7.98 (d, J=8.31 Hz, 3H), 7.91 (s, 1 H), 7.51 (d, J=8.31 Hz, 2 H), 7.39 (td, J=8.80, 2.40 Hz, 1 H), 6.69 (dd, J=11.20, 2.40 Hz, 1 H), 3.85 (s, 2 H), 3.21-3.29 (m, 4 H), 2.07 (s, 3 H), 1.64-1.76 (m, 4 H). MS calcd. for C23H21FNO4S [(M−H)−] 426, obsd. 426.4.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.C([O-])(=O)C.[K+].[C:11]([NH:19][C:20]1[CH:32]=[C:31](I)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:11]([NH:19][C:20]1[CH:32]=[C:31]([CH:1]2[CH2:5][CH2:4][CH:3]=[CH:2]2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1NC(=O)c1ccccc1
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C2C=CCC2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.21 mL of cyclopentene, 0.14 g of potassium acetate, 0.13 g of tetrabutylammonium chloride, 3.1 mg of triphenylphosphine and 2.7 mg of palladium acetate were added to 1.0 mL of N-dimethylformamide solution containing 0.20 g of tert-butyl 2-(benzamido)-4-iodobenzoate at room temperature and stirred under nitrogen atmosphere at the same temperature for 17 hours. 0.21 mL of cyclopentene, 23 mg of potassium acetate, 3.1 mg of triphenylphosphine and 2.7 mg of palladium acetate were added to the reaction mixture and stirred at 70° C. for 3 hours after stirred at room temperature for 9 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; toluene] to obtain 94 mg of tert-butyl 2-(benzamido)-4-(2-cyclopenten-1-yl)benzoate as white solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([NH:16][C:17]([CH3:27])=[CH:18][C:19](=[O:26])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:29]1[C:41]2[NH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:27][C:17]([NH:16][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:38]2[C:39]3[NH:40][C:41]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]=3[CH:35]=[CH:36][CH:37]=2)=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:28])=[CH:18][C:19](=[O:26])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=CC(=O)c1cccnc1)NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 15.7 %

