Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:9]([O-:11])=[O:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2.[C:12]1([S:18]([N:21]2[CH2:28][CH2:27][CH2:26][C@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[CH3:30]N(C)CCCN=C=NCC.CN1CCOCC1>O1CCCC1>[C:12]1([S:18]([N:21]2[CH2:28][CH2:27][CH2:26][C@H:22]2[C:23]([C:3]23[CH2:8][CH:6]([CH2:5][CH2:4]2)[CH2:7][C:2]3([NH2:1])[C:9]([O:11][CH3:30])=[O:10])=[O:24])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1(C(=O)[O-])CC2CCC1C2
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C1(N)CC2CCC1(C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of 2-amino-2-norbornanecarboxylate, methyl ester hydrochloride (400 mg, 2.0 mmol), N-benzenesulfonyl-(L)-proline (510 mg, 2.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (306 mg, 2.0 mmol), 1-hydroxbenzotriazole (202 mg, 2.0 mmol) in 4 mL of tetrahydrofuran at 0° C. was added N-methyl morpholine (0.22 mL, 2.0 mmol). After 15 min at 0° C., the reaction mixture was stirred at room temperature for 16 h, and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 10:1 methylene chloride/ethyl acetate to give the title compound (478 mg, 59%) as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]\[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:23].[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]/[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCOC(=O)/C=C\C=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
As described in Example 99, 3,3-bis(4-fluorophenyl)-2-propenal (9.8 g) was reacted with (carbethoxymethylene)triphenylphosphorane (14.3 g) in ethanol (20 mL) for 30 minutes at ambient temperature. The mixture of esters obtained from the usual work up was purified by HPLC (dichloromethane-hexane; 1:1) to give 2.0 g of the less polar (Z)-5,5-bis (4-fluorophenyl)-2,4-pentadienoic acid ethyl ester as an oil, and 9.3 g of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid ethyl ester. A sample of the (E)-isomer was crystallized from hexane to give the pure ester, mp 71°-72.5° C.
Reaction SMILES: [H-].[Na+].[S:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6](=[O:16])[CH:5]=[CH:4]1.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][Cl:23])[CH3:19].C.[OH-].[Na+]>CN(C)C=O>[ClH:23].[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][CH2:22][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[S:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]1=2
Reactant: CN(C)CCCCl
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2ccccc2c2sccc(=O)c21
Product: Cl
Reaction time: 3 h

Procedure:
A mixture of 2.3 g (0.055 mole) of 50% sodium hydride in mineral oil, 50 ml of dimethylformamide (DMF) and 10.0 g (.05 mole) of thiopyrano [3,2-b]indol-4(5H)-one is stirred for 3 hours, then 12.2 g (0.1 mole) of dimethylamino-propylchloride is added. Stirring is continued for 20 hours at 95°, then the mixture is poured onto ice containing conc. HCl. The cloudy solution is clarified with charcoal, made basic with 20% sodium hydroxide solution, and the precipitated oil extracted with ether. The ether is dried, and dry HCl passed in. The precipitated salt weighed 10.1 g and is recrystallized from isopropanol, mp 226°-228°C.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH2:8][CH2:9][CH3:10])C(O)=O)[CH3:3].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[C:25]([O:26][CH3:27])=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19]([NH:28][CH3:29])[CH:18]=1.Cl[CH:31](Cl)Cl>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:8][CH2:9][CH2:10][C:29]1[N:28]([CH3:31])[C:19]2[C:20]([C:21](=[O:22])[N:23]=1)=[CH:24][C:25]([O:26][CH3:27])=[C:17]([O:16][CH3:15])[CH:18]=2
Reactant: CNc1cc(OC)c(OC)cc1C(N)=O
Reactant: ClC(Cl)Cl
Reactant: CCCC(C(=O)O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc2c(=O)nc(CCCCN(C)C)n(C)c2cc1OC
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
3.80 g (20.9 mmol) dimethylamino-pentanoic acid were added to 25 ml thionyl chloride and stirred for 90 min. at 55-60° C. The remaining thionyl chloride was distilled in vacuum and the residue was added to a solution of 2.00 g (9.51 mmol) 4,5-Dimethoxy-2-methylamino-benzamide (see above) dissolved in 30 ml trichloromethane at 0° C. The mixture was boiled for 4 h. After filtration the residue was dissolved in trichloromethane and saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and evaporated under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)N=Cc2cccc(Cl)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=S1(=O)NCc2cccc(Cl)c21
Temperature: 0 °C
Yield: 97.4 %

