Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[O:16]>C1(C)C(C)=CC=CC=1>[CH3:1][NH:2][C:3]([N:5]([CH3:6])[C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])=[O:16])=[O:4]
Reactant: O=C=Nc1ccccc1F
Reactant: CNC(=O)NC
Solvent: Cc1ccccc1C
Product: CNC(=O)N(C)C(=O)Nc1ccccc1F
Reaction time: 16 h

Procedure:
To a solution of 8.8 g (0.1 mol) of 1,3-dimethyl urea dissolved in 30 ml of xylene there was added a solution of 13.7 g (0.1 mol) of 2-fluorophenylisocyanate dissolved in 30 ml of xylene. The resulting mixture was refluxed for 4 hours and then allowed to stand at ambient temperature for 16 hours. During this time the product crystallized and was removed by filtration. The product weighed 15.8 g. The NMR spectrum had a doublet at 2.86 ppm, a singlet at 3.25 ppm, and a multiplet structure at 7.2 ppm, characteristic of a biuret structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](=[S:41])[NH2:40])[CH2:35][CH2:34]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[N:40][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)C1CCOCC1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (85 g, 243 mmol) in DMA (700 mL), NBS (43.2 g, 243 mmol) was added at 0° C. The reaction mixture was stirred at rt for 1 h. Then tetrahydro-2H-pyran-4-carbothioamide (42.3 g, 291.6 mmol) was added at rt. The mixture was stirred at 60° C. for 1.5 h. The mixture was poured into water and extracted with EtOAc (400 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound. (40 g, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48-9.54 (br, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.76-7.83 (m, 1H), 7.23-7.32 (m, 2H), 7.02 (d, J=5.3 Hz, 1H), 5.87-5.98 (m, 1H), 5.27-5.36 (m, 1H), 5.16-5.21 (m, 1H), 4.54-4.60 (m, 2H), 3.87-3.94 (m, 2H), 3.41-3.50 (m, 2H), 3.27-3.37 (m, 1H), 1.97-2.04 (m, 2H), 1.69-1.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CC([O-])(C)C.[K+].[N:18](OC(C)(C)C)=[O:19]>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:18][OH:19])[C:4]=2[N:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Clc1ncc2c(n1)CCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ON=C1CCCc2cnc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
2-Chloro-5,6,7,8-tetrahydro-quinazoline (Eur. J. Med. Chem. 1982, 17, 75)(1.0 g; 5.9 mmol) is dissolved in THF (80 ml) and cooled to −78° C. KOtBu (667 mg; 5.9 mmol) in THF (10 ml) is added dropwise and stirred for 5 minutes after complete addition. t-Butyl nitrite (2 ml; 27.8 mmol) is added to the orange solution and the reaction mixture warmed to room temperature. After 10 minutes the reaction mixture is poured on water/HOAc (800/1 ml) and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to deliver the title compound as yellow-orange crystals (1.1 g; 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([CH2:37][C:38](O)=[O:39])[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>>[CH3:28][C@@H:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:41])([F:29])[F:42])[CH:32]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21

Procedure:
Prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Preparation 36) and 3-trifluoromethylphenylacetic acid with DIPEA as base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=O)=[CH:5][CH:4]=1.[C:19]1(=O)[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.C([N:28](CC)CC)C.C([O-])(=O)C.[NH4+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:28]=[C:19]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[O:12][C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(CCC(=O)O)oc2-c2ccccc2)cc1

