Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CCO.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH:6]([CH2:5][C:4]([OH:17])=[O:3])[CH2:7][CH2:8]2
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of the crude ester (416 g, 1.77 mol) prepared in Example 2 in EtOH (1 L), was added a solution of NaOH (142 g, 3.54 mol) in water (1.5 L). The reaction mixture was heated to reflux, during which time the color changed to dark red, and the reaction became homogeneous. After 1 h, the reaction was cooled to rt, and the EtOH was removed under reduced pressure. The remaining basic aqueous layer was washed with Et2O (3×500 mL), then acidified with HCl (conc. aqueous solution) to pH˜4 at which point an oily residue formed. The mixture was then extracted with Et2O (4×500 mL), the combined extracts washed with water (2×300 mL) and brine, and then dried over Na2SO4. Filtration and evaporation of the solvents under reduced pressure gave the title compound (305 g, 83%) as a yellow solid after drying for 12 h under vacuum. 1H NMR (CDCl3) δ 7.34 (d, 1H), 6.71 (s, 1H), 6.65 (dd, 1H), 3.71 (s, 3H), 3.47 (m, 1H), 2.80 (m, 3H), 2.35 (m, 2H), 1.71 (m, 1H). MS (CI) m/z 207 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:15]([CH3:19])[C@H:16]([NH2:18])[OH:17])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[C:8]([CH:15]([CH3:19])[C@:16]([NH2:18])([S:21]([CH3:20])(=[O:23])=[O:22])[OH:17])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C(=O)OC(C)(C)C)[C@H](N)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)OC(C)(C)C)[C@@](N)(O)S(C)(=O)=O
Reaction time: 1 h

Procedure:
Methylene chloride (400 mL) and triethylamine (83.9 mL, 0.60 mol) were added to the flask containing (R)-2-boc-amino-propan-1-ol (from step 1). The reaction mixture was cooled in an ice bath for 30 minutes, and then methanesulfonyl chloride (37.0 mL, 0.478 mol) was added dropwise over a five minute period. The reaction mixture was stirred for one hour, then the ice bath was removed and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was washed with 10% aqueous NaOH solution, and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 91.93 g of (R)-2-boc-amino-1-methanesulfonyl-propan-1-ol.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH2:28]([O:30][CH2:31][CH2:32][C:33](=[N:35]O)[NH2:34])[CH3:29]>>[CH2:28]([O:30][CH2:31][CH2:32][C:33]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:34]=1)[CH3:29]
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CCOCCC(N)=NO
Product: CCOCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 320 mg (approx. 1.983 mmol) of 3-ethoxy-N′-hydroxypropanimidamide were reacted Yield: 343 mg (46% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.C(O)(=O)C.Br>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Yield: 92.2 %

Procedure:
To 42 g (0.17 mol) of the above 3'-fluoro-4'-methoxybiphenyl-4-carboxylic acid were added 1.7 l of acetic acid and 300 ml of 48% hydrogen bromide solution, which was refluxed for 20 hours, poured into 3.5 l of water and air cooled. The precipitated crystal was filtered to obtain 36.4 g (yield: 92%) of 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23](C)C.Cl.CN>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH3:22])[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CCNc1nc(NC)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 53 %

Procedure:
0.1 g (0.00031 mol) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol and stirred with 0.6 ml (0.0043 mol) of trimethylamine and 0.1 g (0.0015 mol) of methylamine hydrochloride in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 150 ml of 1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.053 g (54%) of 4-amino-N-(2-ethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 261-263° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([OH:27])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CCC(C)(C)c1ccc(Cl)c(OC)c1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(C)(C)c1ccc(Cl)c(OC)c1
Temperature: -70 °C
Yield: 84.1 %

Procedure:
24.1 g (84.63 mmol) of ethyl-4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate is dissolved in 296 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within 1¾ hours, 236.9 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture then is stirred for 75 more minutes at −70° C. 30.9 g (118.48 mmol) of Davis reagent, dissolved in 296 ml of tetrahydrofuran, is now added in drops within 60 minutes. After two hours of stirring at −70° C., 152 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed, and it is vigorously stirred for 30 minutes. After extraction with diethyl ether, the combined organic extract are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 21.4 g (84.2%) of the desired compound is isolated (easily contaminated).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([CH2:9]O)=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([CH2:9][Cl:20])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCn1c(CO)nc2cc(Br)ccc21
Solvent: ClCCl
Product: CC(C)CCn1c(CCl)nc2cc(Br)ccc21
Yield: 101.3 %

Procedure:
To a solution of [5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-yl]-methanol (1.32 g, 4.44 mmol) in DCM (20 mL) was added thionyl chloride (1.06 g, 8.88 mL) at 0° C. The final solution was stirred at 0° C. for 1 h. The solvent was evaporated and the residue triturated with EtOAc and filtered to give 1.42 g (91%) of 5-bromo-2 chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole as a white solid.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1ccc(C(C)=O)cc1

