Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]([CH:18]1[C:23](=[O:24])[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:17].C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C.O>[CH3:14][O:15][C:16]([CH:18]1[C:23](=[O:24])[CH2:22][CH2:21][N:20]([C:11]([CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:12])[CH2:19]1)=[O:17]
Reactant: COC(=O)C1CNCCC1=O
Reactant: O=C(Cl)C1COc2ccccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)C2COc3ccccc3O2)CCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2,3-dihydrobenzo[1,4]dioxine-2-carbonyl chloride (2.0 g, 10.0 mmol) and 4-oxopiperidine-3-carboxylic acid methyl ester (2.14 g, 11.0 mmol) in DMF (5 ml) was added triethylamine (1.54 ml). The reaction mixture was stirred at RT for 5 h. The reaction mixture was taken up in water, made alkaline with aq NaOH and extracted with DCM to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-4-oxopiperidine-3-carboxylic acid methyl ester. A mixture of this product (0.2 g, 0.62 mmol), K2CO3 (0.17 g, 1.23 mmol) and methyl iodide (0.08 ml, 1.25 mmol) in acetone (20 ml) was irradiated in the microwave reactor at 56° C. for 90 min. Water was added and the reaction mixture extracted with EtOAc (3×5 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methyl-4-oxopiperidine-3-carboxylic acid methyl ester, which was finally reduced with LiAlH4 in THF to afford the title compound.
Reaction SMILES: [S:1]([Cl:4])([Cl:3])=[O:2].[Cl:5][C:6](=[C:10]([Cl:14])[CH:11]([Cl:13])[Cl:12])[C:7](O)=[O:8].S(=O)=O.[ClH:18]>CN(C)C=O>[S:1]([Cl:4])([Cl:3])=[O:2].[Cl:5][C:6](=[C:10]([Cl:14])[CH:11]([Cl:13])[Cl:12])[C:7]([Cl:18])=[O:8]
Reactant: O=C(O)C(Cl)=C(Cl)C(Cl)Cl
Reactant: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(Cl)=C(Cl)C(Cl)Cl
Temperature: 50 °C

Procedure:
An agitated flask is charged with 800 g (6.72 mole) of thionyl chloride together with 2 ml of dimethylformamide as accelerator; the mixture is heated under agitation to 50° C. and, within 2 hours, 350 g (1.56 mol) of crystalline 2,3,4,4-tetrachloro-2-butenoic acid is added in incremental portions. During this step a strong evolution of gas occurs. After the addition has been completed, the mixture is heated for 1-2 hours to boiling (79° C.) until the evolution of sulfur dioxide and hydrogen chloride has ceased (bubble counter at the cooler outlet). Thereafter the reaction mixture is distilled over a 10 cm column, thus obtaining 604 g (5.07 mol) of unreacted thionyl chloride and 359 g (1.48 mol) of 2,3,4,4-tetrachloro-2-butenoic acid chloride; b.p. 102° C./26 mbar; nD20 =1.5478. Yield: 95% of theory.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=O)=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][N:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cc(Cl)cnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(Cc2cc(Cl)cnc2Oc2ccc3c(nnn3CC3CC3)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}-5-chloropyridine-3-carbaldehyde (32, 2.60 g, 6.38 mmol) was dissolved in anhydrous dichloroethane (63.8 mL, 0.1M) and treated with 1-(methylsulfonyl)piperazine (2.10 g, 12.8 mmol, 2 equiv.) and acetic acid (3.65 mL, 63.8 mmol, 10 equiv.). After 30 minutes the solution formed a thick suspension and was treated with sodium triacetoxyborohydride (1.76 g, 8.29 mmol, 1.3 equiv) in small portions over 1 hour. After completion of this addition, the reaction was allowed to stir an additional 2 h at ambient temperature. Upon completion as judged by TLC and LCMS, the reaction was quenched by the slow addition of water (20 mL) and NaHCO3. The mixture was extracted 3× with dichloromethane (3×30 mL), and the combined organic layers were dried over MgSO4. The crude mixture was purified using flash column chromatography (Redisep SiO2, 80 g, 0-100% EtOAc/hexanes) to provide pure 198: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, 1H, J=2.5 Hz), 7.84 (d, 1H, J=2.5 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.33 (d, 1H, 8.8 Hz), 4.53 (d, 2H, J=7.1 Hz), 3.82 (s, 2H), 3.33 (m, 4H), 2.83 (s, 3H), 2.74 (m, 4H), 1.41 (m, 1H), 0.69 (m, 2H), 0.52 (dd, 2H, J=10.8, 5.1 Hz, 2H). LRMS m/z (M+H) 556.9 found, 556.9 required.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:22]=[C:21]4[C:17]([CH2:18][CH:19]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:38]([OH:40])=[O:39])[CH:20]4[S:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-].CC(O)=O>C1COCC1.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:22]=[C:21]4[C:17]([CH2:18][CH:19]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:38]([OH:40])=[O:39])[CH:20]4[S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCSC1c2cc(OCc3ccc4ccc(Cl)cc4n3)ccc2CC1Cc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCCSC1c2cc(OCc3ccc4ccc(Cl)cc4n3)ccc2CC1Cc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