Procedure:
4-Methoxybenzoin (24 g, 0.1 m) prepared according to B. R. Kinney, J.A.C.S., 51, 1595 (1929), succinic anhydride (12 g, 0.12 m), triethylamine (5 ml, 0.035 m) and toluene (30 ml) were heated on a steam cone for three hours under nitrogen. After cooling, acetic acid (60 ml) and ammonium acetate (10.5 g) were added and heating was resumed as 60 ml of solvent were distilled. Acetic acid (30 ml) was added and 30 ml of solvent were distilled. The previous step was repeated twice more. The mixture was cooled and poured into 600 ml of ice water, decanted, triturated twice with ice water and filtered. Recrystallization from 50% aqueous methanol gave 24.2 g, (71%) of 4-(4-methoxyphenyl-5-phenyl-2-oxazolepropanoic acid, m.p. 118°-120° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:16][C:17]([C:18]([NH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:24])=[O:23])=[O:19])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:58][C:59](=[NH:61])[CH3:60]>C(Cl)Cl>[NH2:61]/[C:59](=[N:58]\[O:23][C:22](=[O:24])[C@@H:21]([NH:20][C:18]([C:17]1[N:16]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:19])[C:25]([CH3:27])([CH3:28])[CH3:26])/[CH3:60]
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 2 mL dichloromethane solution of Compound 515 (320 mg, 0.68 mmol) was added to a dichloromethane solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (209 mg, 1.09 mmol) and 1-hydroxybenzotriazole hydrate (167 mg, 1.09 mmol). The solution was stirred for 15 minutes at ambient temperature. N-hydroxyacetamidine (76 mg, 1.02 mmol) was added in one portion as a solid, and the mixture was stirred overnight. After diluting with additional DCM, the reaction mixture was washed with saturated aqueous aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated to a pale yellow foaming solid (Intermediate 49A). LCMS (+ESI) m/z 527.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:24](OC)([N:26](C)C)[CH3:25].[NH2:31]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:31][NH:26][C:24]([CH3:25])=[C:10]2[N:9]=1
Reactant: NN
Reactant: Cc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: COC(C)(OC)N(C)C
Product: CC1=C2N=C(c3ccccc3Cl)c3cc(C)c(C)cc3N=C2NN1

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVw) was prepared by reacting 0.0005 moles of 5-(2-chlorophenyl)-1,3-dihydro-7,8-dimethyl-2H-1,4-benzodiazepin-2-thione (IIw) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=337.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][NH:6][C:7](=[O:11])[CH:8](Cl)[CH3:9].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[C:25]([SH:26])=[CH:24][C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[C:22]([F:40])[CH:21]=1.Cl>C(#N)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][NH:6][C:7](=[O:11])[CH:8]([S:26][C:25]1[CH:24]=[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])[C:22]([F:40])=[CH:21][C:20]=1[Cl:19])[CH3:9]
Reactant: COC(=O)CCNC(=O)C(C)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S)c(Cl)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)CCNC(=O)C(C)Sc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of 3-(2-chloropropionylamino)propionic acid methyl ester (6.93 g) and potassium carbonate (4.72 g) in acetonitrile (150 mL) was added dropwise a solution of 3-(4-chloro-2-fluoro-5-mercaptophenyl)-1-methyl-6-trifluoromethyl-1H-pyrimidin-2,4-dione (11.54 g) in acetonitrile (75 mL) at 45° C. to 50° C. for 1 hour. The reaction mixture was stirred at the same temperature for 2 hours and neutralized at 5° C. with 1 N hydrochloric acid. Water and ethyl acetate were added to separate the organic layer. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, filtered, concentrated, and recrystallized with ether to give the target compound (13.00 g, yield 78%, white solid).
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[O:38]([CH2:45][C:46](O)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[O:38]([CH2:45][C:46]([O:22][C@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C:3]2=[N:1][OH:2])[CH2:13]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: O=C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)COc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.6 %

Procedure:
To the stirred solution of 17-Oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.342 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml), phenoxyacetic acid (0.24 g, 1.6 mmol) was added. The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered and the solvent removed under vacuum. The resulting residue was crystallized from ethyl acetate:petroleum ether (60:80) to give 17-oximino-5-androsten-3β-yl phenoxyacetate (16) (0.27 g, 54.0%) mp 118-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]>C(#N)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2)c1
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1

Procedure:
The title compound was prepared from methyl 2-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (EXAMPLE 98) according to the procedure for the preparation of Example 97, part B. 1H NMR (400 MHz, DMSO-d6): δ 5.41 (2H, s), 6.00 (1H, d, J=2.0 Hz), 7.61 (1H, d, J=1.6 Hz), 7.67-7.69 (2H, m), 7.77 (1H, dd, J=0.8 Hz, J=4.8 Hz), 7.87-7.89 (2H, m), 8.10 (1H, s), 8.70 (1H, d, J=5.2 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.104 min. [M+H] Calc'd for C17H12N4O3, 321. Found, 321.
Reaction SMILES: S(=[N:4][CH2:5][C:6]([OH:8])=[O:7])(=O)=O.[CH3:9][O-].[Na+].C=O.C[O:15][P:16]([O:19]C)[O:17]C>CO>[CH2:5]([NH:4][CH2:9][P:16]([OH:19])([OH:17])=[O:15])[C:6]([OH:8])=[O:7]
Reactant: COP(OC)OC
Reactant: O=C(O)CN=S(=O)=O
Reactant: C[O-]
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 5 h

