Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:32][C:33]([CH:35]1[CH2:37][CH2:36]1)=[NH:34]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]1[O:5][N:34]=[C:33]([CH:35]2[CH2:37][CH2:36]2)[N:32]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(NO)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 500 mg Z-Pro-OH in 6 ml DMF was added a solution of 325 mg 1,1′-carbonyldiimidazole in 2 ml DMF. After stirring for 30 minutes a solution of 201 mg N-Hydroxy-cyclopropanecarboxamidine in 2 ml DMF was added and the solution stirred for 12 h at room temperature until LCMS showed complete conversion to the intermediate O-acyl amide oxime. Further 325 mg CDI were added and the mixture stirred at 115° C. for 5 h. It was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude product as colorless oil. Yield: 228 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2.C(OCC)(=O)C>C(O)(=O)C.[Pt](=O)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16][CH2:15]2
Reactant: c1ccc2cc(Nc3ccc4ncccc4c3)ccc2c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1ccc2cc(Nc3ccc4c(c3)CCCN4)ccc2c1
Reaction time: 6 h
Yield: 77.4 %

Procedure:
A solution of 7.00 grams of N-2-naphthylquinolin-6-amine from above in acetic acid (60 mL) and ethyl acetate (10 mL) containing 0.55 grams of platinum(IV) oxide was hydrogenated at 45 psi for 6.0 hours on a Parr low-pressure hydrogenator. The solution was filtered through diatomaceous earth; concentrated in vacuo; and neutralized with 3N aqueous sodium hydroxide. The aqueous phase was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine; dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 5.5 grams solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate gradient to afford 3.5 grams of the desired product as a yellow solid. 1H NMR (CDCl3/D2O) δ 6.4-7.8 (m, 10H), 3.1-3.5 (m, 2H), 2.6-2.9 (m, 2H), 1.95 (p, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28]C(=O)OC(C)(C)C)=[O:18])=[C:11]([F:36])[C:10]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1>ClCCl>[NH2:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[NH:20][C:19]([C:17]([NH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:11]=1[F:36])=[O:18])=[CH:27]2
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cccc(N)c4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Trifluoroacetic acid (0.028 mL, 0.369 mmol) was added to a solution of 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-7-yl)carbamate (0.021 g, 0.037 mmol) in dichloromethane. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to give the title compound (0.009 g, 45%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.46 (s, 1H), 9.07 (s, 1H), 7.81 (s, 1H), 7.43-7.58 (m, 3H), 7.32-7.43 (m, 1H), 7.09-7.22 (m, 2H), 6.82-6.97 (m, 1H), 6.62-6.75 (m, 1H), 4.58 (s, 2H), 4.20 (br s, 2H). MS: m/z 469 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.Cl[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:10]=[C:4]2[CH:3]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: O=C(CCl)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Cl)cc2nc(C(F)(F)F)cn12
Temperature: 120 °C

Procedure:
5 g (28.5 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 6.26 g (42.7 mmol) of 3-chloro-1,1,1-trifluoropropanone are dissolved in 200 ml of DMF and heated at 120° C. for 16 h. After the reaction is complete, water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the product is purified by silica gel chromatography. Drying under high vacuum results in 3.5 g (45% of theory) of the product as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH2:3][C:4]2[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH3:15])[CH:8]=2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccc(C#N)cc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]—N-(1-ethyl-1-phenylpropyl)propylamine (0.5 g) was reacted with 4-cyanobenzoyl chloride (0.27 g) in a similar manner to Example 55 to give 4-cyano—N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]imidazol-4-yl)ethyl}benzamide, m.p. 107-109° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13]>CO>[NH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Reactant: N
Solvent: CO
Product: Nc1ccc(CO)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 52 %

Procedure:
Fifty grams (0.27 mole) of 4-chloro-3-nitrobenzyl alcohol, 250 ml. of methanol and 200 ml. of liquid ammonia were loaded into a cold autoclave. The autoclave was sealed and heated to a temperature of 150° C. After cooling, the autoclave was vented and the volatile constituents removed by evaporation in vacuo. The residue was taken up in ether and the ether solution was filtered to remove ammonium chloride which had precipitated. The ether filtrate was evaporated in vacuo to yield a solid product. The product was recrystallized from 95% ethanol/ethyl acetate to give 23.6 g. (52 percent yield) of 4-amino-3-nitrobenzyl alcohol, mp 100°-101° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][N:12]1[C@H:18]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH3:10][C@H:11]1[CH2:16][N:15]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[C@H:14]([CH3:17])[CH2:13][N:12]1[C@H:18]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3ccc(O)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.05 %

