Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)CNS(=O)(=O)c1cccnc1
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of Example 74 (55.0 mg, 0.167 mmol) in DMF (1 mL) was added triethylamine (0.070 mL, 0.50 mmol) and pyridine-3-sulfonyl chloride (35.5 mg, 0.200 mmol). After 4 hours, the reaction was quenched with 20% brine and extracted with EtOAc (2×). The organic layers were combined, concentrated, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (28.5 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, DMSO-d6) ppm 0.89 (s, 6H), 2.68 (d, J=7.02 Hz, 2H), 3.13 (s, 2H), 6.80 (s, brd, 1H), 6.89 (d, J=1.22 Hz, 1H), 6.94 (s, 1H), 7.22 (dd, J=8.09, 4.73 Hz, 1H), 7.60 (dd, J=7.63, 4.58 Hz, 1H), 7.77 (t, J=6.87 Hz, 1H), 8.12-8.18 (m, 2H), 8.28-8.35 (m, 2H), 8.77 (d, J=6.41 Hz, 1H), 8.94 (d, J=2.14 Hz, 1H), 12.19 (s, 1H). MS (APCI+) m/z 471.2 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7]#[N:8]>O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7](=[N:1][OH:2])[NH2:8]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: NO
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Hydroxylamine (10 mL of a 50% solution in water) was added in one portion to a stirred suspension of 3,5-dibromo-4-hydroxybenzonitrile (30 g, 110 mmol) in ethanol (100 mL) at room temperature and the mixture was heated to reflux for 3 hours before cooling back down to room temperature. The solid was filtered, washed with cold ethanol and dried to yield the title compound (25.5 g, 75%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 5.92 (2H, br s), 7.87 (2H, s), 9.69 (1H, br s), 10.19 (1H, br s).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20].CCN(CC)CC.[Cl:38][CH2:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[Cl:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:19]([NH:18][C@@H:10]1[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]1[NH:8][S:40]([CH2:39][Cl:38])(=[O:42])=[O:41])=[O:20])=[CH:29]2
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=S(=O)(Cl)CCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NS(=O)(=O)CCl)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-5-chloro-1H-indole-2-carboxamide trifluoroacetic acid salt (Method 5, 2.2 g, 5.0 mmol) and Et3N (2.1 mL, 15.0 mmol) dissolved in dry THF (30 mL) at 5° C., chloromethyl sulphonyl chloride (820 mg, 5.5 mmol) in dry THF (5 mL) was added and the reaction allowed to warm to ambient temperature for 2 hours. The volatiles were removed by evaporation under reduced pressure and the residue dissolved in EtOAc (75 mL), washed with water (2×25 mL), brine (25 mL) and dried (MgSO4). Removal of the volatiles under reduced pressure gave the title compound (2.16 g, 98%) as a buff powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC1CCCCCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCCCC1
Yield: 80 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cycloheptanol (39 mg, 0.34 mmol) as the coupling partner. Concentration (no chromatography) yielded 53 mg (80%) of the titled compound. ESI-MS m/z 388 (MH+), 386 (M−H−).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[N:16]=[CH:17][NH:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[NH:18][CH:17]=[N:16][C:15]=3[CH:10]2[C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:29])=[CH:24][CH:25]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)c1ccc(C2c3nc[nH]c3CCN2C(=O)CCc2ccc(F)cc2)cc1
Yield: 33.3 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[NH:35][C:36](=[NH:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:42]=[C:36]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)CC(=N)NO
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](c2nc(CS(C)(=O)=O)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and N-hydroxy-2-(methylsulfonyl)ethanimidamide, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=455.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([NH:11][NH:10][C:4]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=1[Cl:2])(=[O:16])[CH3:15]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NNc1ccc(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 1.25 h
Yield: 98 %

Procedure:
A slurry of 101.4 grams (0.4751 mole) of 2,4-dichlorophenylhydrazine hydrochloride in 600 mL of water was stirred, and a solution of 20.9 grams (0.5225 mole) of sodium hydroxide in 100 mL of water was slowly added. During the addition, the reaction mixture thickened. An additional 50 mL of water was added. to aid fluidity. Upon completion of addition of the sodium hydroxide solution, an additional 70 mL of water was added. The reaction mixture was stirred for about 75 minutes, then it was extracted with three 300 mL portions of ethyl acetate. The extracts were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate containing free 2,4-dichlorophenylhydrazine (1) was transferred to an appropriate reaction vessel. The stirred solution was cooled to about 10° C., and 58.2 grams (0.5701 mole) acetic anhydride was added dropwise. Upon completion of addition, gas chromatographic (GC) analysis of the reaction mixture indicated the reaction was about 99% complete. The cooling medium was removed, and a solution of 62.5 grams of potassium carbonate in 200 mL of water was added to the reaction mixture. The mixture was stirred for about five minutes and the organic layer was separated. The organic layer was concentrated under reduced pressure, yielding 102.0 grams (98% yield) of 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2).
Reaction SMILES: ClC1C=C(Cl)C=CC=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1C1CCCCC1NS(C)(=O)=O.O1CCCCC1OC1C=C(C=CC=1)CO[NH2:46].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(OCC)(=O)C.CN(C=O)C>[O:22]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]([C:19]([NH2:46])=[O:20])[CH2:9][NH:10]1
Reactant: NOCc1cccc(OC2CCCCO2)c1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1CNC(=O)c2ccccc21
Reaction time: 3 h

