Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)[CH3:4].[O:15]([CH3:17])[Na].[CH3:18]O>>[OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:17](=[O:15])[CH2:18][NH:14][C:12]2=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(=NO)c1ccc(NC(N)=O)cc1
Reactant: CO
Reactant: CO[Na]
Product: CC(=NO)c1ccc(N2C(=O)CNC2=O)cc1

Procedure:
0.02 mol of this urea is dissolved in 300 mL of CH3OH. The pH is adjusted to approximately 10.0 using 25% NaOCH3 solution in CH3OH. The solution is heated to reflux for 2.5 hours, after which time the solvent is removed in vacuo. The residue is washed with cold water and dried in vacuo to yield the crude 3-[4-(1-hydroxyiminoethyl)phenyl]hydantoin. The hydantoin is purified by recrystallization from CH3OH:H2O.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O.Cl.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:11](=[O:13])[CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[F:1])[O:14][CH2:15][CH3:16])=[CH:22][CH:21]=1)#[N:18]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Temperature: 0 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
To an ice cooled mixture under Ar of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid, 4-aminomethyl-benzonitrile hydrochloride (10.6 g) and 1-hydroxybenzotriazole (9.8 g) in DMF (140 ml) was added EDC (13.9 g) and triethylamine (55 ml). The mixture was stirred 2.5 h at 0° C. and 2 d at rt. The solvent was evaporated and H2O (250 ml) was added. The product was extracted with AcOEt (2×200 ml). The organic layers were washed with 5% NaHCO3 aq. sol. (100 ml), brine 100 ml). After drying (Na2SO4) the solvent was evaporated. CC (AcOEt/Hept 2:3) afforded 7.66 g (49%) of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetamide. White solid. MS 364.1 ([M+NH4]+).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]\[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41]C)=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]\[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([OH:41])=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a mixture of methyl 3-[4-({4-[({4-[(Z)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (1.38 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-({4-[({4-[(Z)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (1.26 g, yield 93%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: [CH2:1]([N:8]1C(=O)C2=CC=CC=C2C1=O)CCCCC=C.[OH-:19].[Na+].[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=CC=1>>[NH2:21][C:30]1[C:25]([CH3:24])=[C:26]([OH:19])[CH:27]=[CH:28][C:29]=1[C:1]#[N:8]
Reactant: c1ccc2ncccc2c1
Reactant: [OH-]
Reactant: C=CCCCCCN1C(=O)c2ccccc2C1=O
Agent: [Na+]
Product: Cc1c(O)ccc(C#N)c1N
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A mixture of compound 75 (19 g, 0.1 mol) in quinoline (50 mL) was heated to 170° C. for 2 h (until effervescence ceased). The reaction mixture was cooled to RT and aqueous NaOH solution was added (1M, 500 mL) followed by pet. ether (500 mL). The reaction mixture was stirred for 15 min and the aqueous layer was separated. The aqueous layer was further washed with pet. ether (2×300 mL) to remove quinoline completely. The aqueous layer was acidified with 1.5N HCl to pH=5, the solid was filtered off and dried under vacuum. The obtained solid was further washed with 5% ethyl acetate in pet. ether to give pure title compound (12 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:22](Cl)(=[O:24])[CH3:23].CN(C1C=CC=CN=1)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH:5][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cc(-c3ccc(N)c(OC)c3)ccc2c1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(NC(C)=O)c(OC)c3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 2-methoxy-4-(6-methoxy-2-naphthyl)aniline (140 mg, 0.50 mmol, 1 eq) in 20 ml of dry dichloromethane are added acetyl chloride (64 μl, 71 mg, 0.91 mmol, 1.8 eq) and trace amounts of DMAP (dimethylaminopyridine). After stirring for 18 h at RT, the reaction mixture is stopped by adding a 2% sodium carbonate solution, the phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with a gradient of dichloromethane/methanol 10/0 to 9.8/0.2 yielded the desired product in a yield of 66%, 108 mg.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)[C:9]2[CH2:8][CH2:7][C:6]3[O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH2:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[C:4](=[C:5]4[CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]5[O:25][C:6]4=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3c2CCC2=C3C3CCCCC3O2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N2CC[C@@H](N)C2)c2ccc3c(c2n1)C1CCCCC1O3
Reaction time: 16 h

Procedure:
A solution of the product from Example 7A (28 mg, 0.065 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.2 mL) at ambient temperature and stirred for 16 hours. The mixture was diluted with dichloromethane (20 mL), and basified with sodium hydroxide (1 N). The organic layer was separated, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with ammonium hydroxide/methanol/dichloromethane (0.8/8/92) to provide the dehydrogenated material as the major product and title compound: 1H NMR (CD3OD) δ 1.00-1.18 (m, 1H), 1.27-1.41 (m, 1H), 1.45-1.58 (m, 1H), 1.62-1.75 (m, 2H), 1.92-2.07 (m, 3H), 2.11-2.24 (m, 1H), 2.24-2.39 (m, 2H), 3.38-3.52 (m, 1H), 3.74-3.92 (m, 2H), 3.98-4.12 (m, 1H), 4.10-4.24 (m, 2H), 6.87 (d, 1H), 8.08 (d, 1H); MS (DCl/NH3) m/z 326 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:65]([NH:68][CH2:69][CH2:70][NH2:71])(=[O:67])[CH3:66]>CN(C=O)C.CCOCC>[C:65]([NH:68][CH2:69][CH2:70][NH:71][C:22](=[O:24])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)(=[O:67])[CH3:66]
Reactant: CC(=O)NCCN
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(-c2nc(-c3cccc(CC(=O)NCCNC(C)=O)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of crude (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (preparation described in Example 24, Step 1, 308 mg; 0.74 mmol) in DMF (6 mL) at 0° C. was added DIEA (267 4, 1.5 mmol) and HATU (282 mg; 0.74 mmol). After 10 min, a solution of N-acetylethylenediamine (75 mg, 0.74 mmol) in DMF (2 mL) was added and the reaction mixture was stirred at RT overnight. Et2O was added and the mixture was washed with water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by preparative HPLC affording the title compound as a white fluffy solid. LC/MS (Method B): 499.3 (M+H)+. HPLC (Method A) Rt 4.89 min (Purity: 100.0%).
