Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-chlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[N:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[NH:15][CH:16]([CH:19]([CH3:21])[CH3:20])[C:17]=2[OH:18])=[N:3]1.[N+:29]([O-])([OH:31])=[O:30]>OS(O)(=O)=O>[OH:18][C:17]1[C:16]([CH:19]([CH3:21])[CH3:20])=[N:15][N:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:13](=[O:27])[C:12]=1[C:4]1[NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:29]([O-:31])=[O:30])=[CH:8][C:7]=2[S:2](=[O:1])(=[O:28])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)CCN1NC(C(C)C)C(O)=C(C2=NS(=O)(=O)c3ccccc3N2)C1=O
Agent: O=S(=O)(O)O
Product: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc([N+](=O)[O-])ccc3N2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 5h (0.097 g, 0.025 mmol) in conc H2SO4 (0.65 mL) cooled on ice bath was added conc HNO3 (0.10 mL). After stirring 30 min at 0° C., the reaction mixture was poured onto crushed ice (1.5 g). The resulting precipitate was collected by filtration to give 5i (0.091 g, 85%) as a yellow solid. 1H NMR (400 MHz, D6-DMSO) δ 13.90 (s, 1 H), 8.57 (d, J=2.8 Hz, 1 H), 8.49 (dd, J=9.2, 2.8 Hz, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 4.11 (t, J=6.8 Hz, 2 H), 3.23 (m, 2 H), 1.61 (m, 2 H), 1.21 (d, J=8 Hz, 6 H), 0.93 (d, J=8 Hz, 6 H). MS (ESI+) m/e 450 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 2-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 390.17 g/mol.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([Cl:13])[C:5]=1[C:14]#[N:15].O.[NH2:18][NH2:19].C(O)(=O)C>CO>[Cl:13][C:6]1[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]([Cl:10])=[C:4]2[C:5]=1[C:14](=[N:18][NH2:19])[NH:15][C:3]2=[O:16]
Reactant: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NN=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
119.6 g of 3,4,5,6-tetrachloro-2-cyanobenzoic acid methyl ester are dissolved in 600 ml of methanol and 70.6 g of a 30.6% strength methanolic solution of Na methylate. The solution is cooled to 10° C and is added dropwise at 10° C to a solution of 200 ml of hydrazine hydrate in 400 ml of methanol. A yellowish precipitate is formed. The reaction mixture is stirred at room temperature for 2 hours and is then warmed to 35° C over the course of 30 minutes and 200 ml of glacial acetic acid are added at this temperature. After stirring for 1 hour at room temperature, the product is filtered off and the filter residue is washed with methanol and water. The material filtered off is then extracted by boiling in 1 l of methylcellosolve for a further 2 hours, filtered off at room temperature and washed with methylcellosolve and methanol. After drying at 70° C, 98 g (82% of theory) of analytically pure 4,5,6,7-tetrachloro-isoindolin-1-on- 3-ylidene hydrazine of the formula ##STR31## are obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:14]([O:18][C:19](=[O:22])[CH2:20][NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[C:14]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1C#N
Temperature: 110 °C
Yield: 95.8 %

Procedure:
To a solution of 2-fluoro-5-trifluoromethylbenzonitrile 1A (10 g, 52.9 mmol) in N-methylpyrrolidinone (NMP) (100 mL) was added glycine tert-butyl ester 5A (13.8 g, 105 mmol) and diisopropylethylamine (20 g, 155 mmol). The reaction mixture was heated at 110° C. for 4 hours. Ethyl acetate (500 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide (2-cyano-4-trifluoromethylphenylamino)acetic acid tert-butyl ester 5B (15.2 g, 50.7 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=O)[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Cl-].[NH2:15][OH:16]>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6](/[C:10](=[N:15]/[OH:16])/[CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: NO
