Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)CC3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C5=CCNCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
4-(4-{[4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (10 mg, 0.017 mmol), as prepared in Example 61, was dissolved in 50% TFA/DCM (5 mL). The solution was stirred at room temperature for 4 h. It was evaporated and the residue was quenched with 2N ammonium in MeOH (6 mL). The solvent was removed and the residue was washed with water, dried in vacuo to afford the title compound as a white solid (8 mg, 100%). 1H NMR (300 MHz, CD3OD) δ 8.94 (s, 1H), 7.58 (s, 1H), 7.42 (s, 4H), 7.32 (s, 1H), 6.12 (m, 1H), 4.37 (m, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 3.93 (m, 1H), 3.82 (m, 2H), 3.44 (t, J=6.29 Hz, 2H), 3.22 (m, 2H), 2.78 (m, 2H), 1.93-2.10 (m, 4H). LC-MS (ESI) calcd mass 473.2, found 474.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:20])[C:3]=1[CH:21]=O.Cl.[CH3:24][O:25][NH2:26].C([O-])(=O)C.[K+].C(O)C>ClCCl.O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:20])[C:3]=1[CH:21]=[N:26][O:25][CH3:24]
Reactant: CON
Reactant: Cc1c(OC2CCCCO2)ccc2c(O)c(C=O)c(=O)oc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CON=Cc1c(O)c2ccc(OC3CCCCO3)c(C)c2oc1=O
Yield: 86.7 %

Procedure:
A mixture containing 2.0 g of the product prepared in Stage A, 1.08 g of methoxyamine hydrochloride, 1.93 g of potassium acetate and 20 ml of ethanol is heated under reflux for 1 hour. After evaporating to dryness, the product obtained is dissolved in a mixture of dichloromethane and water (100 ml-100 ml), washed with a dilute solution of sodium acid phosphate and dried. After evaporation, the residue is triturated under ultrasound in the presence of ethyl ether, separated and dried. 1.90 g of product is obtained.
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O>C1COCC1>[C:1]([C:3]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)=[CH:40][C:36]1[S:35][CH:39]=[CH:38][N:37]=1)#[N:2]
Reactant: CCOP(=O)(OCC)C(C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2nccs2)CC1
Reaction time: 0.5 h

Procedure:
In a 100 ml 3 necked round bottle flask, tert-butyl 4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate (5.0 g) was taken in dry THF (25 ml) under nitrogen. Sodium bis trimethylsilyl amide (3.0 g) was added drop wise at 0° C. and stirred for 30 min, then thiazole-2-carboxaldehyde (1.60 g) in 15 ml dry THF was added drop wise to the above reaction mixture at 0° C. Reaction mixture was stirred at room temperature for overnight. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with brine, dried and concentrated to get crude product tert-butyl 4-(1-cyano-2-(thiazol-2-yl)vinyl)piperazine-1-carboxylate as yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(CCCBr)c1
Yield: 87.9 %

Procedure:
Compound 75-2 (4.45 g) was dissolved in methylene chloride (95 ml), triphenylphosphine (8.13 g) and N-bromosuccinimide (5.51 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.44 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25]CCCCC)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25][CH2:10][C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Product: COC(=O)c1cccc(NCc2cc3ccccc3o2)c1C(=O)OC
Yield: 83 %

Procedure:
Benzofuran-2-carbaldehyde (1.17 ml, 8 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 50% methylene chloride/hexane) to give 1.12 g (83%) of product as a yellow oil: 1H NMR (CDCl3) δ 7.50-7.43 (m, 2H), 7.33-7.16 (m, 3H), 6.88-6.84 (m, 2H), 6.58 (s, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:26])[CH2:11][CH2:12][CH2:13][C:14]([CH3:25])=[CH:15][CH2:16][CH2:17][C:18]([O:20][Si](C)(C)C)=[CH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:32]N1C(=O)CCC1=O.CCOCC>O1CCCC1.[Cl-].[Na+].O>[CH2:1]([O:8][CH2:9][CH:10]([CH3:26])[CH2:11][CH2:12][CH2:13][C:14]([CH3:25])=[CH:15][CH2:16][CH2:17][C:18](=[O:19])[CH2:20][Br:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCC=C(C)CCCC(C)COCc1ccccc1)O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=CCCC(=O)CBr)CCCC(C)COCc1ccccc1
Reaction time: 4 h
Yield: 108.7 %

