Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11].CN(C)/[CH:18]=[N:19]/[N:20]=[CH:21]/N(C)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][N:11]1[CH:21]=[N:20][N:19]=[CH:18]1
Reactant: CN(C)/C=N/N=C/N(C)C
Reactant: CCCCC(CN)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCC(Cn1cnnc1)c1ccc(Cl)cc1Cl
Yield: 125.7 %

Procedure:
A mixture of 10 g (0.04 mole) of 2-(2,4-dichlorophenyl)hexyl amine, 5.7 g (0.04 mole) of N,N-dimethyl formamide azine and 0.5 g of p-toluene sulfonic acid in 100 ml of dry toluene is heated under reflux for 16 hours. The solvent is evaporated to give 15 g of a white solid which can be further purified by recrystallization from benzene to give 7.5 g of pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C(P(C(C)(C)C)=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(N)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH](=O)C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ccc(C)cc2C)cc1
Temperature: 25 °C

Procedure:
Into a 1 liter three-necked reaction vessel fitted with a cooling tube and a mechanical stirrer, 133 g (1.1 mols) of 2,4-dimethylphenylamine, 171 g (1.0 mol) of 1-bromo-4-methylbenzene, 11.2 g (0.05 mol) of palladium acetate, 32.4 g (0.2 mol) of 2-tert-butylphosphinoyl-2-methylpropane, 212 g (1.0 mol) of tripotassium phosphate and 500 mL of dimethylformamide were introduced to effect reflux for 12 hours in a nitrogen gas atmosphere and with heating in an oil bath. After the reaction was completed, the reaction mixture was left to cool to room temperature, followed by extraction with toluene/water, then washing with hydrochloric acid water, and thereafter distillation of the organic layer under reduced pressure to obtain the desired (2,4-dimethylphenyl)-p-tolylamine. The compound obtained was in a yield of 189.5 g corresponding to 84%. The compound obtained was measured with the same elementary analyzer as the above.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](NC1C(C(OC)=O)=C2C([C@H]3CCO[C@H]3CO2)=CC=1)(=[O:11])=[O:10].[NH2:30][C:31]1[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]2[C:34]([CH:35]3[C:45]([F:47])([F:46])[CH:36]3[CH2:37][O:38]2)=[CH:33][CH:32]=1.BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:30][C:31]1[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]2[C:34]([CH:35]3[C:45]([F:47])([F:46])[CH:36]3[CH2:37][O:38]2)=[CH:33][CH:32]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OCC1C2C1(F)F
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1C2C1(F)F

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from methyl (1aRS,7bSR)-5-amino-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 61) and 2-bromo-4-fluorobenzene sulfonyl chloride, as a colourless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOC(C)=O>[CH2:12]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:11]=[CH2:10]
Reactant: Nc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCNc1ccc(F)cc1
Yield: 47 %

Procedure:
A suspension of 4-fluorobenzenamine (25 g, 225 mmol), 3-bromoprop-1-ene (19.0 ml, 225 mmol) and K2CO3 (31.1 g, 225 mmol) was stirred in THF (1 L) for 2 days. Water (20 mL) and EtOAc (1 L) were added into the reaction mixture. The organics was separated and washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexane) to afford the product (16 g, 47.0% yield) as orange brown oil. 1H NMR (400 MHz, CDCl3): δ 6.85-6.90 (m, 2H), 6.53-6.60 (m, 2H), 5.89-6.01 (m, 1H), 5.25-5.32 (m, 1H), 5.15-5.20 (m, 1H), 3.71-3.77 (m, 2H), 3.66 (br s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[N:9]=[C:8]([C:10]2[S:14][C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[O:7][N:6]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:16]1([CH2:15][C:13]2[S:14][C:10]([C:8]3[O:7][N:6]=[C:5]([CH2:4][NH:3][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:9]=3)=[CH:11][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1noc(-c2ccc(CN3CCCCCC3)s2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1noc(-c2ccc(CN3CCCCCC3)s2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.3 %