Procedure:
0.15 ml of guaiacol 67, 167 mg of 4-fluoroacetophenone 68 and 335 mg of potassium carbonate are heated in 5 ml of dimethyl sulfoxide at 170° C. in a microwave for 10 min. The reaction solution is poured into water, and the emulsion is extracted three times with an ethyl tert-butyl ether. The combined organic phase is extracted twice with 1 N NaOH and once with saturated NaCl solution, dried and concentrated in vacuo. 240 mg of the desired product are obtained. C15H14O3 (242.28) MS (ESI): 215.10 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1Br)([CH3:8])[CH3:7].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:26]=[CH2:27])([CH3:8])[CH3:7]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)C(CC(C)(C)c1cc(F)ccc1Br)C(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(F)cc1C(C)(C)CC(C(=O)OC)C(=O)c1ccccc1

Procedure:
A solution of 0.53 g (1.25 mmol) of 2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl ester and 77 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium in 40 ml of toluene is refluxed with vinyl(tributyl)stannane for 8 hours. Then, it is concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 320 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=1)=[O:4].[O-:12][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) in acetone/water (50 mL, 1:1) was added a solution of KMnO4 in acetone/water (70 mL, 1:1) dropwise within one hour. The mixture was stirred for 3 h at RT whereupon it was poured into a solution of NaHSO3 (10% in 1 N HCl, 100 mL). The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and extracted with 2N aqueous K2CO3 solution. The basic aqueous phase was acidified with 2N HCl and extracted with ethyl acetate The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (530 mg) which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[S:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][N:19]4C(OCC4C=CC=CC=4)=O)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O>[NH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[C:16]1[S:17][C:13]([C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=3[N:11]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4C(=O)OCc4ccccc4)s3)nc12
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4)s3)nc12

Procedure:
A solution of EXAMPLE 28E (0.21 g) in TFA (10 mL) was stirred at ambient temperature overnight and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile; 0-100% gradient). 1H NMR (DMSO-d6) δ 1.62-1.76 (m, 1H), 1.84-1.96 (m, 2H), 2.00-2.08 (m, 1H), 2.10-2.20 (m, 1H), 2.19-2.28 (m, 1H), 3.06-3.13 (m, 1H), 3.34-3.47 (m, 1H), 4.36-4.50 (m, 1H), 7.02 (s, 1H), 7.28 (t, J=7.9 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.81 (d, J=4.0 Hz, 1H), 7.98 (d, J=7.3 Hz, 1H), 9.40 (s, 1H), 9.50 (s, 1H), 10.10 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CN=CC=1.[O:21]=[S:22](=[O:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:11][C:12]([S:22]([OH:24])(=[O:23])=[O:21])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccco1
Reactant: O=S(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1ccc(S(=O)(=O)O)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A solution of 2-(tert-butoxycarbonylaminomethyl)-furan (9.8 g, 50 mmol) in 150 mL of dichloromethane was added into a flask, and the reaction mixture was cooled to 0° C. in an ice bath. A solution of pyridine-sulfur trioxide adduct (15.9 g, 100 mmol) in 100 mL of dichloromethane were added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for additional 8 h. After the completion of the reaction, the reaction mixture was then extracted with water (400 mL×2). Aqueous hydrochloric acid (10%) was slowly added dropwise to the aqueous layer. The aqueous layer was adjusted to pH 6.5-7, and extracted with dichloromethane (500 mL×2). The organic layer was washed by saturated brine, and concentrated under reduced pressure to give 5.5 g (40.0% yield) of 5-(tert-butoxycarbonylaminomethyl)furan-2-sulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.[OH-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O)c12

Procedure:
Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (Intermediate III) (1.0 g), sodium hydroxide 1M (10 ml), methanol (20 ml) and THF (20 ml) were stirred at rt overnight. The mixture was concentrated and diluted with EE and water. The aqueous layer was acidified with hydrochloric acid and filtrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[Br:15]C1C=C(CBr)C=CC=1OC(F)(F)F>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:15])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Br
Reactant: OCc1ccc(Cl)c(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cc(CBr)ccc1Cl

Procedure:
Compound 35.2 was synthesized from (4-chloro-3-(trifluoromethoxy)phenyl)-methanol using the procedure described for the preparation of 19.2. 1H NMR (500 MHz, DMSO-d6) δ 7.74 (1 H, d, J=2.0 Hz), 7.38-7.53 (2 H, m), 4.53 (2 H, d, J=5.6 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21](=[O:30])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])(C)(C)C>ClCCl>[O:20]=[C:17]1[N:16]([C:21](=[O:30])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:15]([C:13]([OH:14])=[O:12])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)C1CCC(=O)N1C(=O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1C(=O)CC[C@H]1C(=O)O)c1ccccc1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Trifluoroacetic acid (40 ml) was added to a solution of 5-oxo-1-(2-oxo-2-phenylacetyl)pyrrolidine-2-carboxylic acid tert-butyl ester (5.00 g) in dichloromethane (40 ml) and the solution was stirred for 2 hours. All volatiles were removed under reduced pressure and the residue triturated with ether:hexane (1:1). The white solid was collected by filtration and washed with hexane to give the sub-title compound (4.09 g).
Reaction SMILES: B(O)O.[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1.N1C=CC=CC=1.CC1N([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)N=C(C(OCC)=O)C=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)[N:6]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc3cc(OC)ccc3c2)n1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1-c1ccc2cc(OC)ccc2c1
Reaction time: 96 h
Yield: 37 %