Procedure:
11-Benzyloxy-6,10-dimethyl-2-trimethylsiloxy-undec-1,5-diene (15.36 g, 41 mM) in dry tetrahydrofuran (400 ml) is treated with sodium bicarbonate (4.1 g, 49 mM) and N-bromosuccinimide (7.3 g, 41 mM) at -70° C. and allowed to stir for 4 hours. The reaction mixture is allowed to reach room temperature after which saturated sodium bicarbonate, ether and brine are added. The phases are separated, the aqueous phase is extracted with ether and the combined organic extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give crude 11-benzyloxy-1-bromo-6,10-dimethyl-2-oxo-undec-5-ene (17 g).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH3:29])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]2[C:25](=[O:28])[CH2:26][CH2:27][C@@H:20]12.[CH2:30]([C:32]1[CH:33]=[C:34]([C@H:42]([NH:44][CH3:45])[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH3:31]>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH2:30]([C:32]1[CH:33]=[C:34]([C@H:42]([N:44]([CH3:45])[C:5]([N:24]2[CH2:23][CH2:22][N:21]3[C:25](=[O:28])[CH2:26][CH2:27][C@H:20]3[C@@H:19]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:29])=[O:11])[CH3:43])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH3:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1[C@@H]1NCCN2C(=O)CC[C@@H]12
Reactant: CCc1cc([C@@H](C)NC)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cc([C@@H](C)N(C)C(=O)N2CCN3C(=O)CC[C@H]3[C@@H]2c2ccccc2C)cc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 32 %

Procedure:
To a solution of triphosgene (47 mg, 0.16 mmol) in EtOAc (2 mL) at 0° C. was added solution of (1S,8aS)-1-o-tolylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (74 mg, 0.32 mmol), DMAP (4 mg, 0.032 mmol) and TEA (49 mg, 0.48 mmol) in EtOAc (2 mL). The mixture was stirred for 1.5 h, followed by addition of (R)-1-(3-ethyl-5-(trifluoromethyl)phenyl)-N-methylethanamine (111 mg, 0.48 mmol) in EtOAc (2 mL) and TEA (97 mg, 0.963 mmol). The reaction was stirred at 50° C. for 48 h and quenched with water. The resulting mixture was extracted with EtOAc and the organic layer was washed with 1 M aqueous HCl solution, dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by Prep-HPLC to give the title compound (25 mg, yield: 17%). 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.20 (s, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.13 (dd, J=14.9, 7.3 Hz, 2H), 7.06 (s, 1H), 5.49 (q, J=6.8 Hz, 1H), 4.11 (dd, J=20.6, 11.3 Hz, 2H), 3.71 (dd, J=16.8, 7.4 Hz, 1H), 3.28 (d, J=11.9 Hz, 1H), 3.11 (t, J=12.3 Hz, 1H), 2.95 (td, J=11.8, 2.9 Hz, 1H), 2.66 (d, J=10.2 Hz, 4H), 2.61 (d, J=7.6 Hz, 1H), 2.55 (s, 3H), 2.47 (m, 1H), 2.38-2.26 (m, 1H), 1.84 (ddd, J=16.7, 13.0, 3.9 Hz, 1H), 1.67 (ddd, J=17.3, 13.1, 9.3 Hz, 1H), 1.36 (d, J=6.6 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H); m/z (ES+): 488 [M+H]+.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20].[C:26](=[S:28])=[S:27]>CCCCCC>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:16][C:26](=[S:27])[S-:28])=[CH:17][CH:18]=2)[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:19]([NH+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]
Reactant: CCN(CC)CC
Reactant: S=C=S
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: CCCCCC
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(NC(=S)[S-])cc2)CC1
Product: CC[NH+](CC)CC
Reaction time: 65 h

Procedure:
A solution of 390 mg of p-[trans-4-(trans-1-pentenyl)cyclohexyl]aniline (purity 93%) in 4 ml of hexane was treated successively with 446 μl of triethylamine and 214 μl of carbon disulphide and the mixture was then left to stand at 0° C. for 65 hours. The yellow precipitate obtained was filtered off, washed twice with hexane and dried in a high vacuum. There were obtained 428 mg of triethylammonium p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyldithiocarbamate which was processed directly without additional purification.
Reaction SMILES: [NH2:1][NH2:2].C(N(CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](F)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(#N)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21]([NH:1][NH2:2])=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(F)C1(c2ccc(Cl)cc2)CCC1
Reactant: NN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NNC(=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
Anhydrous hydrazine (2.02 mL, 1.4 eq) was dissolved in acetonitrile (100 mL) and cooled to 0° C. Triethylamine (12.8 mL, 2.0 eq.) was added followed by 1-(4-chlorophenyl)cyclobutanecarbonyl fluoride (10 g, 1.0 eq) in acetonitrile (25 mL). After stirring at room temperature for one hour the acetonitrile was removed by evaporation. Product was obtained after silica gel chromatography.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].II.Cl>CCOCC.[Zn]>[CH3:1][C:2]1[CH:3]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CSc1ccc(CC2c3ccccc3C(=O)C2C)cc1
Reactant: COC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: CCOCC
Product: COC(=O)CC1C(C)=C(Cc2ccc(SC)cc2)c2ccccc21
Temperature: 0 °C