Reactant: COc1cc(C)c(C(C)=O)cc1C
Agent: [Cl-]
Solvent: CO
Product: COc1cc(C)c(/C(C)=N/O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of 0.5 g (2.6 mmol) of 1-(4-methoxy-2,5-dimethylphenyl)ethanone obtained in Step 2 and 0.36 g (5.1 mmol) of hydroxylamine chloride in 15 mL of methanol was added 1.0 g of a molecular sieve for dehydration. The reaction mixture was stirred at room temperature for 3 hours and filtered through celite and the filtrate was concentrated in a vacuum. The concentrate was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified through silica gel chromatography to produce (E)-1-(4-methoxy-2,5-dimethylphenyl)ethanone oxime as a white solid (0.45 g, yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([N:14]=[C:15]=[O:16])=[C:4]([F:17])[CH:3]=1.[OH:18][CH:19]([C:24]([CH3:26])=[CH2:25])[C:20]([O:22]C)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:20](=[O:22])[C:19](=[C:24]([CH3:26])[CH3:25])[O:18][C:15]2=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OC
Reactant: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A 20-L stainless steel vessel equipped with a mechanical stirrer and a dropping funnel was charged with a solution of 4-chloro-5-cyclopentyloxy-2-fluorophenylisocyanate (4.00 kg, 15.6 mol) and methyl 2-hydroxy-3-methyl-3-butenoate (2.40 kg; purity=ca. 90%; 18.4 mol) in toluene (10 L). To the solution being cooled in an ice water bath, triethylamine (40 mL) was added dropwise slowly enough to ensure against the increase in the temperature of the solution. The solution was stirred at the same temperature for 3 h until TLC confirmed that the starting materials had disappeared. Subsequently, potassium carbonate (200 g) was added and, with the resulting methanol being removed with a fitted distillator, the mixture was stirred under heating in a water bath (100° C.) for 5 h. After completion of the reaction, the reaction mixture was washed with 1N HCl (10 L), 1N sodium hydroxide (10 L) and again with 1N HCl (10 L). The toluene layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under vacuum; thereafter, hexane was added in an amount about one half of the resulting oil and the mixture was left to stand at room temperature, thereby producing 3N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropyliden-2,4-oxazolidinedione as whitish yellow solids (4.19 kg, 11.8 mol; yield=75.7%; primary crystal). MP: 104.5°-105.0° C. 1H-NMR(CDCl3,TMS,ppm): δ1.49-1.97(8H,m), 2.03(3H,s), 2.31(3H,s), 4.73(1H,m), 6.88(1H,d,JHF =6.6Hz), 7.33(1H,d,JHF =8.5Hz). IR (KBr disk, cm-1): 2970, 1815, 1740, 1500, 1200.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].F[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)c3cn(-c4ccccn4)c4cc(Cl)ccc34)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) in dry DMF was added NaH (1 eq) and the reaction mixture stirred at room temperature for 30 min and then treated with 2-fluoropyridine (1.5 eq) and heated at 140° C. under microwave irradiation for 15 min. Purification by preparative HPLC gave the desired product in 38% yield.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:31][C:32]([F:46])([F:47])[C:33]1[CH:34]=[C:35]([C:28]2[O:27][C:22]3=[C:23]([NH2:26])[N:24]=[CH:25][C:20]([C:18]4[CH:17]=[N:16][N:15]([C@H:12]5[CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]5)[CH:19]=4)=[C:21]3[CH:29]=2)[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine (83 mg, 0.18 mmol), 3,5-bis(trifluoromethyl)benzeneboronic acid (71 mg, 0.28 mmol), (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (13.5 mg, 0.0186 mmol), and potassium carbonate (77 mg, 0.56 mmol) in 1,4-dioxane (1.0 mL) and water (0.30 mL) was degassed 3× with