Procedure:
585 mg (2.0 mmol) of the free form compound obtained in Example 8 was dissolved in 20 ml of methylene chloride, 0.6 ml (4.0 mmol) of triethylamine, 0.28 ml (2.4 mmol) of benzoyl chloride and 4-DMAP (cat.) were added, and the mixture was stirred at room temperature for 19 hours. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (80:1) to give 510 mg of the title compound in its free form. Using 140 mg (1.2 mmol) of fumaric acid, a 490 mg (1.24 mmol) portion of this compound was subjected to salt formation to give 348 mg of the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=O)[NH2:2].O=P(Cl)(Cl)Cl.CC(=O)OCC>N1C=CC=CC=1>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(N)=O)C1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(C#N)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of tert-butyl 3-carbamoylpiperidine-1-carboxylate (5 g, 21.49 mmol, 1.00 equiv, 98%) in pyridine (50 mL). To this solution, POCl3 (5 g, 32.24 mmol, 1.50 equiv, 98%) was added drop wise at 0° C. and allowed to stir at 0° C. for 1 hour. The progress was monitored by TLC (EA:PE=1:1). The pyridine was removed by distillation. The mixture was diluted with H2O (40 mL) and pH was adjusted to 8 by addition of aqueous NaHCO3. Then, the resulting mixture was extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The crude was purified by distillation under reduced pressure (30 mm Hg) and the fractions collected at 40° C. to afford tert-butyl 3-cyanopiperidine-1-carboxylate as yellow oil (2.6 g, 53%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
To a solution of ethyl 2-[4-(2-benzyloxyethyl)phenoxy]-2-methylpropionate (480 mg) in ethanol (3.0 ml) was added 10% palladium on activated carbon (30 mg), and the mixture was stirred for 48 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the solvent of the filtrate was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent:hexane/diethyl ether=1/1) gave ethyl 2-[4-(2-hydroxyethyl)phenoxy]-2-methylpropionate (310 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1O>C(Cl)Cl.N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: CC(C)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Trifluoromethanesulfonic anhydride (2.14 g, 7.6 mmol) was dissolved in DCM (5 ml) and cooled to 5° C. To this was added 2-chloro-4-isopropyl-phenol (1.23 g, 7.2 mmol), in 10 ml DCM and 1.75 ml pyridine, dropwise. The reaction mixture was stirred at 110° C. for 2 hours. The resultant dark solution was washed with 1M HCl (20 ml), water (20 ml) and saturated aqueous NaHCO3 (20 ml). The DCM extract was dried and concentrated in vacuo to provide the title compound as a dark orange oil (1.71 g, 78%). 1H NMR (CDCl3) 1.22-1.29 (6H, d, J=6.87 Hz), 2.88-3.00 (1H, sept, J=6.89 Hz), 7.15-7.20 (1H, m), 7.24 (1H, d, J=8.36 Hz), 7.36 (1H, d, J=2.17 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:17]=[O:18])=[N:13][C:14]=1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:27])=O>CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:17]=[O:18])=[N:13][C:14]=1[CH2:15][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=Cc1ccc(OCc2ccccc2)c(CO)n1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccccc2)c(CCl)n1

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxymethyl-2-pyridinecarboxaldehyde (5.86 g., 0.0241 mol) in 100 ml. of ethyl acetate is added 4.056 g. (0.0265 mol) of phosphorus oxychloride and the mixture is refluxed for 20 minutes. Additional phosphorus oxychloride (0.4 ml.) is introduced and the mixture is heated further for 30 minutes. The reaction mixture is cooled, diluted with ether and then washed with 5% sodium bicarbonate solution and brine. The ethereal solution is dried, treated with charcoal, filtered and evaporated to leave an oil which crystallizes to give 5-benzyloxy-6-chloromethyl-2-pyridinecarboxaldehyde, m.p. 72°-73°C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:4]([CH2:3][N:2]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN=Cc1ccccc1

Procedure:
To ethyl glycinate hydrochloride (36.4 g) suspended in 500 ml methylene chloride were added magnesium sulfate (22 g) and triethylamine (72 ml, 52.4 g). Benzaldehyde (27.6 g) was added dropwise at 15°-20° C. with stirring. The mixture was stirred at room temperature for two hours, filtered and stripped. To the residue was added 300 ml diethylether and 150 ml brine. After separation the organic layer was collected, and the aqueous layer was extracted with 100 ml ether. The organic phases were combined, dried (MgSO4), filtered and stripped to yield the title product as a pale yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14]([I:15])=[CH:13][NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>C(#N)C>[C:1]1([NH:7][C:8]([C:10]2[C:14]([I:15])=[CH:13][N:12]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(Nc1ccccc1)c1n[nH]cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(I)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of 4-iodo-1H-pyrazole-3-carboxylic acid phenylamide (670 mg; 2.14 mmol) in acetonitrile (10 ml) was treated with potassium carbonate (360 mg; 2.57 mmol)) followed by 4-methoxybenzyl chloride (320 μl; 2.35 mmol). The mixture was stirred at room temperature overnight then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine; the ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography eluting with 1:3 ethyl acetate/hexane and the product containing fractions combined and evaporated to give 660 mg of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4cc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
1-(3-Hydroxynaphthalen-2-yl)-ethanone (249 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-(N,N-dimethylamino)-pyridine (164 mg) were dissolved in 1,2-dichlorobenzene (5 ml) to prepare a solution which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (27 mg, yield 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1.[SH:17][CH2:18][CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(O)CCC.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[S:17][CH2:18][CH2:19][O:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cn2cncn2)cc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2(Cn3cncn3)OCCS2)cc1
Yield: 15.7 %

Procedure:
To a slurry of 32.5 g 1- (4-methoxyphenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone in 500 ml dry toluene and 250 ml 1-butanol was added 23.4 g 2-mercaptoethanol and 38.0 g p-toluenesulfonic acid. The thickened slurry was refluxed under a Dean-Stark trap for about 40 hours, until no more water collected. The solvent was evaporated leaving a solid residue which was dissolved in dichloromethane and washed twice with 10% aqueous sodium hydroxide and once with water. The organic layer was dried, filtered and evaporated to leave an oily residue which partially solidified on high vacuum pumping. The residue was triturated with hot toluene/cyclohexane, cooled and filtered to give 6.5 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:24]([O-])=O.Cl.C(O)(C)C.[H][H]>CO.[Pd]>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[O:8][C:7]3[C:2]([NH2:1])=[C:3]([NH2:24])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(N)c3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(N)c(N)c3O2)cc1

Procedure:
Toluene-4-sulfonic acid (2R)-8-amino-7-nitro-2,3-dihydro-benzo(1,4)-dioxin-2-ylmethyl ester (4.1 g, 11 mmole) was dissolved in 200 mL of methanol to which 0.50 g of 10% palladium on carbon had been added. 4 N isopropanol HCl (10 mL) was then added and the mixture treated with 60 psi of hydrogen on a Parr apparatus overnight. The mixture was filtered through celite and concentrated in vacuum to give 4.6 g of the (R)-enantiomer of the title compound as a pink solid (m.p. 178-180° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]2[C:31]([CH3:32])=[CH:30][CH:26]=[C:27]2[CH3:29])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 62.2 %

Procedure:
A mixture of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (8.0 g) and acetonylacetone (4.34 g) in toluene (250 ml) containing p-toluenesulphonic acid (0.5 g) was heated under reflux with a Dean and Stark take-off head fitted to the flask. After 311/2 hours evaporation in vacuo gave a dark solid, which was dissolved in dichloromethane (100 ml) and washed in turn with water (100 ml) and saturated sodium carbonate solution (50 ml). The organic layer was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a dark semisolid. Purification by dry column chromatography (Kieselgel 60G) eluting with dichloromethane/hexane (1:3) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethyl- phenyl)-5-(2,5-dimethylpyrrol-1-yl)-4-trifluoromethylthiopyrazole as a white solid (5.9 g), m.p. 142.3°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Cl
Reactant: NCc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1cccc(Cl)c1
Reaction time: 2 h
Yield: 96 %

Procedure:
3-Chlorobenzylamine (0.8129 g) was dissolved in pyridine (5 ml), and to the solution was added dropwise ethyl chloroformate (0.659 ml) during 5 minutes under ice-cooling. After the mixture was stirred for 2 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1.181 g, 96%).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Cl.[CH2:13]([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])[NH2:18])[CH3:14].C(N(C(C)C)C(C)C)C.O>C(O)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]2[NH:18][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])[CH2:19][S:20]2)=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CSC(c2ccc(O)c(OC)c2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1.52 g (10 mM) of vanillin (4-hydroxy-3-methoxybenzaldehyde) in 20 mL of absolute ethanol was added a solution of 1.85 g (10 mM) L-cysteine ethyl ester hydrochloride in 15 mL absolute ethanol, containing 1.7 mL (10 mM) of N-ethyldiisopropylamine. The reaction mixture was stirred at room temperature for about six hrs, until no starting material was present when monitored by thin layer chromatography (TLC). After adding 200 mL of water with stirring, the white precipitate was filtered, washed with 2×50 mL water, and vacuum dried. Yield 1.9 g (67%) of 1.1H NMR (DMSO-d6; ˜1:1 diastereoisomeric mixture at C2) δ; (1.22 m, 3H); (3.01m and 3.15 m, 1H); (3.33 m, 2H); (3.75 s and 3.77s, 3H); (4.15 m, and 4.38 bs, 2H); (5.40 d and 5.49d, 1H); 6.79-6.73 m, 2H); 6.83-6.89 m 1H); (7.02 d and 7.12d, 1H); (8.99 s and 9.05 s, 1H). Mass analysis: Calculated for C13H17NO4S: 284 [M+H]+. Found: 284.
Reaction SMILES: C(OC([NH:8][C:9](=[N:54]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:53]=[CH:52][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:50])[C:25]([N:27]([CH2:36][C:37]3[CH:38]=[C:39]([CH:47]=[CH:48][CH:49]=3)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:26])=[C:20]([Cl:51])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:50])[C:25]([N:27]([CH2:36][C:37]3[CH:38]=[C:39]([CH:47]=[CH:48][CH:49]=3)[C:40]([OH:42])=[O:41])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:20]([Cl:51])[CH:19]=2)=[O:16])=[CH:52][CH:53]=1)[C:9]([NH2:54])=[NH:8]
Reactant: CC(C(=O)N(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OC(=O)c2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)N(CC(=O)O)Cc1cccc(C(=O)O)c1)c1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-{[{2-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]propanoyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (180 mg) in dichloromethane (1.92 mL) was added trifluoroacetic acid (0.646 mL), followed by stirring at room temperature overnight. After completion, the reaction solution was concentrated under reduced pressure, and then to the residue was added acetonitrile (20.0 mL), followed by concentrating under reduced pressure again. This operation was repeated twice, to the residue was added a 50% aqueous acetonitrile solution (5.00 mL), and a 1 M aqueous sodium hydroxide solution (0.208 mL) was added thereto under ice-cooling. After stirring for 1 hour under ice-cooling, the precipitated crystals were collected by filtration, and washed with a 10% aqueous acetonitrile solution and then dried under reduced pressure to obtain 3-{[(2-{4-[(4-carbamimidamidobenzoyl)oxy]-2-chlorophenyl}propanoyl)(carboxymethyl)amino]methyl}benzoic acid (92 mg).
Reaction SMILES: C([O:3][C:4](=[CH:8][C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11][CH2:10]1)[C:5]([OH:7])=[O:6])C.C(O)(=O)C.O>S(=O)(=O)(O)O>[O:3]=[C:4]([CH2:8][C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])[CH2:10][CH2:11][CH2:12]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Yield: 97.9 %

Procedure:
4.6 g of 2-Ethoxy-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-acrylic acid was stirred in 100 ml of 1M sulfuric acid and 15 ml of concentrated acetic acid overnight at 100° C. Water was added, extracted with ethyl acetate, and ethyl acetate solution was dried and concentrated by evaporation in a vacuum. The product (4.1 g) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1cccn1C
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: CCN(Cc1cccn1C)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(1-methyl-1H-pyrrol-2-ylmethyl)-amine