Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.CCN(CC)CC.[CH:20](OCC)=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][CH:20]=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(SCCN)cc1
Reactant: CCOC=O
Solvent: CCN(CC)CC
Product: COc1ccc(SCCNC=O)cc1

Procedure:
A solution of compound 1 (550 mg) and Et3N (1 mL) in HCO2Et (20 mL) was refluxed for 12 h. The mixture was cooled down and washed with 1 N HCl and sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 14 as solid: 606 mg. The crude product appeared to be pure by TLC and NMR and used for the next step reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[C].[Pd].CO>[NH2:11][C:10]1[C:2]([F:1])=[C:3]([C:7]([F:14])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c(C(=O)O)c1F
Yield: 93 %

Procedure:
A solution of 2,6-difluoro-3-nitrobenzoic acid and 10% palladium carbon added to 10 ml of methanol was stirred in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was filtered off and then the solvent was removed under a reduced pressure to obtain the desired product (Yield: 93%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:44]5[CH2:45][CH2:46][N:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:42][CH2:43]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(S(C)(=O)=O)CC1
Yield: 21.3 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and 1-methylsulfonyl-piperazine (187 mg, 1.14 mmol) in the manner described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea as a colorless solid (53 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 8.99 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.29-7.51 (m, 5H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 3.99 (s, 3H), 3.14-3.15 (m, 4H), 2.86-2.87 (m, 5H), 2.66-2.67 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 656 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:7]([CH:9]([CH2:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:8].[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:7]([CH:9]([CH2:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:18])=[O:19])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8]
Reactant: CCCCCN(CCCOC)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN(CCCOC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of methyl 4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoate (2.50 g) in ethanol (30 ml) was added a 1N sodium hydroxide solution (5.1 ml). After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo, acidified with a dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was recrystallized from isopropyl ether to give 2.15 g of 4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoic acid.
Reaction SMILES: C(O)C.O.[OH-].[K+].[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([O:22]CC)=[O:21])=[CH:19][C:15]=2[C:14](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13]1)[CH3:11])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:15]=2[C:14](/[CH:25]=[CH:26]/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:13]1)[CH3:11])[CH3:8]
Reactant: CCOC(=O)c1cc2c(/C=C/c3ccccc3)nn(C(C)OCC)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(C)n1nc(/C=C/c2ccccc2)c2cc(C(=O)O)sc21
Temperature: 85 °C
Yield: 97.3 %

Procedure:
2 cm3 of ethanol, 2 cm3 of water and 0.60 g (10.8 mmol) of potassium hydroxide are successively added with stirring to a solution of 2.0 g (5.4 mmol) of ethyl 1-(1-ethoxyethyl)-3-((E)-styryl)-1H-thieno[2,3-c]pyrazole-5-carboxylate in 15 cm3 of tetrahydrofuran. The reaction medium is heated at a temperature in the region of 85° C. for 5 hours and is then cooled to a temperature in the region of 25° C. and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is dissolved in 150 cm3 of water and extracted with twice 100 cm3 of diethyl ether. The aqueous phase is acidified to a pH of about 5 by adding solid citric acid, and is then extracted with three times 100 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.8 g of 1-(1-ethoxyethyl)-3-((E)-styryl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid are thus obtained in the form of a pale yellow solid melting at 160° C. Mass spectrum (EI): m/z 342 [M+], 270 (base peak): [M+] —C2H5—O—CH—CH3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@@:11]1([CH3:24])[N:20]=[C:19]([NH2:21])[C:14]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[S:13](=[O:23])(=[O:22])[CH2:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:11]2([CH3:24])[N:20]=[C:19]([NH2:21])[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[S:13](=[O:22])(=[O:23])[CH2:12]2)[CH:4]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Temperature: 23 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (R)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (210 mg, 591 μmol, Eq: 1.00) in ethanol (10 ml) was added at 23° C. under inert atmosphere triethylamine (59.8 mg, 82.4 μl, 591 μmol, Eq: 1.00) and after inertisation Pd/C 10% (62.9 mg, 59.1 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 1 hour. The catalyst was filtered off, washed three times with ethanol and evaporated to give the crude and nearly pure (R)-8-(5-amino-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (182 mg, 559 μmol, 94.7% yield) as an off-white foam. MS (ISP): m/z=326.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH:11]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:20]=1)[CH2:12][CH2:13][CH3:14])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+].O>ClCCl.C(O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH:11]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:20]=1)[CH2:12][CH2:13][CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCCC(c1ccc(NC(=O)C(C)(C)C)nc1)C(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCCC(c1ccc(NC(=O)C(C)(C)C)nc1)C(C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
This crude 2-{1-[6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-butyl}-malonic acid diethyl ester was dissolved in a mixture of dichloromethane (2.5 mL) and ethanol (5 mL) at 0° C. and a solution of potassium hydroxide (87%, 111 mg, 5.4 mmol) in ethanol (4 mL) was added. The mixture was allowed to warm up slowly to room temperature and stirring was continued for 24 h. Then dichloromethane (20 mL), water (20 mL) and brine (3 mL) was added. The mixture was stirred vigorously for 2 min. Then the layers were separated, the aqueous was washed with dichloromethane. The combined aqueous layers were acidified (pH 5) with citric acid, and extracted three times with dichloromethane. The combined organic layers were washed with brine and dried. Concentration under reduced pressure gave crude 2-[1-{6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-butyl}-malonic acid monoethyl ester (258 mg, 41%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1.[CH:22]1(C=O)C[CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH:18]4[CH2:23][CH2:22]4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1
Reactant: CCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21
Reactant: O=CC1CC1
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC1CC1