Procedure:
A suspension of 17.9 g of 7-chloro-1,2-benzisothiazole-1,1-dioxide in 180 ml of absolute ethanol was cooled to 0° C. and treated with 3.33 g of sodium borohydride at such a rate that the temperature remained below 5° C. The mixture was warmed to room temperature for 30 minutes, recooled to 0° C. and treated with glacial acetic acid to destroy excess hydride. The mixture was concentrated to dryness, the resulting solid suspended in water, filtered, washed with water and dried in vacuo at 50° C. for 16 hours to give 17.6 g of the title compound as a white powder, m.p. 159°-161° C.
Reaction SMILES: [CH3:1][O:2]C(=O)[C:4](C)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.ClS(O)(=O)=O>C(Cl)Cl>[C:6]1([CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:1][OH:2]
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CO
Product: Cc1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
2-methyl-2-phenyl propanoic methyl ester (1.1 g, 6.17 mmol) was dissolved in 20 mL of anhydrous DCM and the reaction mixture was cooled down to −78° C. The chlorosulfonic acid (2.05 mL, 30.86 mmol, 5 eq) dissolved in 10 mL of anhydrous DCM was added dropwise during a period of 2 h. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by addition of ice and the product extracted with DCM (3×50 mL) The organic layer was washed with NaCl sat, dried over MgSO4, evaporated to give an oil (1 g, yield: 59%, HPLC purity: 84%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CC1C=CC(S(O[C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([O:1][C@@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)=[N:9]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A suspension of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give N-(1-methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide as a white foam. This was dissolved in ethanol (5 mL) and ammonium formate (182 mg, 2.88 mmol) added in one portion. The reaction was blanketed with argon and 10% palladium on activated carbon (30 mg) was added. This mixture was heated in a microwave reactor at 140° C. for 10 minutes, the catalyst filtered off and the volatiles removed in vacuo to give the title product as a white solid (305 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29]6[CH:34]=[N:33][CH:32]=[CH:31][N:30]=6)[CH2:24][CH2:25]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: c1cnc(N2CCNCC2)cn1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(c2cnccn2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)pyrazine (1.2 equiv) to give 178 (8.7 mg, M+1 460.1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].C(O)C.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:19][O:18][C:14]([CH2:15][S:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])=[O:17]
Reactant: O=Cc1cccc(CBr)c1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)CSCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 1.00 g of 3-(bromomethyl)benzaldehyde and 20 ml of ethanol were added 0.65 ml of methyl thioglycolate and 0.47 g of potassium carbonate, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added diethyl ether, this was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.36 g of oily 3-[(methoxycarbonylmethylthio)methyl]benzaldehyde [Compound No. (u)].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([CH:39]=[C:40]([CH3:42])[CH3:41])[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([CH:39]=[C:40]([CH3:41])[CH3:42])[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(C=C(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(C=C(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.21 g), sodium hydrogen carbonate (0.34 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-1-(2-methylprop-1-en-1-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.080 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-carbonyldiimidazole (0.050 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.050 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.029 g, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:25][C:26]([NH2:28])=[O:27].Cl>C(O)C.[OH-].[Na+].O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:25][C:26]([NH2:28])=[O:27])=[C:7]([NH:6][CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:31]=[C:30]([F:32])[CH:29]=3)[CH:12]=2)=[CH:19][CH:18]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)c1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)Cc1cnc(Nc2ccc(C(=O)O)cc2)cc1NCc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 31.8 %

Procedure:
302 mg of 4-[(3,5-difluorobenzyl)amino]-6-[(4-ethoxycarbonylphenyl)amino]pyridine-3-carboxyamide (the compound of Example 321) was dissolved in 13 mL of ethanol, to which 2.5 mL of 2 mol/L sodium hydroxide in water was added, and stirred at 50° C. for 4 hours. After cooling, the reaction mixture was neutralized by adding 1 mol/L hydrochloric acid in water, extracted with chloroform, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 90 mg (yield 32%) of the title compound as a light brown solid.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=2)[CH:27]1[C:38]([OH:40])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][C:48]=1[Si:49]([CH3:52])([CH3:51])[CH3:50])[NH2:45].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:41][C:42]1[CH:43]=[C:44]([NH:45][C:38]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:40])[CH:46]=[CH:47][C:48]=1[Si:49]([CH3:51])([CH3:50])[CH3:52]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: C[Si](C)(C)c1ccc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
T3P (4.46 mL, 7.50 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.537 g, 5 mmol), 3-fluoro-4-(trimethylsilyl)aniline (0.916 g, 5.00 mmol), DIEA (4.35 mL, 25.00 mmol) and DMAP (0.672 g, 5.50 mmol) in ethyl acetate (35 mL), and the mixture was stirred at 70° C. for 18 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→20% ethyl acetate/hexane), and the precipitate was washed with IPE/hexane to give tert-butyl 1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.85 g, 3.91 mmol, 78%) as white crystals.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]=[C:15](OC)[C:14]2=[O:21])=[CH:9][CH:8]=1>CN(C=O)C>[Cl:3][C:15]1[C:14](=[O:21])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nccn(-c2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Product: O=c1c(Cl)nccn1-c1ccc(F)cc1
Temperature: 0 °C
Yield: 64 %