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.[S:27]([Cl:31])([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][Cl:31])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][O:17][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:14][N:15]=1)[CH3:10])([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CCl)o1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(COS(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of {2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl}-methanol (455 mg, 1.77 mmol) in dry CH2Cl2 (4.5 mL) was treated at 0° C. with Et3N (0.32 mL, 2.30 mmol) followed by DMAP (22 mg, 0.18 mmol) and Ms-Cl (0.17 mL, 2.12 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give in a 2:1 ratio the title compound (LC-MS-conditions 02: tR=1.13 min, [M+H]+=276.06) along with methanesulfonic acid 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl ester (LC-MS-conditions 02: tR=1.07 min, [M+H]+=336.45) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16].[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])=[O:32]
Reactant: O=C(NCC1CCCN1)c1ccc(Cl)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCCN1C(=O)Nc1ccc(-n2ccccc2=O)cc1F)c1ccc(Cl)s1

Procedure:
75.3 Using general method H, rac-5-chloro-thiophene-2-carboxylic acid (pyrrolidin-2-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give rac-2-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 475.1 ([M+H]+)
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[C:5](=[O:8])([O-])[O-].[Na+].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[CH:13]1[C:12]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=[C:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=N[O-]
Reactant: O=C([O-])[O-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 140 °C
Yield: 93.8 %

Procedure:
A mixture of 69 g (1.0 mol) of sodium nitrite, 53 g (0.5 mol) of sodium carbonate, 5 g (0.01 mol) of hexadecyltributyl-phosphonium bromide, 220 ml of water and 78.5 g (0.5 mol) of 4-chloro-nitrobenzene is heated to 140° C. for 7 hours. After cooling, the solid product is filtered off and washed, first with a little dilute hydrochloric acid and then with a little alcohol. After drying, 61 g (91.5% of theory) of 4,4'-dinitrodiphenyl ether (melting point: 139°-140° C.) are obtained.
Reaction SMILES: Cl.N[OH:3].[C:4]([O:7]C(=O)C)(=[O:6])C.O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:17]([C:16]1[O:3][C:13]([C:4]([OH:7])=[O:6])=[CH:14][CH:15]=1)#[N:12]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: NO
Agent: Cl
Solvent: O
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 2-fornyl-5-furancarboxylic acid (0.28 g, 2.0 mol) in pyridine (5.0 mL) was added hydroxylamine hydrochloride (“NH2OH.HCl”) (0.27 g, 4.0 mol). The mixture was heated to 85° C. before the addition of acetic anhydride (4.0 ml). The reaction mixture was stirred at 85° C. for 3 h, cooled to 60° C. and poured into water (25 mL). The mixture was cooled to room temperature and stirred overnight (the pH of the solution was measured to be 5-6). The impurities were extracted with a solution of 4/1 DCM/isopropanol (3×30 mL). The aqueous layer was then basified with NaOH solution (2 N) to a pH of about 9, and the pyridine was extracted with a solution of 4/1 DCM/isopropanol (3×30 mL). The aqueous solution was then acidified to a pH of about 2 and the product was extracted with a solution of 3/1 DCM/isopropanol (3×50 mL). The combined organic extracts were dried over MgSO4, and the solvent was evaporated to afforded the pure product as a light brown solid in 90% yield. 1H NMR (DMSO-d6): δ 13.80 (bs, 1H), 7.75 (d, 1H), 7.40 (d, 1H). IR (neat): (cm−1) 3200, 2250, 1053, 1025, 1006.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[CH2:26]=O>C(O)=O>[CH3:26][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: C=O
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Solvent: O=CO
Product: CN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (25 g, 61 mmol) in 140 mL of formic acid (96%) was added 50 g of formaldehyde (37%). The solution was stirred at 75° C. for 48 h and was cooled to room temperature. The excess formic acid was removed under reduced pressure and the residue was dissolved in 100 mL of water. the solution was added to concentrated NH4OH/H2O and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (1×250 mL) and was dried over Na2SO4. The solution was filtered and concentrated to leave a white solid. The solid was triturated with ether and was filtered to afford the title compound: MS (M+H): 353 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20]O>CC(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: COc1ccc(CO)cc1OC