To a solution of the product of Step 6 (131 mg, 0.229 mmol) in THF/MeOH (1.5 ml, 1:2) was added 1M K2CO3 (0.687 ml). The mixture was stirred at room temperature for 20 hrs. NH4Cl solution was added and the pH was adjusted to 5 with HOAc. Extraction with EtOAc followed by chromatography of the crude product on silicic acid (eluted with 30% EtOAc/hexane) gave 100 mg of the title compounds.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH3:60])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:55][CH2:56][Cl:57])=[C:35]3[C:39]([O:41]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(C)C)(C)C.[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71]>CCOCC>[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH3:60])[C:27]([NH:29][C@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34]([S:55][CH2:56][Cl:57])=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCCl)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)N[C@H]1C(=O)N2C(C(=O)O)=C(SCCl)SC[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
162 mg of the product of step A in 1.5 ml of trifluoroacetic acid was stirred at 0° C. in an inert atmosphere for 5 minutes and the solution obtained was poured into 25 ml of isopropy ether. The mixture was cooled to 0° C. stirred for several minutes. and then centrifuged. The residue was suspended in 25 ml of ether and this was centrifuged again and the operation was repeated. The trifluoracetate was dried under reduced pressure to obtain 88 mg of syn isomer of racemic cis 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-chloromethylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid trifluoroacetate.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[C:9](=[O:15])[NH:10][C:11](S)=[N:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(O)C>C(OCC)(=O)C.ClCCl.[Ni]>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[C:9](=[O:15])[NH:10][CH:11]=[N:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2cnc(S)[nH]c2=O)cc1
Agent: [Ni]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc(Oc2cnc[nH]c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of 5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one (2.49 g, 10.28 mmoles), ethanol (250 mL) and wet Raney Ni (50% slurry in water, active catalyst) (Aldrich) (10.9 g) was refluxed with stirring for 3 hours. The reaction was cooled to about 40° C. and filtered through a pad of CELITE 545 (Fisher). The pad was washed with hot ethanol (2×75 mL) and placed in a beaker of water. The combined filtrates were spin evaporated in vacuo to a syrup. The syrup was dissolved in ethyl acetate and reevaporated to give a gray solid. The solid was dissolved in ethyl acetate (40 mL) and applied to a column (4.2×9.5 cm) of Silica Gel 60 (E. M. Science, 230-440 mesh) that was equilibrated with ethyl acetate. The column was eluted with ethyl acetate by flash chromatography, and twelve 100 mL fractions were collected. Fractions 4-10 were combined and spin evaporated in vacuo. The residual oil was dissolved in ethyl acetate and evaporated to give a mixture of light green and white crystals. The crystals were dissolved in dichloromethane and spin evaporated in vacuo to give 1.37 g (63% yield) of 5-(4-ethylphenoxy)pyrimidine-4(3H)-one. Recrystallization of a sample from ethyl acetate gave analytically pure 5-(4-ethylphenoxy)pyrimidine-4(3H)-one as white needles, mp 144-146° C.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:9](=O)[CH2:10]Br)=[C:6]([CH3:8])[N:7]=1.[NH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[S:4][C:5]([C:9]2[N:13]=[C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:10]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Nc1ncccn1
Reactant: Cc1nc(N)sc1C(=O)CBr
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)sc1-c1cn2cccnc2n1
Yield: 15.2 %

Procedure:
A solution of 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (7.2 g), 2-aminopyrimidine (3.8 g) and triethylamine (11 ml) in ethanol (200 ml) was refluxed for 8 hours and the reaction mixture was evaporated in vacuo. To the residue was added water and the resulting mixture was acidified to pH 1.0 with 10% hydrochloric acid. The acidified solution was treated with charcoal and filtered. The filtrate was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed successively with water and ethyl acetate, and recrystallized from aqueous ethanol to give 2-(2-amino-4-methyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (0.8 g). mp 285°-286° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.BrC1C=CC=CC=1C(Cl)=O.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]O>C(Cl)Cl.S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:8][CH2:23][C:22]([CH3:26])([CH3:25])[N:21]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=C(Cl)c1ccccc1Br
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Br)cc2)=N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
4-Bromo benzoic acid (50 g, 0.25M) placed in a 500 mL round bottom flask fitted with a reflux condenser was added 150 mL of thionyl chloride and for 8 h. The excess of thionyl chloride was removed under vacuum and the white solid obtained was dissolved in 100 ml of dry CH2Cl2 and kept in an ice bath. To this ice cooled solution of bromo benzoylchloride was added drop wise 45 g of 2-amino-2-methylpropan-1-ol dissolved in another 100 mL of dry CH2Cl2 with stirring for the period of 1 h. The ice bath was removed and the reaction mixture was stirred at room temperature for over night. The precipitated white solid was filtered and washed several time with CH2Cl2 (4×100 mL). The combined CH2Cl2 was removed under rotaevoporator and the solid obtained was slowly dissolved in 150 mL of thionyl chloride and refluxed for 3 h. The excess of SOCl2 was evaporated to one-six volumes and poured in to 500 mL of dry ether cooled in ice bath and kept in the refrigerator overnight. The ether was removed and the precipitated hydrochloride was dissolved in 500 mL of cold water. The aqueous solution was carefully neutralized using 20% KOH solution on cold condition (ice bath) and the brown oily residue separated was extracted with CH2Cl2 (3×200 mL) and dried over anhydrous Na2SO4. Removal of the solvent gave 42 g (67%) of 2-(4-bromophenyl)-4,4-dimethyl-1,3-oxazoline as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.36 (s, 6H), 4.08 (s, 2H), 7.52 (d, 2H), 7.79 (d, 2H). Mass: 254.3 (M+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[CH:38][C:37]=1[F:54])#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:37]([F:54])[CH:38]=4)=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(F)c1)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 82.9 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and ethyl 2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (6.4 g) in diethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (4.3 g, 82%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[K+].[C:9]([C:13]1[CH:14]=[C:15]([NH:24][C:25](=[O:29])[CH:26]=[CH:27][CH3:28])[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:12])([CH3:11])[CH3:10].Cl>O1CCCC1.C(O)C>[C:20]([C:17]1[CH:16]=[C:15]([N:24]2[CH2:28][CH:27]([CH3:2])[CH2:26][C:25]2=[O:29])[CH:14]=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[C:18]=1[OH:19])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC=CC(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[S+](C)(C)=O
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1CC(=O)N(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1
Temperature: 25 °C
Yield: 13.9 %

Procedure:
Trimethyl sulphoxonium iodide (5.9 g, 27 mmol) was added to 5.2 g (45 mmol) of 35% potassium hydride in an oil dispersion (previously washed with pentane) in 25 ml of tetrahydrofuran at 0° C. Ten minutes later, 5.2 g (18 mmol) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-butenamide dissolved in 100 ml of tetrahydrofuran was added and the mixture was allowed to warm to room temperature. Twenty four hours later, 10 ml of ethanol was added and the mixture was made acidic by the addition of 1N hydrochloric acid. The acidic mixture was concentrated to 50 ml, diluted with 100 ml of ethyl acetate and 50 ml of water and the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated to a solid. The solid was chromatographed on silica gel with methylene chloride and triturated in pentane to afford 0.76 g of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-methylpyrrolidin-2-one, mp 157°-159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:30])[C:17]3[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=3[F:18])[C:11](=[O:20])[N:10]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=2[F:29])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:31][O:32][C:33]([NH:35][C:36](=NC(OC)=O)SC)=[O:34].[OH-].[Na+]>C(O)(=O)C>[C:27]([C:23]1[C:22]([F:29])=[C:21]([N:10]2[C:11](=[O:20])[C:12]3[C:17](=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[C:9]2([C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:36]([NH:35][C:33](=[O:34])[O:32][CH3:31])=[N:1][C:2]=3[CH:3]=2)[OH:30])[CH:26]=[CH:25][CH:24]=1)#[CH:28]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc(N)c(N)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc3[nH]c(NC(=O)OC)nc3c2)c1F