Procedure:
4-Hydroxybenzaldehyde (488 mg, 4.0 mmol) was dissolved in a solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (759 mg, 2.0 mmol, Example 2) and acetic acid in tetrahydrofuran (10 mL). Sodium triacetoxy borohydride (848 mg, ˜4 mmol) was added portionwise over 5 min, then the reaction mixture sealed under nitrogen and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue partitioned between water (6 mL) and ethyl acetate (20 mL). The aqueous solution was further extracted with ethyl acetate (2×10 mL) and the combined extract and washings diluted with an equal volume of ether. The organic solution was extracted with 3M-HCl and the acidic aqueous solution carefully neutralized, initially with 5M-NaOH, then saturated NaHCO3. At pH 4 the solution was filtered through a 0.45 mM syringe filter to remove a small quantity of an off-white gummy solid. The pH of the filtrate was adjusted to 8.5 to precipitate a flocculent white solid which was filtered off, washed well with cold water and dried overnight at 2 mm Hg at room temperature to yield 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide (73.05%). Calc. for C31H39N3O2 1.5H2O C, 72.62; H, 8.26; N, 8.20. Found C, 72.58; H, 7.83; N, 8.40% 1H NMR (1% NaOD in D2O, 300 MHz); □□0.75 (br m, 3H); 0.81 (br d, J=7.3 Hz, 6H); 0.94 (br m, 3H); 1.71 (m, 1H); 1.84 (m, 1H); 2.29 (m, 2H); 2.49 (br m, 2H); 2.91 (m, 3H); 3.22 (m, 2H); 3.57 (br m, 2H); 5.02 (s, 1H); 6.39 (d, J=7.5 Hz, 2H); 6.80 (d, J=7.3 Hz, 2H); 7.01 (m, 7H); 7.17 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH3:42][CH:41]([CH3:43])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:32][CH2:31]2)[CH:34]=1)=[O:44]
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 59 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 2H, J=10.8 Hz), 7.32–7.17 (m, 17H), 6.87 (d, 1H, J=7.7 Hz), 6.32–6.26 (m, 1H), 3.41 (q, 2H, J=6.0 Hz), 2.83 (d, 2H, J=10.5 Hz), 2.48 (quintet, 1H, J=6.7 Hz), 2.43–2.33 (m, 1H), 2.26 (t, 2H, J=6.7 Hz), 1.89 (t, 2H, J=11.5 Hz), 1.73–1.62 (m, 4H), 1.56–1.44 (m, 2H), 1.22 (d, 6H, J=6.7 Hz); ESMS m/e: 574.3 (M+H)+; Anal. Calc. for C38H43N3O2.0.730 CHCl3: C, 70.38; H, 6.67; N, 6.36. Found: C, 70.42; H, 6.57; N, 6.47.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O-])=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:33]([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]1[CH3:20])(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])=[O:36]
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Reactant: C[Si](C)(C)CCOC(=O)CCCCCCCCC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC(=O)CCCCCCCCC(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a solution of the compound 1 (334 mg, 1 mmol), 60 (303 mg, 1.00 mmol) and N,N-dimethylaminopyridine (122 mg, 1 mmol) in methylene chloride (5 mL) was added 1,3-dicyclohexylcarbodiimide (206 mg, 1.08 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 18 hours. The precipitated insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluate: hexane - ethyl acetate (1:1)) to give the compound 64 (580 mg, 94%) as oil. Rf 0.27 (1:1 EtOAc-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2ccccc2)c1O
Yield: 90 %