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1═H, n=1) and cyclopropanecarboxaldehyde. 1H NMR (400 MHz, CDCl3) 11.44 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 3.40 (t, 2H, J=5.6), 3.21 (d, 2H, J=6.2), 2.90 (t, 2H, J=6.3), 1.99 (m, 2H), 1.07 (m, 1H), 0.58 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: CN(C)Cc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.31 g, 7.7 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 26A (1.0 g, 5.9 mmol) in DMF (10 mL) was added drop-wise over 10 minutes. The mixture was stirred for 30 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.63 g, 6.5 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (100 mL) was added and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. The residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-50% acetonitrile in water/acetonitrile/formic acid (95/5/0.2), 100 mL/min. Fractions were collected, pooled and concentrated in vacuo. DCM was added and the solution was filtered through a phase separator and concentrated by evaporation. There was obtained 1.2 g (55%) of 26B as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.58 (s, 6H), 3.90 (s, 2H), 3.95-4.05 (m, 2H), 4.25-4.35 (m, 2H), 4.81-4.92 (m, 1H), 6.45-6.65 (m, 2H), 7.35-7.45 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: C[NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>CC(O)C.[Cl-].C([N+](CC)(CC)CC)C>[CH2:17]([C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=1[S:3]([NH2:2])(=[O:5])=[O:4])[CH:16]=[CH2:15]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCBr
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Product: C=CCc1cc(C)ccc1S(N)(=O)=O
Reaction time: 1 h

Procedure:
N-methyl-4-methylbenzenesulfonamide (5.55 g, 0.05 mol) was dissolved in 2-propanol (75 ml). Tetraethyl ammonium chloride (0.1 g) and 50% sodium hydroxide (2.40 gm) were added to the solution. Allyl bromide (2.30 g, 0.03 mol) was added to the reaction mixture and the solution stirred for 1 hr. The solution was filtered to remove sodium bromide and the 2-propanol evaporated in vacuo. The crude product was diluted with ethyl acetate and washed with water (2×), dried over anhydrous magnesium sulfate and evaporated in vacuo to give N-methyl-N* allyl-4-methylbenzenesulfonamide. MS m/z 225. (M+ calcd for C11H15NO2S=225). H NMR (300 Mhz, CDCl3) d 2.44 (s, 3, CH3), 2.67 (s, 3, NCH3), 3.63 (m, 2, CH2 epoxypropyl), 5.21 (m, 2, CH2 epoxypropyl), 5.66-5.77 (m, 1, CH epoxypropyl), 7.33 (m, 2, aromatic), 7.67 (m, 2, aromatic).
Reaction SMILES: [NH4+].[N+:2]([CH2:5][C:6]([NH-:8])=[O:7])([O-:4])=[O:3].C([O-])(=O)C.[NH2+]1CCCCC1.C(O[CH:22]=[CH:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C.Cl>O.CO>[N+:2]([C:5]1[C:6](=[O:7])[NH:8][C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=1)([O-:4])=[O:3]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: [NH-]C(=O)C[N+](=O)[O-]
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
To a solution of 2-nitroacetamide ammonium salt (4 g, 33 mmol) in water (165 mL) was added piperidinium acetate (33 mmol) in water followed by slow addition of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (6.1 mL, 43 mmol) in MeOH (11 mL). The reaction was stirred for 2 h at room temperature and at reflux for 3 h. The reaction mixture was allowed to cool to 45° C. and aqueous HCl (1N) was added until the pH was acidic. After 1 h at room temperature, the reaction mixture was extracted with CH2Cl2 (3×). The combined organic layer was successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc, then EtOAC:MeOH, 9:1) to give 3-nitro-6-(trifluoromethyl)-2(1H)-pyridinone (2.7 g, 40% yield) as a yellow solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10]>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCO
Reactant: CC(C)C(=O)O
Product: CCCCOC(=O)C(C)C

