Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:16])[CH:5]=2)[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=1.C(O)C>C(=O)(O)[O-].[Na+]>[CH:1]1([C:4]2[C:13]([C:14]3[NH:24][C:19]4[CH:18]=[N:17][CH:22]=[CH:21][C:20]=4[N:23]=3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:16])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C=O)c(C2CC2)cc1C
Reactant: Nc1ccncc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(-c2nc3ccncc3[nH]2)c(C2CC2)cc1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
Into a 100-mL round-bottom flask was placed a mixture of methyl 4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1, 500 mg, 2.29 mmol), pyridine-3,4-diamine (500 mg, 4.58 mmol), NH4OAc (1.42 g, 18.4 mmol) and ethanol (50 mL). The resulting mixture was stirred open to the air for 3 days at 70° C., then cooled to room temperature and diluted with aqueous sodium bicarbonate (sat., 50 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent to yield 268 mg (38%) of the title compound as a yellow semi-solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[ClH:22]>CO.CCOC(C)=O>[ClH:22].[NH2:20][C:19]([NH2:21])=[N:18]/[N:17]=[C:1](/[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)\[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: C/C(=N\N=C(N)N)c1ccc(C(=O)O)cc1
Temperature: 20 °C

Procedure:
4-Acetylbenzoic acid (L1) (1.041 g, 6.34 mmol), amino guanidine bicarbonate (1.12 g, 8.2 mmol, 1.3 eq) and c.HCl (0.7 ml, 7.0 mmol) in MeOH (30 mL) was refluxed for 1 h. The reaction mixture was diluted with EtOAc cooled to 20° C. and the resulting precipitate was filtered and recrytallized from MeOH/EtOAc to give L2 (887 mg, 55%), mp (MeOH/EtOAc)>300° C.; 1H NMR ([(CD3)2SO] δ7.97-7.89 (m, 4 H, ArH), 6.75 (br, 4 H, 2×NH2), 2.25 (s, 3 H, CH3), mass APCI+ 221.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:19]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:10]([CH3:19])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C)[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a vial is added ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide (180 mg, 0.61 mmol) in 3 ml of THF, followed by the addition of NaH (35 mg, 0.92 mmol). Then iodomethane (131 mg, 0.92 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 116 mg of ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-methyl-amide.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH2:20]>>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH:20][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1cnc(-c2ccccn2)nc1Cl
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2nc(-c3ccccn3)ncc2OC)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (50 mg, 0.226 mmol) and 2,5-dimethoxyaniline (35 mg, 0.226 mmol) similar to Example 11 and isolated as a gray solid (46 mg, 61%). 1H NMR (CDCl3): 8.77-8.74 (m, 1H), 8.72 (d, J=3.0 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.83-7.77 (m, 1H), 7.33-7.29 (m, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.56 (dd, J=3.0, 8.7 Hz, 1H), 4.04 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([O:51][S:52]([OH:55])(=[O:54])=[O:53])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:30][O:31][S:32]([OH:35])(=[O:34])=[O:33])[O:13][C@H:12]([CH2:14][O:15][S:16]([OH:19])(=[O:18])=[O:17])[C@@H:11]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C@@H:10]2[O:25][S:26]([OH:29])(=[O:28])=[O:27])[C@H:5]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C@@H:4]([O:41][S:42]([OH:45])(=[O:44])=[O:43])[C@@H:3]1[O:46][S:47]([OH:50])(=[O:49])=[O:48].[OH-].[Na+:57]>>[CH2:1]([O:51][S:52]([O-:55])(=[O:53])=[O:54])[C@H:2]1[O:7][CH:6]([O:8][C@:9]2([CH2:30][O:31][S:32]([O-:35])(=[O:34])=[O:33])[O:13][C@H:12]([CH2:14][O:15][S:16]([O-:19])(=[O:17])=[O:18])[C@@H:11]([O:20][S:21]([O-:24])(=[O:23])=[O:22])[C@@H:10]2[O:25][S:26]([O-:29])(=[O:28])=[O:27])[C@H:5]([O:36][S:37]([O-:40])(=[O:38])=[O:39])[C@@H:4]([O:41][S:42]([O-:45])(=[O:44])=[O:43])[C@@H:3]1[O:46][S:47]([O-:50])(=[O:49])=[O:48].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57]
Reactant: O=S(=O)(O)OC[C@H]1O[C@@](COS(=O)(=O)O)(O[C@H]2O[C@H](COS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@H](OS(=O)(=O)O)[C@H]2OS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@@H]1OS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)([O-])OC[C@H]1O[C@@](COS(=O)(=O)[O-])(OC2O[C@H](COS(=O)(=O)[O-])[C@@H](OS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H]2OS(=O)(=O)[O-])[C@@H](OS(=O)(=O)[O-])[C@@H]1OS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
One portion of sucrose octasulfate solution prepared as described in I above was adjusted with 10% w/w aqueous sodium hydroxide to pH=9 with stirring at room temperature. The solution was evaporated at 50° C. in vacuo to remove pyridine and water. When 250 ml were distilled, 580 ml of ethylene glycol were added and the evaporation was continued until 10 mm vacuum. 100 ml of ethanol were added to the solution. The solution was filtered, and pH was adjusted to 9.5. 350 ml of ethanol were slowly added with vigorous stirring at 30°-35° C., and the substance will then precipitate. After the addition was ended, the mixture was cooled to 10° C., and the solid substance was filtered and washed with 50 ml of 1:1 ethanol/ethylene glycol and 200 ml of methanol. The wet filter cake was dried in vacuo at 50° C. The crude product was dissolved in 520 ml of ethylene glycol and heated to 40° C., and 100 ml of ethanol were added. The solution was filtered and pH was adjusted to 9.5. 350 ml of ethanol were slowly added with vigorous stirring at 30°-35° C. and the substance will then precipitate. After the addition was ended, the mixture was cooled to 10° C. and the solid substance was filtered. It was washed with 50 ml of 1:1 ethanol/ethylene glycol and 200 ml of ethanol. The wet filter cake was dried in vacuo at 50° C. The substance was reprecipitated once as above and then dried for 2 hours at room temperature in 500 ml of ethanol. The substance was filtered, washed with 200 ml of ethanol and dried at 50° C. in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:22][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1cc(I)ccn1
Product: COC(=O)CCc1ccc(C#Cc2ccnc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 4-iodo-2-methylpyridine (0.07 mL, 0.59 mmol) according to the general procedure IF to give 62 mg (44%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.50 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 8.48-8.46 (m, 1H), 7.48-7.45 (m, 2H), 7.25-7.20 (m, 4H), 3.67 (s, 3H), 2.98 (t, J=7.8 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.56 (s, 3H); 13C NMR (CDCl3) δ 173.1, 158.6, 149.3, 142.0, 132.1, 131.8, 128.6, 125.1, 122.7, 120.3, 93.4, 86.9, 51.8, 35.4, 31.0, 24.5; ESI-MS m/z 302.1 (M+Na+).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].N1C2C(=CC=CC=2)C=CC=1.[CH3:16][C:17]([OH:25])([C:19]#[C:20][C:21]([CH3:24])([OH:23])[CH3:22])[CH3:18].[H][H]>CO>[CH3:16][C:17]([OH:25])(/[CH:19]=[CH:20]\[C:21]([CH3:24])([OH:23])[CH3:22])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)(O)C#CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(O)/C=C\C(C)(C)O
Yield: 99.4 %

Procedure:
1.6 g of 5% palladized calcium carbonate and 0.6 g of quinoline were added to a solution of 24 g of 2,5-dimethyl-hex-3-yne-2,5-diol [Ray et al, Am. Soc., Vol. 74 (1952), p. 1247]in 200 ml of methanol and the mixture was stirred with hydrogen until hydrogen absorption ceased. The catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to obtain 24.2 g of cis 2,5-dimethyl-hex-3-ene-2,5-diol melting at 64° C. which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:28][CH2:27][CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Yield: 97.3 %

Procedure:
A solution of 2.69 grams (0.010 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 2.38 grams (0.010 mole) of (tert-butoxy)-N-(3-bromopropyl)carboxamide (commercially available) and 1.52 grams (0.011 mole) of potassium carbonate in 40 mL of DMF was stirred at ambient temperature during a four-day period. After this time the reaction mixture was shaken in diethyl ether and water, and the separated organic layer was washed with one portion of water and with one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.15 grams of the subject compound.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CCOc2cc3nccc(Oc4cc5ccccc5nc4C)c3cc2OC)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and ethyl piperidine-3-carboxylate (60 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (36 mg, yield 54%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[O:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].CN(C)C(N(C)C)=N.C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[C:13](=[O:15])[CH2:14][O:10][C:11]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1COC(=O)N1
Reactant: BrCc1ccc(Br)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1COC(=O)N1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A solution of 1.50 g (6 mmol) of 4-bromobenzyl bromide and 0.73 g (7.2 mmol) of 1,3-oxazolidine-2,4-dione in 6 ml of tetrahydrofuran is admixed dropwise with a solution of 1.39 g (12 mmol) of 1,1,3,3-tetramethylguanidine in 6 ml of tetrahydrofuran. The mixture is stirred at ambient temperature overnight. 50 ml of ice-cold aqueous hydrochloric acid (1N) and 100 ml of ethyl acetate are added. The organic phase is separated after settling out and washed successively with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. 1.14 g of product are obtained in the form of white crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:15]([S:38][C:10]=2[CH2:9]1)=[N:16][C:17]([CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37])=[C:18]([Cl:30])[C:19]=3[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)C1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O>[Pd].C1(C)C(C)=CC=CC=1>[Cl:30][C:18]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[C:14]2[C:11]3[C:10](=[CH:9][N:8]=[CH:13][CH:12]=3)[S:38][C:15]2=[N:16][C:17]=1[CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37]
Reactant: COc1ccc(-c2c(Cl)c(CN3CCCC3=O)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2c(Cl)c(CN3CCCC3=O)nc3sc4cnccc4c23)cc1OC
Yield: 10.1 %

Procedure:
A mixture of the compound obtained in Example 28B (3.0 g), palladium on carbon (5%, 5.0 g), nitrobenzene (1.3 g) and xylene (100 ml) was stirred under reflux for 4 hours and the insoluble solid was filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on SiO2 with ethyl acetate to give 3-chloro-4-(3,4-dimethoxyphenyl)-2-(2-oxopyrrolidin-1-ylmethyl)thieno[2,3-b:5,4-c']dipyridine (0.25 g, 10%) as crystals. Recrystallization from ethyl acetate-hexane give colorless prisms, m.p. 228-230° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:23][CH3:24])[CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21]O)[CH3:14]>>[C:1]([O:12][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:15]([CH2:23][CH3:24])[CH2:13][CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)CCOCCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCCOCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 3-(2-(diethylamino)ethoxy)propan-1-ol as starting materials to give the aimed compound. Compound 14 was obtained by the purification using silica gel column chromatography.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37]Cl>C1COCC1>[CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:35][O:36][CH3:37])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(C)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 223 mg (0.51 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 352 mg of potassium carbonate and 116 μL of methoxymethyl chloride in 1 mL THF using procedure x. Yield: 200 mg of a white solid. LC-MSD, m/z for C18H19ClF3N3O5S [M+H]+=482.0, 484.0; HPLC retention time: 2.5 min.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]2[NH:34][CH:35]=[CH:36][N:37]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=1)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH3:4].[CH3:41][CH:42](O)[CH3:43]>>[CH:42]([O:14][C:13](=[O:15])[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:2][CH2:3][CH3:4])[CH2:38][CH2:39][CH3:40])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]2[NH:34][CH:35]=[CH:36][N:37]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=1)([CH3:43])[CH3:41]
Reactant: CCCN(CCC)CCCCN(CCC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: CC(C)O
Agent: Cl
Product: CCCN(CCC)CCCCN(CCC(=O)OC(C)C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (88.0 mg) of the compound obtained in Example 51-1 was added with 2-propanol (10 ml) and the whole was refluxed under heating for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (32.8 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2C(N[C:22](=[O:23])[C:17]=12)=O)(OCC)=[O:12].Cl>C([O-])([O-])=O.[Na+].[Na+].O>[CH:25]1[CH:26]=[C:16]2[C:11]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:22](=[O:23])[C:17]2=[CH:18][CH:24]=1)=[O:12]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
In a solution of Na2CO3 (51.5 g) in water (350 ml) at 5° C. was dissolved L-glutamic acid (29.4 g). Carboethoxy phthalimide (59.6 g) was added to the solution and suspended therein and thereafter reacted at 350° C. for 30-40 minutes. Then the solution was freed from insoluble matter, adjusted to pH 2.5 with 6N-HCl, and allowed to stand at 0° C. The resulting precipitate was filtered, and recrystallized from water to give N,N-phthaloylglutamic acid, yield 35.7 g, 64.4%; specific rotation [α]D25 =-48.6°(C=1, dioxane).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([Mg]Cl)([CH3:14])[CH3:13].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>C1COCC1>[CH:12]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:8][Br:9])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(CBr)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 4-nitrobenzyl bromide (432 mg, 2 mmol) in THF (5 mL) at −70° C., was treated dropwise with isopropylmagnesium chloride (1 mL, 2-M in Et2O, 2 mmol), stirred for 1 h, treated with DDQ (499 mg, 2.2 mmol) and stirred at room temperature for 16 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo and filtered. The resulting solid was purified by chromatography [SiO2; EtOAc:Heptane (1:4)] to give the title compound (183 mg, 35%) as a pale yellow solid which was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccc(OC)c(OC)c1
Yield: 93.8 %

Procedure:
263 g (0.885 mol) of ethyl 2-bromo-4-(trifluoromethyl)benzoate, 750 ml of 1,2-dimethoxyethane, 4 g of tetrakis(triphenylphosphine)palladium, 177 g (0.974 mol) of 3,4-dimethoxyphenylboronic acid and 1000 ml of a 2M aqueous sodium carbonate solution are introduced successively, under an inert atmosphere, into a four-liter round-bottomed flask. The reaction mixture is brought to reflux for fourteen hours and then evaporated to a third under reduced pressure. The reaction mixture is poured onto two liters of water; the precipitate which forms is filtered on sintered glass, rinsed with water and then dried under a stream of air. There is thus obtained 294 g (yield: 94%) of ethyl 2-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)benzoate in the form of a beige solid melting at 89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1c(F)cccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1c(F)cccc1F
Reaction time: 24 h

Procedure:
Methyl 2,6-difluorophenylacetate (2.141 g, 11.50 mmol), NBS (2.6 g, 14.61 mmol) and AIBN (0.057 g, 0.345 mmol) were taken up in CCl4 (45 mL). The reaction mixture was stirred at reflux for 18 hours. Additional NBS (1.433 g, 8.05 mmol) and AIBN (0.038 g, 0.230 mmol) were added and stirring at reflux continued for 24 hours. Room temperature was attained and the reaction mixture filtered through Celite, washing with DCM. The filtrate was concentrated in vacuo and the residue purified by MPLC (0-10% EtOAc-hexanes) to give methyl bromo(2,6-difluorophenyl)-acetate as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[C:3]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CSCC1CN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Temperature: 85 °C
Yield: 53.3 %

Procedure:
2-(4-Methyl-tetrahydro-thiophen-3-ylmethyl)-isoindole-1,3-dione (410.0 mg, 1.59 mmol) and NBS (312.0 mg, 1.75 mmol) were dissolved in CCl4 (8.0 mL). AIBN (100 mg) was added in one portion. The mixture was heated at 85° C. under N2 for 90 min. After cooling down, the mixture was passed through a short silica gel column (4×10 cm), eluted with CH2Cl2. The solution obtained was concentrated and the residue was recrystallized from EtOAc/Hexanes (5/1) to give 2-(4-Bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione (285 mg, 50%) as a white solid. 1H NMR (CDCl3) δ 4.74 (s, 2H), 4.91 (s, 2H), 7.29-7.30 (d, 1H, J=3.3 Hz), 7.70-7.71 (d, 1H, J=3.3 Hz), 7.70-7.73 (m, 2H), 7.82-7.87 (m, 2H).