Procedure:
To 400 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yl oxy)benzyl]hydroxylamine, 159 mg of HOBt, and 243 mg of WSC, followed by stifling at room temperature for 3 hours. The reaction solution was added with ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue was added methanol, and concentrated hydrochloric acid was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour. The precipitated crystal was collected by filtration to obtain 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-Rmesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31]CC)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([OH:31])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C(=O)O)C1
Reaction time: 4 h
Yield: 99 %

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (290 mg, 0.607 mmol) was dissolved in 3 ml of MeOH. LiOH hydrate (76 mg, 1.821 mmol) was dissolved in 1 ml of water and added to the reaction mixture and allowed to stir for 4 hours. The MeOH was removed under reduced pressure. The aqueous residue was washed with Et2O and then acidified with 3N HCl to give a white precipitate which was filtered and dried to give 270 mgs (99%) of 3-[2-Carboxy-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white powder.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[O:27]CC1C=CC=CC=1)[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16])=[N+:2]=[N-:3].C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>C(Cl)Cl>[N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[OH:27])[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16])=[N+:2]=[N-:3]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(OCc1ccccc1)c2=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(O)c2=O
Temperature: 23 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of intermediate 195, (R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide, (0 030 g, 0.052 mmol) in CH2Cl2 (1 mL) was added CF3CO2H (1 mL) at 23° C. The reaction mixture was stirred at 23° C. for 3 h. Toluene (20 mL) was then added and the solvents evaporated in vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18) to afford the title compound (0.008 g, 31%): 1H NMR (400 MHz, MeOD) δ ppm: 7.55 (1H, dd, J=6.6 Hz), 7.16 (2H, m), 4.47–4.24 (2H, m), 4.05 (2H, m), 3.98 (2H, m), 3.56 (2H, s), 2.70–2.45 (4H, m), 2.11 (1H, m), 1.64 (3H, s), 1.61 (3H, s). HRMS calcd for C22H25N7O5F: 486.1901. found 486.1923.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1C2C(=CC=CC=2)C=CC=1)(C)C.C(C1C2C(=CC=CC=2)C=CC=1)(=[O:27])C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:27]
Reactant: CC(=O)c1cccc2ccccc12
Reactant: Oc1cccc2ccccc12
Agent: CC(C)c1cccc2ccccc12
Product: Oc1ccc2ccccc2c1

Procedure:
990 parts of the same crude β-naphthol as used in Example 2 were melted and added to 1,300 parts of ethanol under stirring, and the mixture was heated while stirring until the crude naphthol was completely dissolved. Then the solution was gradually cooled to 0° C. with crystals separating. The mixture was then filtered using a centrifuge. 923 parts of the crystals were obtained with 230 parts being ethanol as a solvent. Therefore, it can be said that centrifugal removal of the mother liquor is not good. The crystals were dried to remove the ethanol and the β-naphthol thus obtained had a purity of 96.1% and contained 1.4% of α-naphthol, 0.3% of isopropylnaphthalene and 0.6% of acetylnaphthalene. The recovery of the β-naphthol obtained as crystals was 77.0%.
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].C(=O)([O-])O.[Na+].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1.S(=O)(=O)(O)O>O.C(OCC)(=O)C>[O:4]=[C:3]1[C:11]2[CH:10]=[CH:15][O:16][C:12]=2[CH2:13][CH2:14][CH2:2]1
Reactant: O=CCCl
Reactant: O=C1CCCC(=O)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCc2occc21
Yield: 80 %