Procedure:
To a solution of 2-(1-methyl-3-oxo-3-(3-pyridyl)-propenylamino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.22 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water(3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.04 g, 16%). HRMS calcd for C32H29N3O4: 519.6001. Found: 519.6003. MA calcd for C32H29N3O4: C, 73.97%; H, 5.63%; N, 8.09%. Found: C, 73.84%; H, 5.65%; N, 8.11%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH:10]([C:23](O)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]([NH2:57])[CH:54]=[CH:55][CH:56]=1>ClCCCl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])=[O:15])[CH:10]([C:23](=[O:24])[NH:57][C:53]2[CH:54]=[CH:55][CH:56]=[C:51]([F:50])[CH:52]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCC[Si](C)(C)C)C(C(=O)O)C1
Reactant: Nc1cccc(F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)OCC[Si](C)(C)C)C(C(=O)Nc2cccc(F)c2)C1
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
To a solution of 4-(2-trimethylsilanyl-ethoxycarbonylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (3200.00 mg; 8.54 mmol; 1.00 eq.) in DCE (40.0 ml), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (2392.68 mg; 9.40 mmol; 1.10 eq.) was added. After stirring for 15 mins. DIEA (1.69 ml; 9.40 mmol; 1.10 eq.) and 3-fluoro-phenylamine (1044.40 mg; 9.40 mmol; 1.10 eq) were added. The reaction mixture was stirred overnight at 45° C. The reaction solution was diluted with EtOAc, washed, dried and concentrated to give the crude product, which was subjected for SNAP (100 g) column for purification (eluted with 20-50% EtOAc in hexane) to afford the title compound (1700 mg, 42.5%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][CH:31]([CH2:36][CH3:37])[CH2:32][C:33](O)=[O:34]>>[CH3:30][CH:31]([CH2:36][CH3:37])[CH2:32][C:33]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:34]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: CCC(C)CC(=O)O
Agent: Cl
Product: CCC(C)CC(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3-methylvaleric acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methylvaleroyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 464 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]([CH2:16][CH2:17][CH3:18])([CH2:12][CH2:13][CH2:14][CH3:15])C(O)=O)[CH3:7].[N-:19]=[N+]=[N-].[Na+].[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[CH2:6]([C:8]([NH2:19])([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7]
Reactant: CCCCC(CC)(CCC)C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCC(N)(CC)CCC
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a condenser, were introduced 70 ml of chloroform, 18 ml of concentrated sulphuric acid (d=1.83) and 11 g (0.06 mol) of 2-ethyl-2-n-propylhexanoic acid prepared as described above. The mixture was heated to 50° C. and while stirring 7.5 g of sodium azide in powder form were added. The operation of addition lasted 90 minutes after which the reaction mixture was heated to 50° C. for 2 hours. The mixture was then neutralized with a 40% aqueous solution of sodium hydroxide previously cooled to 0° C. The amine was extracted with ether and the ethereal phase was washed with water and dried over magnesium sulphate. The ether was evaporated out under vacuum and the oil so obtained was taken up in dry ether, which provided 1-ethyl-1-n-propyl-n-pentylamine in free base form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCCCCC.C([Li])CCC.Cl[Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][Si:24](Cl)([CH3:26])[CH3:25].[Cl-].[Na+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][Si:21]2([CH3:29])[CH3:28])=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Cl)cn1
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a tetrahydrofuran (350 ml) solution of 5-chloropyridin-2-ylamine (10.28 g, 80.0 mmol) was added a hexane solution (1.58M, 50.6 ml, 80.0 mmol) of n-butyl lithium at −78° C. The resulting mixture was stirred for 1 hour. At the same temperature, a tetrahydrofuran (50 ml) solution of 1,2-bis(chlorodimethylsilyl)ethane (17.22 g, 80.0 mmol) was added to the reaction mixture, followed by stirring for 1 hour. A hexane solution (1.58M, 50.6 ml, 80.0 mmol) of n-butyl lithium was added at the same temperature and the resulting mixture was stirred for 30 minutes. At room temperature, a saturated aqueous solution of sodium chloride was added to the reaction mixture. Diethyl ether was added to the resulting mixture to separate it into layers. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was distilled under reduced pressure (120° C./3.0 mmHg) to give the title compound (12.97 g, 47.9 mmol, 60%) as a colorless acicular substance.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]=[O:19])[C:12]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=[C:25]2[CH:24]=[CH:23]1.CO.[OH-].[K+]>O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:24]2[C:25]3[C:26](=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=3)[NH:22][CH:23]=2)[OH:19])[C:12]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: N#Cc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2[nH]cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Into a reaction vessel, (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (25, 10.00 g, 34.3 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 4.91 g, 34.3 mmol), 50.00 mL of anhydrous methanol, and potassium hydroxide (2.77 g, 49.4 mmol) were added under nitrogen and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 500 mL of water and extracted with 3×500 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting residue was purified using silica gel column chromatography to provide the desired compounds (26, 4.62 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10].[OH:21]OS([O-])=O.[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]
Reactant: O=S([O-])OO
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(Cl)c2)OC1(C)C
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OC(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 27, 0.83 g, 3.2 mmol) in THF (16 ml) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under N2 and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo and the residue filtered through a silica gel cake with arbocel on top washing through with EtOAc. The filtrate was concentrated in vacuo to give a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 ml) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 ml) and EtOAc (20 ml), the combined organic phase was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography eluting with 0-40% EtOAc in Heptane to afford the title compound (0.53 g, 82% yield) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][NH:18][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10])=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-2-hydroxybenzaldehyde (1.5 g, 9.3 mmol), tert-butylcarbazate (1.25 g, 9.3 mmol) and acetic acid (0.54 mL, 9.3 mmol) in CH2Cl2 (50 mL) was stirred under a N2 atmosphere for 30 min at RT. Then sodium triacetoxyborohydride (6.20 g, 27.9 mmol) was added portion wise and the resulting mixture was stirred at RT overnight. The reaction was thoroughly quenched with 2 M HCl (15 mL) and stirred at RT for 1 h. The reaction mixture was partitioned between water (50 mL) and CH2Cl2 (25 mL). The aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with water (2×75 mL), dried (Na2SO4) and evaporated to dryness to give hydrazine 1 as a white solid, 2.6 g (100%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CCOCC>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:21])=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1ccccn1
Yield: 66.2 %

Procedure:
An anhydrous solution of 1,1'-carbonyldiimidazole (13.13 g, 81 mmol) in dimethylformamide (80 mL) was treated with picolinic acid (10.0 g, 81 mmol), and after 1 hour 4-fluoroaniline (8.46 mL, 89 mmol) was introduced. After 27 hours the reaction mixture was poured into saturated sodium bicarbonate solution (900 mL) and ether (400 mL). The aqueous layer was extracted again with ether (3×400 mL) and the ethereal layers were dried and concentrated. The crude solid residue was recrystallized from a mixture of ether and petroleum ether to yield N-(4-fluorophenyl)-2-pyridinecarboxamide (11.6 g, 66%) as beige crystals, m.p. 100°-103° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:22])[CH3:21]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OC(C)C(=O)OCC)ccc(C(C)=O)c1O
Yield: 73 %

Procedure:
A mixture of 10.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 8.4 ml of ethyl 2-bromopropionate and 10.7 g of anhydrous potassium carbonate in 125 ml of anhydrous acetone was stirred at reflux for 42 hours. The reaction mixture was filtered and the filtrate was concentrated to an oil which was purified by high pressure liquid chromatography using 2% ethyl acetate-toluene to yield 11.4 g (73%) of racemic-(4-acetyl-3-hydroxy-2-propylphenoxy)-alpha-methylacetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Nc1ncccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(Nc2cc3ccccc3o2)nc1
Temperature: 25 °C

Procedure:
A mixture of 2-amino-3-bromopyridine (1.0 g, 5.7 mmol), benzofuran-2-boronic acid (1.03 g, 6.4 mmol), Pd(dppf)2Cl2 (50 mg) and K2CO3 (1.83 g, 13.3 mmol) in dioxane/H2O (4:1, 5 under nitrogen at 80° C. for 16 h, cooled to RT, and concentrated in vacuo. The solid residue thus obtained was dissolved in EtOAc (30 mL) and washed with water (20 mL) and dried in vacuo. The crude material was purified by chromatography on silica gel using EtOAc/Hexanes (1:4) to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=5.61 (brs, 2H), 6.82 (dd, J=7.2, 4.1 Hz, 1H), 7.05 (s, 1H), 7.25-7.28 (m, 2H), 7.60 (d, J=7.2 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 8.19 (d, 2.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(-c2c(C)[nH]c3ccc(O)cc23)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccc(C)cc3)c2c1

Procedure:
The above compound was prepared from 2-methyl-3-(4-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[CH:11]=1.C(N(CC)CC)C>O1CCOCC1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([O:8][C:17](=[O:18])[NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)=[CH:2][CH:3]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Oc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)Oc1ccc(O)cc1

Procedure:
Benzene-1,4-diol Compound 25a was reacted with 1-chloro-3-isocyanato-benzene Compound 28a and a catalytic amount of triethylamine in 1,4-dioxane at room temperature to provide (3-chloro-phenyl)-carbamic acid 4-hydroxy-phenyl ester Compound 28b.
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([CH3:12])[C:4]=1[Br:13])C.CO.Cl>O1CCCC1>[Br:13][C:4]1[C:5]([CH3:12])=[C:6]([CH2:7][OH:8])[CH:10]=[CH:11][CH:3]=1
Reactant: CCc1ccc(C(=O)O)c(C)c1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Br)cccc1CO
Yield: 90 %

Procedure:
Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 67.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H).