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)C(F)(F)F)cc1OC
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
4-Chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and 3,4-dimethoxybenzyl alcohol (7.39 g, 44 mmol) were added to 2-propanol (40 mL). TSOH (76 mg, 0.4 mmol) was added and the mixture heated to 60° C. and held 3.5 hours. The solution was concentrated in vacuo to 1/2 the original volume, diluted with water (10 mL) and stirred at room temperature. The resulting slurry was filtered and the product dried in vacuo at 30° C. to give 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile: mp 82-84° C.; 1H NMR (CDCl3) δ 9.05 (brs, 1H), 7.75 (brt, J=2 Hz, 1H), 7.35 (dd, J=2, 8 Hz, 1H), 6.8 (d, J=8 Hz, 3H), 6.75 (d, J=8 Hz, 1H), 4.43 (d, J5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3) δ 179.9, 151.9, 149.4, 148.7, 137.4, 130.8, 130.8, 130.7, 129.4, 119.4, 114.5, 111.5, 111.4, 110.3, 56.1, 56.0, 47.0; 19F NMR (CDCl3) δ -69.61.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.C(N(CC)CC)C.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl.C(Cl)(Cl)Cl>[OH:9][CH2:8][CH:3]([NH:2][C:36]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)N1CCCCC1
Reactant: COC(=O)C(N)CO
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.43 mmol) of methyl 2-amino-3-hydroxypropionate hydrochloride and 960 mg (14.1 mmol) of imidazole were dissolved in 10 ml of dichloromethane. 10 ml of a solution of 1.07 g (7.07 mmol) of t-butyldimethylchlorosilane in dichloromethane was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 1 hour. After concentrating under reduced pressure, ethyl acetate was added to the residue. The reaction mixture was washed with saturated aqueous ammonium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane. 1.35 ml (9.65 mmol) of triethylamine and 0.97 ml (7.72 mmol) of 1-piperidinecarbonyl chloride were added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. 20 ml of chloroform was added to the reaction mixture, and they were stirred at 50° C. for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 15 ml of methanol. 10 ml of 2 N hydrochloric acid was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 hours. After the concentration under reduced pressure, ethyl acetate was added to the residue. The product was washed with 1 N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane:methanol=1:0 to 9:1) to obtain the title compound.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[C:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)=[CH:7][C:8](=[O:24])[N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([O:16]CC)=[O:15])[CH:10]=1.Cl>C1COCC1.O>[F:4][C:5]1[C:6]([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=2)=[CH:7][C:8](=[O:24])[N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([OH:16])=[O:15])[CH:10]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(SC)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Lithium hydroxide monohydrate (165 mg, 6.68 mmol) was added to a solution of ethyl (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (0.492 g, 1.12 mmol) in THF:water (1:1, 14 mL) and the reaction was allowed to stir at rt for 18 h. The reaction mixture was acidified using 4 M aq HCl to afford a precipitate. The solid was collected via filtration and dried under vacuum to afford the title compound as a solid (339 mg, 73%). MS (LCMS) m/z 414.1 (M+1). 1H NMR (400 MHz, DMSO-d6)δ ppm 1.54 (s, 3 H) 2.17 (ddd, J=13.42, 10.00, 5.07 Hz, 1 H) 2.41-2.45 (m, 1 H) 2.49 (s, 3 H), 3.14 (s, 3 H) 3.78-4.15 (m, 2 H) 6.46 (d, J=7.81 Hz, 1 H) 7.28-7.39 (m, 2 H) 7.43-7.55 (m, 2 H) 8.01 (d, J=6.83 Hz, 1 H).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.O>[CH3:33][S:34]([O:4][CH:2]([CH3:3])[CH2:1][O:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:36])=[O:35]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
To a solution of propane-1,2-diol (4.00 g, 52.0 mmol) in dry dichloromethane (50 mL) at 0° C. was added trityl chloride (15 g, 0.052 mol), N,N-dimethylaminopyridine (0.82 g, 6.8 mmol) and triethylamine (13.13 g, 1.33 mmol). The resulting mixture was stirred at room temperature for 14 hours. Methanesulfonyl chloride (6.36 g, 56.0 mmol) slowly at 0° C. Then the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL*3). The organic layer was washed with water (100 mL), and 1 N hydrochloric acid (100 mL*2). The combined organic layers were dried over sodium sulfate and concentrated to give a crude product, which was purified on silica gel column (petroleum ether: ethyl acetate=8:1 to 10:1) to give the title compound (15 g) as a viscous oil, which was used in the next step without further purification.