Procedure:
To a mixture of 10 ml of ethyl acetate, 2 ml of 40% aqueous solution of chloroacetaldehyde and about 3 ml of water was added 1.0 g (12 mmoles) of sodium hydrogencarbonate while cooling with ice, and then the resulting mixture was stirred. To the reaction mixture was added dropwise 5 ml of aqueous solution containing 1.12 g of 1,3-cyclohexanedione while cooling with ice at a rate of 0.05 ml/minute. The reaction mixture was maintained at a pH of from 6.2 to 8.7 throughout the reaction. After completing the dropping, the reaction mixture was stirred at a room temperature overnight, and then acidified with sulfuric acid. After stirring the mixture for one hour, the ethyl acetate layer was separated, washed with an aqueous solution of potassium carbonate for removing the unreacted 1,3-cyclohexanedione, and then dried on magnesium sulfate. After distilling away the solvent, the residue was applied to a column of silica gel and eluted with dichloromethane to give 1.09 g (yield: 80%) of 4-oxo-4,5,6,7-tetrahydrobenzofuran.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:38])[CH:7]([NH:22][CH:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3].ClCCl.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1>[CH3:1][C:2]([O:5][C:6](=[O:38])[C@H:7]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:50])=[O:49])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(N)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
58 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 73 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 4 mL dichloromethane under nitrogen. The mixture was cooled to 0° C. and 0.015 mL benzenesulfonyl chloride was added immediately followed by 0.1 mL pyridine. The mixture was allowed to warm to room temperature and was stirred for 18 h. The solvent was removed by evaporation and the residue was purified by reverse phase H.P.L.C. The solvent was removed by evaporation to afford the title compound; 31.8 mg
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:12]2[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccc(C(=O)O)o2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1ccc(C(=O)O)o1
Yield: 74.4 %

Procedure:
5-(2-methoxy-3-nitro-phenyl)furan-2-carboxylic acid 9a (4.23 g, 16.09 mmol) was dissolved in 125 mL of ethyl acetate followed by addition of 423 mg of palladium on carbon and ammonium formate (4.054 g, 64.35 mmol). The reaction mixture was heated to reflux for 3.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 9b (2.79 g, yield 74.4%) as a light green solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=C([N+]([O-])=O)C=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:27]([O-])=O.C(O)C.O.NN.[H][H]>[Ni].O>[NH2:27][C:3]1[CH:4]=[C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C(C(F)(F)F)C(F)(F)F)ccc1O

Procedure:
30 parts by weight 2,2-bis (4-hydroxy-3-nitrophenyl)-1,1,1,3,3,3-hexafluoropropane are suspended in a mixture of 240 parts by weight ethanol and 120 parts by weight water. 1.5 parts by weight Raney nickel and two times 18.5 parts by weight hydrazine hydrate are added to the suspension, and subsequently, the mixture is heated for the reflux. After the development of hydrogen has abated at the end of about 4 hours, suction is applied to remove the Raney nickel and the ethanol/water mixture is removed in a vacuum. The residue is taken up with about 400 parts by weight of diluted hydrochloric acid and optionally filtered off from insoluble components. After the addition of sodium acetate and sodium carbonate, the 2,2-bis (3-amino-4- hydroxy phenyl)-1,1,1,3,3,3-hexafluoropropane is precipitated; the yield is approximately 66%. Analysis (reported/found) revealed the following data: C 49.2%/49.0%; H 3.3%/3.4%; N 7.7%/7.5%; F 31.1%/31.0%; 1H-NMR in d6 -DMSO: δ (ppm)=9.2 (2H,s,OH), 6.6 (6H, m,aromatic), 4.6 (4 H, s, --NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9]Cl>C(Cl)(Cl)(Cl)Cl>[Br:9][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[OH:8].[Br:9][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[C:2]([Cl:1])[CH:7]=1
Reactant: Oc1ccccc1Cl
Reactant: ClBr
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1c(Cl)cccc1Br
Product: Oc1ccc(Br)cc1Cl

Procedure:
Furthermore, it is known from the U.S. Pat. No. 3,449,443 that on reaction of 2-chlorophenol with bromine chloride in carbon tetrachloride at 0° C. there is formed, besides 74% of theory of 2-bromo-6-chlorophenol, only 22% of theory 4-bromo-2-chlorophenol; and at 23° to 26° C. there is formed, besides 61.7% of theory of 2-bromo-6-chlorophenol, only 26.3% of theory of 4-bromo-2-chlorophenol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-:16].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:16])[CH2:14][CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: CCI
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidine (0.02 g, 0.081 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), iodoethane (0.007 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 275 (M+, 14), 274 (M+, bp), 260 (67), 258 (bp), 240 (23), 173 (9).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cncnc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (39 mg, 53%), MS (ISP) m/z=297.5 [(M+H)+], mp 289° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8](OC(C)(C)C)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1CBr)[C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH2:8][N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH2:6][NH:5]2)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)c(OC)c1

Procedure:
Following the above procedure, 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and methyl 3-methoxy-4-(bromomethyl)benzoate are reacted together to give methyl 3-methoxy-4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate.