Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-])=[C:4]2[CH2:9][CH2:10][CH2:11][C:3]=12.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:9]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[CH2:11][CH2:10]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cnc(Cl)c2c1CCC2
Product: CC(=O)OC1CCc2c(Cl)ncnc21
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 40 g of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrmidine-1-oxide [prepared as described in step (a) above] in 1 liter of acetic anhydride was added dropwise, whilst heating at 50° C., to 1.5 liters of acetic anhydride. After the addition was complete, the solution was stirred at 110° C. for 2 hours. At the end of this time, the mixture was cooled to room temperature, and the solvent was evaporated off under reduced pressure. 400 ml of a mixture of toluene and hexane were added to the resulting residue, the mixture was stirred, and the solvent was separated by decantation; these operations were repeated a further 2 times. The decanted solvents were combined and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, using chloroform as the eluent, to give 39.3 g of the title compound as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][NH:9]1)=[O:7])C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F)([O-:17])=[O:16]>O.C(O)C>[CH3:14][N:12]1[CH2:11][CH2:10][N:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:8]([C:6]([OH:5])=[O:7])[CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C1CN(C)CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccccc2[N+](=O)[O-])C(C(=O)O)C1

Procedure:
A solution of 6.6 g. (0.164 mole) of sodium hydroxide, 28.2 g. (0.165 mole) of ethyl-4-methylpiperazine-2-carboxylate, 20 ml. of water and 200 ml. of ethanol is refluxed for 3 hours. This solution is then added under nitrogen to a hot stirred solution of o-nitrofluorobenzene in 300 ml. of ethanol and 30 ml. of water. The resultant solution is refluxed for 48 hours, cooled and filtered to give 12.8 g. of yellow product, m.p. 222-225°. Concentration of the mother liquors to ~100 ml. and adjusting the pH to 6 yields an additional 6.6 g. of product. Further concentration of mother liquors gives yet another 3 g. of product. Total yield is 22.4 g., 51.5%. The analytical sample had m.p. 234° dec.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:8]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:19][C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=1)[CH2:9][CH3:10]
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Reactant: Cn1c(=O)c(CBr)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(OC)(c1cccc(OCc2cc3ccccc3n(C)c2=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.5 g, 2 mmol), 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one (0.5 g, 2 mmol), potassium carbonate (0.35 g, 2.5 mmol) and dimethylformamide (3 ml) was stirred at ambient temperature for 48 hours. The mixture was filtered, the filtrate was added to water (30 ml) and the mixture was extracted with elhyl acetate (3×15 ml). The organic extracts were combined, washed with a dilute aqueous sodium hydroxide solution and with a saturated sodium chloride solution dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (7/3 v/v) to give 2-[1-methoxy-1-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-3-ylmethoxy)phenyl]propyl]thiazole (0.84 g, 100%), m.p. 123°-125° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[O:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=O)[O:30]C3C=CC([N+]([O-])=O)=CC=3)[CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=[N:18]1>C(#N)C.CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]4[O:17][N:18]=[CH:19][N:20]=4)[CH:23]=3)=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(-c3ncno3)c2)[C@@H]1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 0.0030 mol, from example 1, part B) and [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester (1.08 g, 0.0033 mol) in acetonitrile (25 mL) and dimethylformamide (20 mL) was stirred at 80° C. for one hour. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (2:1) and Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated with anhydrous ether and dried in vacuo to yield 1.08 g of the title compound, m.p. 168°-170° C. TLC, silica gel, EtOAc/Hexane(2:l), Rf =0.42. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 9.0 (s, 1H), 8.5 (s, 1H), 7.5 (m, 4H), 7.0 (d, J=8.8 Hz 1H), 6.8 (d, J=8.8 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J=5.9 & 3.5 Hz, 1H), 3.4 (s, 1H), 1.5 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.8, 158.6, 156.3, 155.7, 141.4, 132.6, 132.5, 130.0, 125.9, 123.7, 122.3, 120.6, 119.1, 117.9, 116.7, 102.7,l 80.4, 71.3, 49.5, 26.6, 18.9; IR (KBr) 2228, 1667, 1574, 1551, 1489 cm-1.M.S. (M+H)+ at 406, M.W. 405; [α]D =-55.20° (c=0.86 DMSO).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([O:26][CH3:25])[CH:28]=3)=[O:23])[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: COc1cccc(N)c1
Product: CCc1ccc(C2CC(C(=O)Nc3cccc(OC)c3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 27 mg (0.22 mmol, 1.1 eq.) of 3-methoxyaniline were reacted according to General Method 1. Yield: 52 mg (60% of theory)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:1][S:2]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.56 g, 4.7 mmol) was added to a stirred solution of tert-butyl trans-4-aminocyclohexylcarbamate (J. Org. Chem. 8811, 61, 1996) (1.0 g, 4.7 mmol) and N-ethyl-N-isopropyl-2-propanamine (0.67 g, 0.52 mmol) in dichloromethane (30 ml). The reaction mixture was stirred for 30 min at room temperature and then partitioned between ethyl acetate (300 ml) and water (100 ml). The organic layer was washed twice with 1 molar aqueous citric acid solution and then with a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous sodium sulfate and the solvent removed under reduced pressure to give a residue that was triturated with diethyl ether to give the title compound (0.99 g) as a white solid.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:30])[C:14]([CH2:26][CH2:27][C:28]#N)=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:31].[Na+].[OH2:33]>CCO>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:30])[C:14]([CH2:26][CH2:27][C:28]([OH:33])=[O:31])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O
Reactant: CCCCCCCCN1CCc2c(C)c(CCC#N)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCN1CCc2c(C)c(CCC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21