Procedure:
N-sulfonylglycine (5 grams, 0.032 mole), prepared in the prior example, was suspended in methanol (50 mls) and sodium methoxide (25% sodium hydroxide in methanol) was added to adjust the pH of the suspension to 8-9. Paraformaldehyde (1 gram, 0.033 mole) and trimethylphosphite (3.8 mls, 0.032 mole) were added to the suspension and the resulting reaction mixture was then refluxed. The pH was adjusted with sodium methoxide solution from time to time to maintain it between 8 and 9. After 5 hours, the solids present in the reaction mixture were separated and the filtrate was evaporated. The resulting residue was refluxed with concentrated HCl (25 mls). After 3 hours, the solvent was removed to obtain the product glyphosate. This product was isolated and the structure confirmed by H and 31P NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[C:26]([O:29][CH2:30]C)(=[O:28])C>Br>[ClH:1].[ClH:1].[CH3:30][O:29][C:26](=[O:28])[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][N:12]2[CH2:11][CH2:10][O:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCN2CCOC(c3cccc(Cl)c3)C2)cc1
Reactant: CCOC(C)=O
Agent: Br
Solvent: CO
Product: COC(=O)COc1ccc(CCN2CCOC(c3cccc(Cl)c3)C2)cc1
Product: Cl
Reaction time: 4 h

Procedure:
A mixture of 4-[2-(2-[3-chlorophenyl]morpholino)ethyl]anisole (2.6 g) in 48% aqueous hydrobromic acid (90 ml) was heated under reflux, with stirring, for 4 hours, cooled and evaporated to dryness. The residue was dissolved in acetone (80 ml), added to a mixture of anhydrous potassium carbonate (11 g), potassium iodide (50 mg) and methyl bromoacetate (1.5 ml) and the resultant mixture heated under reflux, with stirring, overnight. After cooling, filtering and evaporating the filtrate to dryness, the residue was dissolved in dichloromethane, washed with aqueous sodium carbonate (×2), brine (×1), dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residue on silica gel in 0-2% methanol in dichloromethane gave an oil, which, on treatment with an ethereal solution of hydrogen chloride, gave the title compound, m.p. 156°-7° C. (methanol-ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-carboxylate (0.43 g, 1.01 mmol) was suspended in THF (10 mL), MeOH (5 mL) and water (5 mL), and NaOH (0.40 g, 10 mmol) was added. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 0.41 g (99%) of the title compound as a light brown solid. LC/MS m/z 413.3 (MH+), retention time 3.44 min. 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.17 (t, 1H), 7.24-7.29 (m, 2H), 7.58-7.78 (m, 5H), 8.63 (t, 1H), 10.45 (br, 1H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[CH:17]=[N:18][O:19][CH3:20].C(O)(=O)C(O)=O.Cl[C:28]1CC2N(C)C(CC2)[C:29]=1[CH:37]=O.Cl.CON>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[CH:17]=[N:18][O:19][CH2:20][CH:37]1[CH2:29][CH2:28]1
Reactant: CN1C2CCC1C(C=O)=C(Cl)C2
Reactant: CON=CC1=C(Cl)CC2CCC1N2C
Agent: CON
Agent: Cl
Agent: O=C(O)C(=O)O
Product: CN1C2CCC1C(C=NOCC1CC1)=C(Cl)C2