argon and heated in a microwave reactor at 100° C. for 1 h. The mixture was partitioned between EtOAc and brine and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over sodium sulfate and concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:DCM) afforded 104 mg (90%) of the title compound as a foam. 1H NMR (400 MHz, CDCl3): δ 0.06-0.14 (m, 6H) 0.87-0.98 (m, 9H) 1.49-1.64 (m, 2H) 1.85-2.11 (m, 4H) 2.18-2.33 (m, 2H) 3.69-3.82 (m, 2H), 4.17-4.28 (m, 1H), 5.05 (br. s., 1H) 7.34 (s, 1H) 7.70 (s, 1H) 7.82 (s, 1H) 7.92 (s, 1H) 8.00 (s, 1H) 8.31 (s, 2H); MS (ESI): 624.34 [M+H]+; HPLC tR=2.00 min (TOF: nonpolar—3 min).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:26][NH2:27])(=[O:25])[CH2:22][CH2:23][CH3:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:27][NH:26][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (40 mL) were added butanehydrazide 234 (0.14 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N-butanoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 235 (0.31 g, 95%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)=[C:11]([CH3:27])[CH:10]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)=[C:11]([CH3:27])[CH:10]=1
Reactant: COC(=O)c1ccc(C)c(-c2c(C)cc(OCc3ccccc3)cc2C)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(-c2c(C)cc(O)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
A mixture of methyl 4′-(benzyloxy)-2′,6,6′-trimethylbiphenyl-3-carboxylate (255 mg, 0.71 mmol), 10% palladium-carbon (50% water-containing product, 25.5 mg) and ethanol (3 mL) was stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was again subjected to the above-mentioned conditions (10% palladium-carbon (50% water-containing product, 127 mg), stirring time 2 hr) to give the title compound (199 mg, yield 100%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[NH2:1][C:2]1[C:7]([C:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1N
Reactant: C1CCNC1
Solvent: CO
Product: Nc1ncc(Cl)nc1C(=O)N1CCCC1

Procedure:
Methyl 2-amino-5-chloropyrazine-3-carboxylate was treated as described in Example 1 with 25 ml. of pyrrolidine in 100 ml. of methanol. Crystallization from ether yielded 7 g. (72%) of the above-named product with m.p. 90°-95°. Recrystallization from 2-propanol gave pale yellow needles with m.p. 95°-97°.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:6]=[CH:5][C:4]=1[C:19](=[O:27])C[N+]1C=CC=CC=1.[Cl-].CC1C=CC(C(=[O:44])C[N+]2C=CC=CC=2)=C(NC(=O)C2C=CC=CC=2C)C=1.[OH-].[Na+].Cl>CO.O>[CH3:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:6]=[CH:5][C:4]=1[C:19]([OH:27])=[O:44]
Reactant: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)C[n+]1ccccc1
Reactant: Cc1ccc(C(=O)C[n+]2ccccc2)c(NC(=O)c2ccccc2C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
The isomer mixture of 1-{2-[2-methyl-4-(2-methylbenzoylamino)-phenyl]-2-oxoethyl}pyridinium chloride and 1-{2-[4-methyl-2-(2-methylbenzoylamino)phenyl]-2-oxoethyl}pyridinium chloride obtained in the above Reference Example 6 (207.3 g, 0.544 mole) is suspended in methanol (0.4 L) and thereto is added a solution of sodium hydroxide (52.5 g, 1.31 mole) in water (0.6 L), and the mixture is stirred at 60-76° C. for about 4 hours to complete the reaction. To the reaction mixture is added concentrated hydrochloric acid (0.108 L) at the same temperature to adjust pH=1. The mixture is stirred under ice cooling for one hour, and the precipitated crystals are separated by filtration. The resulting crystals are washed with water and dried at around 60° C. to give the crude product (125.5 g, yield 85.6%). A part of this crude product (20 g) is recrystallized from methanol (340 mL) and dried at 60° C. to give the desired product (12.1 g, yield 60.5%, purity by HPLC 99.7%).