Procedure:
N-(1-Octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.14 g) was dissolved in EtOH (26 ml), and a solution of NaOH (1.1 g) in water (7.5 ml) was added, which was followed by refluxing for 14 hr under a nitrogen atmosphere. EtOH was evaporated under reduced pressure. The obtained residue was dissolved in warm water (30 ml) and washed with ArOEt (30 ml). The aqueous layer was neutralized with 2N HCl and extracted with CHCl3 (50 ml). CHCl3 layer was evaporated under reduced pressure to give 830 mg of the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[SH:24][CH:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26](O)=[O:27].C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2]2([S:24][CH:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26](=[O:27])[N:23]2[CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)CC(S)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 200 ml of toluene were dissolved 20.00 g of tert-butyl 4-oxo-1-piperidinecarboxylate and 12.6 ml of β-phenethylamine. After stirring the resulting solution at ambient temperature for 30 minutes, 15.07 g of mercaptosuccinic acid was added, and the resulting mixture was subjected to an azeotropic distillation treatment under reflux for 6 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=5:1] gave 22.10 g of 2-[8-(tert-butoxycarbonyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid as a yellow oily product.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[NH:32][C:31](=[O:33])[C:30]([CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:29][N:28]=2)=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:1]1([S:7]([N:28]2[CH:29]=[C:30]([CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:33])[N:32]=[C:27]2[S:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=c1[nH]c(SCCCCCCCCc2ccc(Cl)cc2)ncc1Cc1cccnc1
Solvent: c1ccncc1
Product: O=c1nc(SCCCCCCCCc2ccc(Cl)cc2)n(S(=O)(=O)c2ccccc2)cc1Cc1cccnc1
Reaction time: 8 h
Yield: 18.5 %

Procedure:
Benzenesulfonyl chloride (41 mg) was added to a solution of 2-(8-(4chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one (103 mg) in pyridine (0.5 ml), and the mixture stirred overnight. Evaporation of the pyridine followed by chromatography (silica, 0-2% methanol in dichloromethane) gave 1-phenylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one (25 mg). 1H-NMR (CDCl3) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.56(2H, t), 2.92(2H, t), 3.87(2H, s), 7.08(2H, d), 7.15-7.8(7H, m), 7.95(2H, m), 8.29(1H, s) and 8.35-8.7(2H, bm).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][C:13](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[C:12]2[CH3:22])=[CH:7][CH:6]=1)=[O:4].[CH3:24][NH:25][OH:26]>>[CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][C:13](/[CH:17]=[CH:18]/[C:19]([N:25]([OH:26])[CH3:24])=[O:20])=[C:12]2[CH3:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNO
Reactant: Cc1cc(/C=C/C(=O)O)c(C)n1-c1ccc(C(=O)N(C)C)cc1
Product: Cc1cc(/C=C/C(=O)N(C)O)c(C)n1-c1ccc(C(=O)N(C)C)cc1

Procedure:
(E)-3-[1-(4-Dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-2-propenoic acid is condensed with N-methylhydroxylamine as described in example 1(a) to yield (E)-3-[1-(4-dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-N-hydroxy-N-methyl-2-propenamide, m.p. 172°-174°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)cn1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: Cc1ccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)cn1

Procedure:
57 mg (0.17 mmol) of the compound of Example 24A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 58 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[N:13]=[C:14]([CH3:24])[S:15][C:16]=3[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:11])=[N:30][C:29]=2[CH:31]=1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1ccc2oc(Cl)nc2c1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 499 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:14][CH2:15][CH3:16])(OCC)[CH2:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH3:10])[C:24](=[O:23])[C:26]([F:29])([F:28])[F:27])=[CH:6][CH:7]=1
Reactant: CCOC(CC)(OCC)c1ccc(Cl)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 2.0 g of 1-chloro-4-(1,1-diethoxypropyl)benzene and 2.5 mL of CH2Cl2 was treated with 1.45 mL of pyridine. The solution was cooled to 0° C. and treated with 5.5 mL of (CF3CO)2O in 2.5 mL of CH2Cl2. After heating overnight at reflux, the reaction mixture was cooled, diluted with CH2Cl2 and 12 mL of ice cold water was added. The organic layer was seperated and washed with 20 mL of 1N HCl, followed by a washing with 20 mL of 10% Na2CO3 and two washings with 20 mL of water. The organic layer was dried over Na2SO4 and concd in vacuo to yield 1.69 g of a dark brown oil. Chromatographic purification (silica, 10% ethyl acetate in hexanes) yielded 1.0 g of a yellow oil. Bulb to bulb distillation gave 0.45 g of a very pure light yellow oil: μ(23,D) 1.5137; major geometric isomer: 1HNMR (CDCl3) δ 1.22 (t, 3H, 7.0 Hz), 1.70 (s, 3H), 3.64 (q, 2H, 7.0 Hz), 7.30 (d, 2H, 8.3 Hz), 7.46 (d, 2H, 8.4 Hz). 19FNMR (CDCl3) δ -74.68 (CF3). Anal. Calcd for C13H12 O2F3Cl: C, 53.35; H, 4.13. Found: C, 53.44; H, 4.10.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(N(C(C)C)CC)(C)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:28][CH2:27][N:29]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 12.5 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro- 1 -methyl-2-oxo-quinoline-3-carboxylic acid (1 gm) and toluene (50 ml) was cooled to 10-15° C. under nitrogen atmosphere. Diisopropylethyl amine (1.78 gm) was added to the resulting mass at 10-15° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (0.52 gm) in one portion at 10-15° C. and then thionyl chloride (0.61 gm) was added at 0° C. The resulting mixture was stirred for 4 hours and toluene was distilled out under vacuum at below 60° C. The resulting residue was dissolved in ethyl acetate (50 ml) and washed with 5% sodium hydroxide solution (6.5 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (2.5 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 1 gm of laquinimod (HPLC Purity: 98.93%).
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>O>[C:10]([O:13][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[CH3:8])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])cc1C
Solvent: O
Product: CC(=O)OCc1ccncc1C
Yield: 30 %

Procedure:
The N-oxide was added portionwise to 60 mL of acetic anhydride and the resulting dark orange solution was heated (water-bath) at about 90° C. for 1 h. The excess acetic anhydride was then distilled off under reduced pressure and the material boiling at 90°-120° C./0.1 torr (39.0 g) was collected. Chromatography of this oil (silica gel/ethyl acetate-pet.ether=2:3) afforded pure 4-acetoxymethyl-3-methylpyridine (19.0 g, 30%) as an oil: ir (neat) 1745 cm-1.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[O:32]=[C:33]([NH:42][C@H:43]([C:48]([NH:50][CH:51]([CH2:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1)[CH:52]([P:54]([CH2:58]C)([O:56][CH3:57])=[O:55])[OH:53])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[CH:61]1([CH2:60][C@H:51]([NH:50][C:48](=[O:49])[C@H:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:42][C:33](=[O:32])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:52]([P:54]([CH3:58])(=[O:55])[O:56][CH3:57])[OH:53])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: CCP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COP(C)(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Hydroxybenzotriazole (120 mg, 0.784 mmol), diisopropylethylamine (127 μl, 0.728 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (150 mg, 0.784 mmol) were sequentially added to a solution of the title A compound obtained from the previous reaction and the title B compound from Example 17 (176.7 mg, 0.672 mmol) in 3 ml dimethylformamide at 0°. The reaction mixture was warmed and stirred at room temperature for 72 hours after which it was concentrated, then treated with 20 ml pH=4.01 buffer and extracted with ethyl acetate (3×30 ml). Drying and concentration followed by chromatographic purification of the crude product gave 146 mg 52.7%) pure title compound lsomer B, m.p. 188°-207°, [α]D =-71.7° (c=0.545, CH3OH) which was characterized by MS, IR, 1H NMR, 13C NMR and 31P NMR [56.0 ppm w.r.t H3PO4 as external reference, CDCl3, 36.4 MHz].
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[S:42])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(OCC)(=O)C>CO.ClCCl>[CH3:14][S:11]([O:10][C@H:8]1[CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:5]([C:3]2[N:43]=[C:41]([CH2:40][NH:39][C:37]([O:36][CH2:35][C:34]3[CH:44]=[CH:45][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)=[O:38])[S:42][CH:2]=2)[CH2:9]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: NC(=S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (840 mg) in a mixture of methanol (30 ml) and dichloromethane (20 ml) was added 2-(4-nitrobenzyloxycarbonylamino)thioacetamide (700 mg) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated and the resulting oil was subjected to a column chromatography on silica gel (30 g) eluting with ethyl acetate to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-{N-(4-nitrobenzyloxycarbonyl)aminomethyl}thiazol-4-yl]pyrrolidine (540 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:35].[Na+].[Na+].C(O)(=O)C>O>[CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[S:16]([C:19]1[C:20](=[O:35])[C:21]2[C:29](=[CH:30][CH:31]=1)[C:28]1[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:22]=2)(=[O:18])=[O:17])([CH3:15])[CH3:14]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3c(c2)Cc2ccccc2-3)c(C(C)C)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)C2=CC=C3C(=Cc4ccccc43)C2=O)c(C(C)C)c1
Yield: 40.3 %

Procedure:
A portion of the 2-(2,4,6-triisopropylphenylsulfonyl)fluorene just described (8.67 g, 20.0 mmol) was placed in a 1 liter flask (equipped with a magnetic stirrer and reflux condenser) along with 17.9 g (60.0 mmol, 3.0 eq) of sodium dichromate dihydrate and 500 ml of glacial acetic acid. The mixture was refluxed for 15 hours, cooled, and poured into 2.0 liters of water. The solids were collected by filtration and washed with additional water (2×1.0 liter). The crude product was dried and purified by chromatography. A total of 3.60 g (8.06 mmol, 40.3%) of pure 2-(2,4,6-triisopropylphenylsulfonyl)fluorenone was obtained in this manner. Its structure was confirmed by IR, NMR, and ultraviolet-visible (UV-VIS) spectroscopy, FDMS, and combustion analysis.