Procedure:
To a solution of the indanone derivative from Step 1 (885 mg, 3.14 mmol) in ether (20 mL) were added successively zinc (840 mg, 12.8 mmol), methyl bromoacetate (0.5 mL, 5 mmol) and iodine (200 mg). The reaction mixture was refluxed for 3 hours, then cooled to 0° C. and 6N aqueous HCl was added dropwise until the zinc complex was completely decomposed. The organic layer was decanted, washed with brine, dried over Na2SO4 and evaporated to dryness. The oily residue was dissolved in formic acid and evaporated to dryness to complete the dehydration of the intermediate methyl [1-hydroxy-2-methyl-3-(4-methylthiobenzyl)indan-1-yl]acetate. The resulting oily residue was chromatographed on silica gel eluting with a 1:19 mixture of ethyl acetate-hexane to afford pure title compound as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[C:8]([CH3:14])=[N:7]1.[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[C:21]([CH2:31][CH2:32][CH3:33])[N:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[ClH:1].[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[C:8]([CH3:14])=[N:7]3)[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH2:31][CH2:32][CH3:33])[N:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nn(CCCCCl)c(=O)[nH]c1=O
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Product: CCCc1cc(N2CCN(CCCCn3nc(C)c(=O)[nH]c3=O)CC2)nc(C(C)(C)C)n1
Product: Cl

Procedure:
2-{4-[4-(2-tert-Butyl-6-propyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-6-methyl-2H-[1,2,4]triazine-3,5-dione hydrochloride was prepared from 2-(4-chloro-butyl)-6-methyl-2H-[1,2,4]triazine-3,5-dione and 2-tert-butyl-4-piperazin-1-yl-6-propyl-pyrimidine by analogy to the process described in example 1.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[C:10]([F:23])[CH:9]=1)#[N:7].Cl.C(=O)([O-])[OH:26].[Na+]>O1CCCC1>[F:23][C:10]1[CH:9]=[C:8]([CH:22]=[CH:21][C:11]=1/[CH:12]=[CH:4]/[CH:3]=[CH:2]/[CH:1]=[O:26])[C:6]#[N:7]
Reactant: [Li]CCCC
Reactant: O=C([O-])O
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1F)OCC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Butyllithium (hexane solution, 1.53 N, 0.5 ml, 0.77 mmol) was added dropwise to a solution of diethyl 4-cyano-2-fluorobenzylphosphonate (209 mg, 0.77 mmol) obtained from Reference example 1-(1) in anhydrous tetrahydrofuran (4 ml) at −78° C. with stirring. The mixture was stirred at −78° C. for 30 minutes. At the end of this time, commercially available fumaraldehyde mono-dimethylacetal (100 mg, 0.77 mmol) in anhydrous tetrahydrofuran (2 ml) was added to the mixture, and the resulting mixture was stirred at −78° C. for 2 hours. The cooling bath was then removed and the mixture was stirred in an ice bath for a further 15 minutes. 0.1N hydrochloric acid (3.9 ml, 0.39 mmol) was added to the reaction mixture and the mixture was then stirred for 30 minutes in the ice bath and then for 1 hour at ambient temperature. At the end of this time, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture in an ice bath. The resulting mixture was partitioned between ethyl acetate and water, the organic layer was washed with water and with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The crystalline residue thus obtained was recrystallized from a mixture of ethyl acetate and hexane to afford the title compound (127 mg, 82% yield) as pale yellow crystals. m.p. 174-177° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10])(=O)[CH3:2].[C:11]([NH:16][NH2:17])(=[O:15])[CH2:12][CH2:13][CH3:14]>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:17][NH:16][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: CC(=O)c1ccncc1Cl
Reactant: CCCC(=O)NN
Solvent: CCO
Product: CCCC(=O)NN=C(C)c1ccncc1Cl
Yield: 25 %

Procedure:
A mixture of 5.20 gm (0.0335 mole) of 4-acetyl-3-chloropyridine, 3.43 gm (0.0336 mole) of butyric acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer. The solid which separated was collected to give 2.01 gm (25%) of white solid having a melting point of 103.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(N(CC)CC)C>O1CCCC1>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: Fc1ccc(S)cc1
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1ccc(F)cc1
Yield: 86.2 %

Procedure:
A solution of 4-fluorobenzenethiol (10 g, 78 mmol) and iodoethane (7.57 mL, 94 mmol) in tetrahydrofuran (100 mL) was treated with triethylamine (13.05 mL, 94 mmol) at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated, washed with hexane and dried under vacuum to provide the title compound (10.5 g, 81%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:37])[CH2:19][NH:20][C:21](=[O:36])[NH:22][C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:12]1([C@H:9]2[CH2:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]2[C:18](=[O:37])[CH2:19][NH:20][C:21](=[O:36])[NH:22][C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Yield: 19.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 4.8 g of ethyl cis-3-{3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}-phenyl}propionate in solution in 25 cm3 of methanol and 0.25 g of potassium hydroxide dissolved in 5 cm3 of water and after treatment, 0.9 g of cis-3-{3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionic acid, melting at 170° C., is obtained.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[C:5]1([CH2:11][N:12]2C(=O)C(C(C)C)[N:14](C)[S:13]2(=[O:23])=[O:22])C=CC=[CH:7][CH:6]=1>CO.[Pd]>[CH2:5]([CH:11]1[NH:12][S:13](=[O:23])(=[O:22])[NH:14][C:1]1=[O:3])[CH2:6][CH3:7]
Reactant: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a suspension of 3.5 g of 10% Pd/C in 150 ml of methanol containing ammonium formate (15 g) was added a solution of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.1 g) in 50 ml of methanol. The mixture was stirred at room temperature for 7 hours, filtered through a pad of CELITE® and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 2-ammonium salt (Formula IV: R1 =H; R2 =isopropyl; R3 =CH3 ; as ammonium salt).
Reaction SMILES: [H-].[Na+].C([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[C:11]=1[CH3:19])(=O)C(C)(C)C.[CH3:20][O:21][CH2:22]Cl>O1CCCC1>[CH3:20][O:21][CH2:22][O:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([OH:9])=[C:11]([CH3:19])[C:12]=1[CH3:18]
Reactant: COCCl
Reactant: Cc1cc(OC(=O)C(C)(C)C)c(C)c(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)cc(O)c(C)c1C
Reaction time: 0.5 h

Procedure:
Sodium hydride (8.51 g, 55% suspension in mineral oil) was added to a solution of 4-hydroxy-2,3,5-trimethylphenol pivalate (35.4 g) in tetrahydrofuran (300 ml) at room temperature. The mixture was stirred for 30 minutes. To the reaction mixture was added dropwise methoxymethyl chloride (15.7 g). This mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (100 ml) and to this solution was added dropwise a solution of potassium hydroxide (16.8 g) in methanol (100 ml). The mixture was stirred at room temperature and concentrated under reduced pressure. The residue was neutralized with 3N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=5:1 as the eluant to afford the title compound (27.5 g, Rf=0.16: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=4:1 as the eluant).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(O)(=O)C>ClC(Cl)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and acetic acid (2.5 mL) in dichloroethane (20 mL). The reaction mixture was allowed to stir overnight before being quenched with 0.5M HCl (30 mL). The mixture was then extracted with dichloromethane one time and then brine was added. The precipitate was filtered and dried to give tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI) m/e (M+H+) 285.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC(C2C=CC=CC=2)=C[C:30]=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:30][CH:26]=3)=[CH:13][C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)sc1NS(=O)(=O)c1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5-phenylthiophene-3-carboxylate and benzenesulphonyl chloride
Reaction SMILES: C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)([Cl:16])=O.O[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24](CO)=[CH:23][C:22]=1[F:30].Cl[C:32]([Cl:35])(Cl)Cl>C1C=CC=CC=1>[Cl:16][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([CH2:32][Cl:35])=[CH:23][C:22]=1[F:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1cc(F)c(CO)cc1F
Reactant: ClC(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Fc1cc(CCl)c(F)cc1CCl
Temperature: 70 °C

Procedure:
While cooling with ice, 3 g of triethylamine are added to a mixture of 25 g of phosphorus pentachloride and 25 g of phosphorus oxychloride. After that, a solution of 2.2 g of α,α'-dihydroxy-2,5-difluoro-para-xylene in 10 ml of tetrachloromethane are added. The batch is heated at 70° C. for two hours. It is then cooled, poured onto ice, and dissolved in benzene. The benzene solution is washed with aqueous sodium carbonate solution, then dried with calcium chloride. The solvent is evaporated and the residue recrystallized several times from aqueous methanol. There are obtained 1.85 g of fine colorless needles melting at 62.5 - 64.5° C.