Reaction SMILES: [OH-].[K+].[CH2:3]([SH:5])[CH3:4].[CH3:6][O:7][C:8](=[O:26])[CH:9](Cl)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.C(OCC)C>CO>[CH3:6][O:7][C:8](=[O:26])[CH:9]([S:5][CH2:3][CH3:4])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CCSC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Potassium hydroxide (0.092 g; 1.64 mmole) was dissolved in methanol. Ethanethiol (0.133 g; 2.14 mmole) and 3-(4-benzyloxyphenyl)-2-chloropropanoic acid methyl ester (0.5 g; 1.64 mmole) were added. The reaction mixture was stirred at room temperature over night. Diethyl ether (15 ml) was added. The mixture was filtered and evaporated. The residue was purified by adding active charcoal in methanol. The mixture was stirred for 15 minutes and the active charcoal was filtered off. Evaporation of the solvent gave 0.47 g (86.7% yield) of 3-(4-benzyloxyphenyl)-2-ethylsulfanyl propanoic acid methyl ester.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([O:6]CC)=[O:5].[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18].C(O)(=O)C.[OH-].[K+].Cl.C(=O)=O>C1COCC1.O>[F:23][C:14]([F:13])([F:22])[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC(CC(=O)O)C(F)(F)F
Temperature: 40 °C
Reaction time: 17 h
Yield: 95 %

Procedure:
To 115 mg (5 mmol) of sodium metal (cut into small pieces and washed with hexanes) in 5 ml of THF was added a solution of diethyl malonate (800 mg, 5 mmol) in 10 ml THF. The mixture was stirred at room temperature until all of the sodium metal was consumed (2-3 hours). A catalytic amount of tetrabutylammonium bromide was added, followed by a THF solution (10 ml) of ethyl 4,4,4-trifluorocrotonate (0.84 g, 5 mmol). This mixture was warmed to 40° C. and stirred for 17 hours. After cooling to 10° C., glacial acetic acid (300 mg, 5 mmol) was added and the THF was removed in vacuo. The resulting residue was treated with a solution of 87.3% KOH (1.28 g, 20 mmol) in 10 ml water and refluxed for 4.5 hours. After cooling to 10° C., 2.5 ml (26 mmol) of conc. HCl was added dropwise via pipette and the mixture was again heated to reflux until CO2 evolution had ceased (ca. 1 hour). The solution was cooled to 15° C. and extracted with Et2O(3×10 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford 3-(trifluoromethyl)glutaric acid as a white solid in 95% yield (m.p. 100°-100.5° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1-n1cccn1)C(=O)OC(C)(C)C
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(N)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 89 %

Procedure:
To a mixture of the compound (4.15 g) obtained in Example 500a, nickel (II) chloride hexahydrate (0.183 g) and methanol (300 ml), sodium borohydride (2.43 g) was added. The reaction mixture was stirred at room temperature for 55 min; thereafter, 2 N HCl was added to render the reaction solution acidic and then a saturated aqueous sodium hydrogencarbonate solution was added to render the reaction solution basic; subsequently, the reaction mixture was concentrated under reduced pressure. To the resulting residue, water was added and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/n-hexane to give the titled compound (yield, 89%).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+].C1COCC1.O>CCO.C(OCC)(=O)C.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:26])[N:8]([C@@H:3]([CH:2]([CH3:27])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[CH2:16]3)=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc([N+](=O)[O-])cc3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O

Procedure:
The compound of example 222 (0.5 g, 0.00135 mol), iron (0.178 g, 0.00319 mol) and ammonium chloride (0.312 g, 0.00585 mol) are taken in EtOH:THF:H2O (7.5 mL; 5:2.5). The reaction mixture was refluxed for about 16 h. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated to obtain a solid residue, which was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by column chromatography (silicagel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: ClC1N=C(OC[C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])C=C(Cl)N=1.CCN(C(C)C)C(C)C.Br.BrCCCN>CN(C)C=O>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:13]1[CH:12]=[CH:11][CH:10]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(COc2cc(Cl)nc(Cl)n2)ccc1Oc1cccc(C(F)(F)F)c1
Agent: Br
Agent: NCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1Oc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of 5-(((2,6-dichloropyrimidin-4-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (600 mg, 1.363 mmol) and DIPEA (1.5 mL, 8.59 mmol) in N,N-dimethylformamide (3 ml) was added 3-bromopropan-1-amine hydrobromide (900 mg, 4.11 mmol) at 0° C. and the reaction mixture was stirred overnight at 0° C. The solution was purified with reverse phase column chromatography (120 g) using water (contained 0.3% TFA) and MeCN as eluent to afford 5-(((6-(3-bromopropyl)amino)-2-chloropyrimidin-4-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (350 mg, 0.646 mmol, 47.4% yield).