Procedure:
POCl3 (5.6 mL, 61.3 mmol) was added dropwise to a solution of 1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one in DMF (30 mL) with stirring at 0° C. followed by heating at 90° C. for 1.5 hours. The residue was cooled to 0° C., quenched by adding saturated sodium acetate solution, extracted with CH2Cl2, washed with water, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (0.7% MeOH in CH2Cl2) to afford 3.52 g (64%) of the desired product. LRMS (ESI pos) m/e 224.9, 227.0 (M+1, Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([C:37]3[CH:41]=[C:40]([C:42]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[NH:43])[S:39][C:38]=3[S:52][CH3:53])(=[O:36])=[O:35])[CH:29]=2)=[C:23]([NH:54][C:55](=[O:72])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63]2[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=2)[CH:22]=1>CC(O)=O.CO>[C:48]([O:47][C:45]([NH:44][C:42](=[NH:43])[C:40]1[S:39][C:38]([S:52][CH3:53])=[C:37]([S:34]([C:30]2[CH:29]=[C:28]([C:24]3[C:25]([CH3:27])=[CH:26][C:21]([NH:20][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:22][C:23]=3[NH:54][C:55](=[O:72])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:64]=[CH:65][C:66]([C:67]([OH:69])=[O:68])=[CH:70][CH:71]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:35])=[O:36])[CH:41]=1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Yield: 22.9 %

Procedure:
1,3-bis(tert-Butoxycarbonyl)-2-methyl-2-thiopseudourea (433 mg, 1.49 mmol) was added to a solution of 4-[5-(3-{4-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-pentyloxy]-benzoic acid (233 mg, 0.298 mmol, Example 283: step e) in 5% AcOH/MeOH (10 mL) over 2 days at 35° C. The solvents were removed in vacuo and the residue was purified by flash chromatography (1–6% MeOH/methylene chloride) to afford the title compound as a yellow solid (70 mg, 23%). ESI-MS (m/z): Calcd. for C48H61N7O12S3: 1024.4 (M+1); found: 1024.0.
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([O:24][C:25](=[O:31])[N:26]([CH3:30])[CH2:27][CH:28]=O)([CH3:23])([CH3:22])[CH3:21].C(B)#N.[Na].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[CH3:30][N:26]([CH2:27][CH2:28][N:12]1[CH2:11][CH2:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13]1)[C:25](=[O:31])[O:24][C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: c1ccc(C2(N3CCCC3)CCNCC2)cc1
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(CCN1CCC(c2ccccc2)(N2CCCC2)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
7 g (1 eq) 4-phenyl-4-(pyrrolidin-1-yl)piperidine bishydrochloride were added to a solution of 4.4 g (1.1 eq) tert-butyl-methyl(2-oxoethyl)carbamate in 70 ml methanol under a nitrogen atmosphere and the reaction mixture was stirred for 10 min at 0° C. 3.62 g (2.5 eq) sodium cyanoboron hydride were then added and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 14 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the methanol was distilled off, saturated NaHCO3 solution was added and the mixture obtained was extracted with chloroform (3×50 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 8 g (89%) of product were obtained in the form of a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.Cl(O)(=O)(=O)=O>O>[C:24]([O:18][C:17](=[O:19])[C@H:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[NH2:16])([CH3:27])([CH3:26])[CH3:25]
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Nδ -(Benzyloxycarbonyl)-L-ornithine tert-butyl ester was prepared according to a general published procedure (Bodanszky, M.; Bodanszky, A.; The Practice of Peptide Synthesis; Spring Verlag: New York, 1984). Specifically, Nδ -(benzyloxycarbonyl)-L-ornithine (10.0 gm, 37.6 mmol, Sigma Chemicals, Inc.) was mixed with tert-butyl acetate (564 ml) and perchloric acid (5.91 ml, 69-72% aqueous solution) at room temperature. The reaction mixture became homogenous after 15 minutes and was stirred at room temperature for 2 days. Water (300 ml) was added to the reaction mixture, and the two layers obtained were separated. The organic layer was extracted twice (2×200 ml) with water, and the combined aqueous layers were adjusted to pH 9.5-10.0 with 50% NaOH. The aqueous layer was then filtered to remove a small amount of insoluble material, and the filtrate was extracted with ethyl acetate (3×300 ml). The combined ethyl acetate extracts were dried over MgSO4 and were concentrated by rotary evaporation at reduced pressure to yield 7.5 g of Nδ -(benzyloxycarbonyl)-L-ornithine tert-butyl ester as an oil (65% yield). 1H NMR (DCCl3) δ 1.44 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 3.31 (t,1H), 5.09 (s,2H and s,1H broad), 7.35 (s,5H) .
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)C(C)C)(C)C.[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Cl.[OH2:31]>C(Cl)Cl>[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[C:24]([NH:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1)=[O:31]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: O
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1Cl
Reaction time: 18 h

Procedure:
To a stirred mixture of 5.19 g of 2-chloro-4-aminobenzoic acid in 150 ml of methylene chloride is added 7.86 g of N,N-diisopropylethylamine and 12.67 g of 2,4-dichlorobenzylchloride and stirring continued for 18 hours. Water is added to the filtrate and the organic layer dried with Na2 SO4 and concentrate in vacuo to give 13.68 g of the desired product, m.p. 171°-175° C.