Procedure:
To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated and purified by flash column to separately afford ethyl 3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc:hexane). ES-MS: (M+H)+311] and ethyl 5-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-3-carboxylate [25% yield. Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)+311]in a 1.5:1 ratio.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16]O)[N:6]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][Br:20])[N:6]=1
Reactant: COC(=O)Cc1nn(CO)c(=O)c2ccccc12
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1nn(CBr)c(=O)c2ccccc12

Procedure:
A solution of methyl-3-hydroxymethyl-4-oxo-phthalazin-1-ylacetate (0.49 g), phosphorous tribromide (0.54 g) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The solution was poured onto ice-water (5 ml) and the separated methylene chloride layer was collected, dried and evaporated to obtain a light yellow solid (yield: 0.43 g; m.p. 98°-104° C.).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8]/[N:9]=[C:10](/[C:16](=[O:18])[CH3:17])\[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:19]Br>>[Br:19][CH2:17][C:16](=[O:18])/[C:10](=[N:9]/[O:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@@H]1C)C(C)=O
Reactant: BrBr
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@@H]1C)C(=O)CBr
Yield: 68 %

Procedure:
Ethyl (Z)-2-(cis-2-methylcyclohexyloxyimino)-3-oxobutyrate (0.46 g) was treated with bromine as described in Example 4c to give the title compound (0.41 g, 68%), νmax (film) 2930, 1740, and 1695 cm-1, δH (CDCl3) 0.95 (3H, d, J 6.7 Hz), 1.35 (3H, t), 1.3-2.1 (9H, m), 4.35 (2H, s), 4.38 (2H, q), and 4.40 (1H, m). [Mass spectrum: +ve ion (ammonia) MH+ (334)].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 110.6 %

Procedure:
A slurry of lithium aluminum hydride (2.08 g, 54.7 mmol) in THF (100 mL) was cooled to −78° C. A solution of 3-chlorocinnamic acid (5.00 g, 27.4 mmol) in THF (25 mL) was added dropwise. The cold bath was removed and the mixture was warmed to room temperature. After 6 h, the reaction was quenched by addition of sodium sulfate decahydrate and the mixture was stirred overnight. The solids were removed by filtration with the aid of EtOAc and the organic solution was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 3-(3-chloro-phenyl)-propan-1-ol (5.17 g) as an oil. 1H NMR (400 MHz, CDCl3) δ7.30-7.07 (m, 4H), 5.06 (bs, 1H), 3.67 (m, 2H), 2.69 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9]P(=O)(OCC)OCC)([O-:5])=[O:4].[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8](/[CH:9]=[CH:31]/[C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)[CH:18]=[CH:19][CH:20]=1)([O-:5])=[O:4]
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Reactant: O=Cc1ccnc2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2ccnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.75 g) in N,N-dimethylformamide (20 ml) was added a solution of diethyl 3-nitrobenzylphosphonate (4.40 g) in N,N-dimethylformamide (20 ml). The mixture was stirred at room temperature for 15 minutes, then a solution of 4-quinolinecarbaldehyde (2.81 g) in N,N-dimethylformamide (20 ml) was added thereto. After stirring at 50° C. for 30 minutes, the mixture was poured into aqueous sodium bicarbonate, and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (chloroform-methanol (50:1)) to give 4-[(E)-2-(3-nitrophenyl)vinyl]quinoline (1.57 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]([N:9]([CH3:27])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]([CH3:26])[CH2:21][CH2:22][C:23]([OH:25])=O)=[O:19])[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:27])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](=[O:19])[N:20]([CH3:26])[CH2:21][CH2:22][C:23](=[O:25])[NH:37][CH3:36])[CH2:14][CH2:13]2)=[CH:28][CH:29]=1
Reactant: CN
Reactant: CN(CC[C@H]1CC[C@H](C(=O)N(C)CCC(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)CCN(C)C(=O)[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.088 g (0.20 mmol) of trans-3-[(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-methyl-amino]-propionic acid in 2 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.019 mL (0.22 mmol, 1.1 eq) of oxalyl chloride and stirring was continued for 90 min. The solvent was evaporated, the residue was redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.25 mL (2.00 mmol, 10 eq) of methylamine (33% solution in EtOH) in 2 mL of CH2Cl2 at 0° C. The reaction mixture was stirred at 0° C. for 3/4 h, then partitioned between Et2O (×3)/aqueous 10% KHSO4. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 20 g silica gel (CH2Cl2:MeOH 98:2 to 95:5) gave 0.042 g (48%) of pure trans-methyl-(2-{4-[methyl-(2-methylcarbamoyl-ethyl)-carbamoyl]-cyclohexyl}-ethyl)-carbamic acid 4-chloro-phenyl ester, MS: 438 (MH+, 1Cl).