Procedure:
47 g isobutyric acid were esterified with excess n-butanol under conditions as in Example I and 67 g butyl isobutyrate were obtained. Butyl isobutyrate was oxidized with oxygen under conditions as in Example I.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:11]=[CH2:12]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C[C@@H](CO)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Yield: 77 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 5, 10.7 g, 26.58 mmol) in THF (25 mL) was added TBAF (31.9 mL, 31.89 mmol) at 0° C. After 1 hour the reaction mixture was concentrated and purified by silica gel chromatography (hexanes/ethyl acetate) to afford the product as a light yellow oil (5.9 g, 77%).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16])(C)(C)C.[CH2:18](N(CC)CC)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6](=[O:5])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CN
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)NCc1ccccc1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl[2-(aminomethyl)benzyl]carbamate (0.2 g, 0.93 mmol) and triethylamine (260 μL, 1.9 mmol) in DCM (10 mL) was added AC2O (0.285 g, 0.00279 mol) dropwise and the reaction stirred for 2 h at r.t. The reaction was concentrated, the residue dissolved in EtOAc (20 mL) then washed with saturated aq NaHCO3 (2×10 mL). The organic layer was dried (Na2SO4) and concentrated to give the crude product (0.25 g, 90%). To a solution of this in DCM (5 mL) was added 2 mL of 4M HCl/dioxane and the solution was stirred for 1 h. The reaction was concentrated to give the title compound (0.16 g, 95%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO[C:35]1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)[CH:40]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:35][CH3:40])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: CC=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1

Procedure:
(3,4-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.96 g, 3.18 mmol), (ethyl)triphenylphosphonium bromide (2.36 g, 6.35 mmol), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.35 ml, 6.35 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (10% EtOAc in hexane gradient to 20% EtOAc in hexane in about 30 min.) to give 4-[1-(3,5-dimethoxyphenyl)prop-1-enyl]-1,2-dimethoxybenzene a light brown oil (0.97 g, 97%): 1HNMR (CDCl3) δ 6.89-6.83 (m, 2H, Ar), 6.76-6.68 (m, 4H, Ar), 6.43-6.39 (m, 3H, Ar), 6.36-6.34 (m, 3H, Ar), 6.20-6.03 (m, 2H, double bond protons), 3.91 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.83 (s, 6H, 2OCH3), 3.78 (s, 6H, 2OCH3), 3.74 (s, 6H, 2OCH3), 1.78-1.74 (m, 6H, 2CH3): 13C NMR (CDCl3) δ 160.7, 160.6, 148.7, 148.7, 148.3, 148.0, 145.4, 142.3, 142.3, 142.2, 135.6, 132.5, 124.4, 122.8, 122.6, 119.9, 113.3, 111.0, 110.9, 110.3, 108.2, 105.8, 99.2, 99.0, 56.0, 56.0, 55.5, 55.4, 15.9, 15.8. Anal. Calcd. For C19H22O4: C, 72.59; H, 7.05. Found: C, 72.43; H, 6.96.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Cl:1][C:2]1[CH:3]=[C:4]([I:15])[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: II
Reactant: Oc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ncc(Cl)cc1I

Procedure:
A 6.48 g sample of 5-chloro-2-pyridinol (Aldrich) and 10.8 g of Na2CO3 were dissolved in 250 mL of water. To this solution was added 12.73 g of I2, and the mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 7 and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was recrystallized from ethanol/water to afford 4 g of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 7.71 (d,1H), 8.18 (d, 1H); MS m/z: 256 (M+H)+, 273 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[C@@H:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:10][C@H:9]1[C:38]([O:40]C)=[O:39].[OH-].[K+]>O.CO>[C:26]([CH2:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][CH2:14][C:13]([N:12]2[C@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C@@H:9]([C:38]([OH:40])=[O:39])[CH2:10][C@@H:11]2[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[O:30])[CH:24]=[CH:23][CH:22]=1)([OH:28])=[O:27]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](C(=O)OC(C)(C)C)C[C@@H](C(=O)OC)[C@H]2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](C(=O)O)[C@@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 64.8 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 0.6 g of 2-tert-butyl 4-methyl (2R*,4R*,5S*)-(-)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}pyrrolidine-2,4-dicarboxylate and 0.12 g of potassium hydroxide in a mixture of 10 cm3 of distilled water and 25 cm3 of methanol. After treatment, there is obtained 0.37 g of 2-tert-butyl hydrogen (2R*,4S*,5S*)-(+)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)pyrrolidine-2,4-dicarboxylate, the spectroscopic analyses of which are in accordance with those of the first product of Example 52.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Cl:30][C:31]1[C:32]([C:39]([OH:41])=O)=[N:33][CH:34]=[C:35]([C:37]#[N:38])[CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:39](=[O:41])[C:32]3[C:31]([Cl:30])=[CH:36][C:35]([C:37]#[N:38])=[CH:34][N:33]=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 22.2 %

Procedure:
A flask was charged with (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.075 g, 0.257 mmol) and 3-chloro-5-cyanopicolinic acid (Bionet Research, 0.047 g, 0.257 mmol). The solids were dissolved in a mixture of THF (2 mL)/MeOH (1 mL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (Aldrich, 0.129 g, 0.436 mmol) was added. The reaction was stirred at RT for 25 min. Additional 0.5 equiv. chloro-5-cyanopicolinic acid and 1 equiv. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride were added. After 1 hour, the reaction was quenched with aqueous saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The filtrate was concentrated and purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.026 g, 0.057 mmol, 22.18% yield) as white solid. MS m/z=457 [M+H]+. Calculated for C18H13ClF4N6O2: 456.8