Procedure:
To a solution of 2-nitro-6-phenylphenol(900 mg, 4.2 mmol) in methanol(50 ml) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(700 mg, 90%). 1H NMR (CD3OD): d 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:37]>C(O)C.C1COCC1.[Ni]>[NH2:34][C:30]1[CH:29]=[C:28]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH3:37])[CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]([F:26])([F:27])[F:25])=[O:15])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc2c(-c3cccc([N+](=O)[O-])c3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(-c3cccc(N)c3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
A mixture solution of 2-[7-chloro-6-methyl-4-(3-nitrophenyl)-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (300 mg) in ethanol (2 ml) and THF (5 ml) was combined with Raney-nickel (50 mg), and stirred under hydrogen atmosphere at room temperature for 5 hours. After catalyst was filtered off, the reaction solution was concentrated. The resultant residue was purified by a silica gel chromatography (eluent: hexane-ethyl acetate=2:1), and further recrystallized from THF-ethyl acetate to obtain the title compound as a colorless crystal (166 mg, yield: 59%). Melting point: 206-207° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (3.2 g, 6.08 mmol) in N,N-dimethylfoLmamide (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.11 mL, 6.38 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (1.18 g, 6.38 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (150 ml), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (2.23 g, 63%) as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.[C:28]([O:32][C:33](=[O:46])[C:34]([CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[CH2:35])([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[CH2:39]([O:38][CH2:37][CH2:36][CH:34]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:46])[CH2:35][C:19]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C1=CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)CC1(C(=O)O)C=CCCC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (8.8 mL, 62.8 mmol) in dry tetrahydrofuran (140 mL) at -50° C. was added a 2.5M solution of n-butyllithium in hexane (25 mL, 12.5 mmol). The mixture was stirred at a temperature from -50° C. to -20° C. over 30 minutes and then cooled again to -50° C. Solid 1-cyclohexene carboxylic acid (3.75 g, 29.7 mmol) was added and the resulting mixture was allowed to warm to room temperature with stirring over 1.5 hours. The reaction was cooled to -78° C. and a solution of 2-(2-benzyloxyethyl)acrylic acid tert-butyl ester (7.45 g, 28.4 mmol) in dry tetrahydrofuran (90 mL) was added over 15 minutes; stirring was continued at -78° C. for 5 hours. The mixture was then allowed to warm to -30° C. over 40 minutes and was quenched by the addition of saturated aqueous NH4Cl solution. After acidification using 3N HCl solution, the mixture was extracted with ether. The extract was washed with brine, dried over MgSO4 and evaporated under vacuum to leave a yellow oil from which 1-(4-benzyloxy-2-tert-butoxycarbonylbutyl)cyclohex-2-ene carboxylic acid (an oily mixture of the two diastereomers), 9.71 g (84%) was isolated by chromatography on silica gel eluting with methylene chloride and then 5% methanol in methylene chloride.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>C(OCC)C.C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:20])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
Sodium hydride (5.2 g, 0.21 mol) was suspended in dry diethyl ether and cooled to 0° C. Diethyl carbonate (17.7 g, 0.15 mol) was added and the contents were stirred for ten minutes, at which time dropwise addition of p-bromoacetophenone (19.9 g, 0.1 mol) in diethyl ether (50 mL) and ethanol (0.2 mL) was initiated. Addition was continued for twenty minutes; the solution was refluxed for three hours, cooled to room temperature and poured onto cold 10% aqueous hydrochloric acid (250 mL). The aqueous solution was extracted twice with diethyl ether (750 mL) and the combined extracts were washed successively with water (250 mL), brine (250 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (4/1), to afford 20.2 g (74%) of the title compound as an oil. 1HNMR (60MHz, CDCl3): δ1.2 (t,3H), 3.9 (s, 2H), 4.1 (q, 2H), 7.55 (d, J=7 Hz, 2H), 7.75 (d, J=2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C[O-].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccc(F)c(F)c2)cc1
Yield: 68 %

Procedure:
A mixture of 3,4-difluorophenylacetic acid (10 g), 4-(methylthio)benzaldehyde (8.84 g) and sodium methoxide (3.14 g) in acetic anhydride (30 ml) was refluxed for 20 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water, dried and concentrated to dryness. The obtained solid material was washed with ethanol and dried to give crystals of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acrylic acid (12.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=1.O.NN.[OH-].[K+].Cl>CCOCC.C1CCCCC1.O.C(O)COCCO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2Br)cc1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: CCOCC
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCc1ccc(-c2ccccc2Br)cc1
Temperature: 100 °C

Procedure:
A mixture of 6.6 gm (0.018 mol) of ethyl 4-(2'-bromo-4-biphenylyl)-4-oxo-butyrate (m.p. 61°-62° C.), 3 gm of 100% hydrazine hydrate and 100 ml of diethyleneglycol was heated at 100° C. for 20 minutes. Then, 5 gm of pulverized potassium hydroxide were added. After refluxing for 5 hours, the reaction mixture was poured into 500 ml of water, acidified with dilute hydrochloric acid, and the precipitate was dissolved in ether. The ether solution was washed with water, dried and evaporated; the residue was dissolved in acetone, and by addition of cyclohexylamine the cyclohexylamine salt of 4-(2'-bromo-4-biphenylyl)-butyric acid, m.p. 148°-149° C. (from acetone), was obtained. Melting point of the free acid: 63° C. (from cyclohexane).