Procedure:
3-Chloro-2-(methoxyiminomethyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate from 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate and methoxyamine hydrochloride, M.p. 180°-185° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[C:22]([C:26]2[N:27]([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[C:28]3[CH:33]=[C:32]([O:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=4)[N:31]=[CH:30][C:29]=3[N:45]=2)=[N:23][O:24][N:25]=1.C([NH:60][CH2:61][CH2:62]O)(OC(C)(C)C)=O.O>O1CCOCC1>[NH2:60][CH2:61][CH2:62][O:52][C:49]1[CH:50]=[CH:51][C:46]([N:27]2[C:28]3[CH:33]=[C:32]([O:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=4)[N:31]=[CH:30][C:29]=3[N:45]=[C:26]2[C:22]2[C:21]([NH2:20])=[N:25][O:24][N:23]=2)=[CH:47][CH:48]=1
Reactant: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(O)cc2)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(OCCN)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
Triphenylphosphine (260 mg, 1.0 mmol) was added to a solution of the product from Step 5 (220 mg, 0.5 mmol) and N—BOC-ethanolamine (161 mg, 1.0 mmol) in dioxane (4 mL) followed by addition of di-isopropylazodicarboxylate (197 uL, 1.0 mmol) and the resulting solution was allowed to stir at rt overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic phases were combined, washed with brine, dried (MgSO4), filtered and the filtrate concentrated. The crude material was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL) for 30 min, then concentrated and the residue was purified by reverse phase HPLC to give the title compound (38 mg, 16%). MS (ES+) m/e 487 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-:14].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:9][C:8](=[O:14])[CH:7]=[CH:6][C:10]1[CH:4]=[CH:3][CH:2]=[CH:13][C:11]=1[OH:12]
Reactant: O=Cc1ccccc1O
Reactant: [OH-]
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
2-Hydroxybenzaldehyde (1q, 1.81 ml, 17.0 mmol) and acetone (19, 0.62 ml, 8.4 mmol) were combined in ethanol (15 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (4 ml) was added and the solution stirred for 1 week at room temperature. The mixture was neutralized with hydrochloric acid (1 N) and the resulting precipitate filtered and recrystallized from ethyl acetate/hexane to give 1.79 g (80%) of a yellow solid: mp 154-157° C. [expected mp 155° C.]; NMR: (DMSO) δ 6.89 (m, 4H), 7.27 (m, 4H), 7.68 (d, 2H, J=7.4 Hz), 7.93 (d, 2H, J=16.1 Hz), 10.22 (s, 2H); 13C NMR: (DMSO) δ 116.1, 119.3, 121.3, 125.3, 128.5, 131.5, 137.6, 156.9, 188.5.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])=[CH:14][C:15]=1[CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1
Reactant: Cc1ccc(N)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Benzyl chloroformate (95%, 4.52 mL, 30.1 mmol) was added dropwise to a stirred mixture of tert-butyl 4-(3-amino-6-methylphenyl)piperidinecarboxylate (6.99 g, 24.1 mmol) and K2CO3 (3.66 g, 26.4 mmol) in tetrahydrofuran (350 mL) and stirred under nitrogen for 18 h. CH2Cl2 was added to the reaction mixture, washed with NaHCO3 solution (saturated), followed by water, then dried over Na2SO4 and concentrated in vacuo to give an oil. Purification by flash column chromatography (eluent: cyclohexane:EtOAc (87:13)) gave tert-butyl 4-{2-methyl-5-[(phenylmethoxy)carbonylamino]phenyl}piperidinecarboxylate (7.90 g, 77.1% yield) as a white foam. ESMS m/e: 425.0 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](OCCN)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[CH3:45][S:46]([N:49]=[C:50](OC1C=CC=CC=1)OC1C=CC=CC=1)(=[O:48])=[O:47].[NH2:65][CH2:66][CH2:67][OH:68]>O1CCCC1>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:68][CH2:67][CH2:66][NH:65][C:50]([NH:65][CH2:66][CH2:67][OH:68])=[N:49][S:46]([CH3:45])(=[O:47])=[O:48])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Reactant: NCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCCNC(=NS(C)(=O)=O)NCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of dichlorophenoxymethane (1 g) in acetonitrile (10 mL) was added methanesulfonamide (0.39 g) under ice-cooling, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resuling mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-(N-methanesulfonylimino)-1,1-diphenoxymethane (0.95 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (50 mg) in tetrahydrofuran (1 mL) was added 1-(N-methanesulfonylimino)-1,1-diphenoxymethane (26 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-aminoethanol (49 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added acetic acid (0.01 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (38 mg).