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(3,4-diaminophenyl)-2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1.15 g, 2.80 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.58 g, 2.80 mmol) was heated to 80° C. for 30 minutes in glacial acetic acid (15.0 mL). The reaction mixture was cooled to room temperature and it was pored into ice water. The pH was adjusted to 8 by the addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (350 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and evaporation resulted in a crude product. It was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was freeze-dried from a mixture of acetonitrile-water (35.0 mL) to give methyl {5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate (1.15 g, 83% yield). 1H NMR (400 MHz, CD3OD): 7.79 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 4H), 7.31 (t, J=7.2 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 1H); MS (EI) for C25H15F3N4O4: 493 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I.[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:17])[C:9]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (201 mg, 1.0 mmol) in DMF (2 mL) was added NaH (120 mg, 3.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 10 min. before the addition of MeI (568 mg, 4.0 mmol). The mixture was then warmed up to room temperature and stirred for 2 hr. Saturated NH4Cl aqueous solution (20 mL) was added into the mixture, and the solution was extracted with EtOAc (3×10 mL). The combined organic layers were concentrated and the residue was dissolved in MeOH (3 ml) with NaOH (3 N, 1 mL). This mixture was stirred at 80° C. for 1 hr and cooled down to room temperature. The clear solution was purified directly on preparative RP-HPLC to provide 1-(tert-butoxycarbonyl(methyl)amino)cyclopropanecarboxylic acid. ESMS m/z 238.2 (M+Na+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:37]([CH3:38])[CH2:36][CH2:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([Cl:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: O=S(=O)(Cl)N1CCN(Cc2ccccc2)CC1
Yield: 88.8 %

Procedure:
A solution of 1-benzylpiperazine (20.0 g, 0.114 mol) in acetonitrile (45 ml) was added to a solution of sulphuryl chloride (28 ml, 0.346 mol) in acetonitrile (50 ml) and the mixture heated under reflux for 17 hours, then cooled. The solvent was removed by evaporation under vacuum, then the residue triturated with ether (20×50 ml) to yield the title compound (27.8 g, 89%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2>>[OH:45][C@H:30]([CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2)[CH2:29][NH:28][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:12])=[O:13])=[CH:20][CH:19]=2)[CH2:22][CH2:23]1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 242) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.50-2.75 (m, 5H), 2.82 (t, J=7.2 Hz, 2H), 3.45-3.55 (m, 2H), 3.63 (s, 3H), 3.72 (s, 3H), 3.70-3.85 (m, 3H), 4.91 (brs, 1H), 6.44 (d, J=8.8 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.5, 2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H),8.72 (s, 1H), 9.17 (brs, 1H); MS (ES) m/z: 627.1 (MH+); HRMS Calcd. for C31H39N4O8S(MH+): 627.2489. Found: 627.2458.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[CH3:18]O>>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1
Reactant: CO
Reactant: COc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (3.1 ml, 42.5 mmol) was added slowly to methanol (30 ml) with stirring under cooling with a Dry Ice/methanol bath. After allowing the reaction to warm to room temperature, 3-(4-methoxyphenyl)propionic acid (5 g, 27.7 mmol) was added and stirred for an additional 1 hour. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed twice with a saturated aqueous solution of sodium bicarbonate, then once with a saturated aqueous solution of sodium chloride. After drying over unhydrous sodium sulfate, the solvent was evaporated in vacuo to produce a pale yellow crystal in an amount of 5.29 g (yield, 98%). Rf1 : 0.83