Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:12]([NH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[CH:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[N:28]=2)=[CH:23][CH:22]=1)=[O:16])=[S:13])([CH3:3])[CH3:2].[C:43]([O-])(=[O:45])[CH3:44].[Na+].C(O)C.BrCC(OC)=O>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:43](=[O:45])[CH2:44][S:13]/[C:12]/1=[N:14]\[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[CH:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:41])([F:42])[F:40])=[CH:34][CH:33]=3)[N:28]=2)=[CH:23][CH:22]=1)=[O:16])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(NC(=S)NC(=O)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Reactant: CC(=O)[O-]
Agent: COC(=O)CBr
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 70 °C
Yield: 67.5 %

Procedure:
To 1-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea (F21) (0.110 g, 0.184 mmol) in a 25 mL vial equipped with a stir bar and Vigreux column was added sodium acetate (0.0600 g, 0.735 mmol), ethanol (2 mL) and methyl bromoacetate (0.0250 mL, 0.276 mmol). The reaction was heated to 70° C. overnight. The reaction was cooled and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided a solid which was dried overnight at 50° C. in vacuo to afford the title compound as a white solid (0.0791 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:34]=1>CS(C)=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:30]2[CH:31]=[C:32]([F:55])[C:33]([S:35]([N:38]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[C:39]3[S:43][N:42]=[CH:41][N:40]=3)(=[O:36])=[O:37])=[CH:34][C:29]=2[Cl:28])=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(Cl)cc3C3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (Preparation 231, 0.500 g, 0.0014 mol) and potassium carbonate (0.579 g, 0.00419 mol) in dimethyl sulfoxide (5.0 mL) was added 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 333, 0.644 g, 0.0014 mol). The mixture was stirred at room temperature under nitrogen for 1.5 hours before diluting with ethyl acetate (10.0 mL) and water (10.0 mL). The aqueous layer was extracted with ethyl acetate (3×10.0 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel column) eluting with ethyl acetate:heptane (gradient 0:1 to 35:65, by volume) to afford 1.03 g of tert-butyl 4-[5-chloro-2-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}-5-fluorophenoxy)phenyl]piperidine-1-carboxylate as a white solid. This material was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) added and reaction stirred for 16 hours at room temperature under nitrogen. Methanol (5.0 mL) was added to afford a white precipitate. This suspension mixture was filtered through a Celite™ pad and washed with methanol. The filtrate was concentrated in vacuo and the residue was diluted with methanol (2.0 mL), dichloromethane (2.0 mL) and saturated aqueous sodium bicarbonate (4.0 mL) and stirred for 1 hour at room temperature to afford a white solid. The suspension was filtered and the solid washed with water and diethyl ether. The collected solid was recrystallised from hot acetonitrile and ethanol (1:1 v/v) to afford the title compound as a white solid, 0.1929 mg, 27% yield.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:8])[CH3:7].C(Cl)Cl>C(Cl)(Cl)Cl>[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][C:15]=2[S:2]([Cl:1])(=[O:5])=[O:3])[CH2:10]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCc2cccc(Cl)c2C1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(S(=O)(=O)Cl)ccc(Cl)c2C1
Temperature: 0 °C

Procedure:
51.75 ml. (0.78 mole) of chlorosulfonic acid was added dropwise with stirring to a solution of 20.7 g. (0.099 mole) 2-acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline in 25 ml. of methylene chloride at -70° C. To effectuate a solution of the reactants 10 ml. of dry chloroform was added and the reaction mixture stirred for one hour at -70° C. The reaction mixture was then refluxed at 40°-45° C. for 2 hours and then stirred at ambient temperature for about 16 hours. The reaction mixture was then cautiously poured onto one liter of ice. The crude reaction product was then extracted into methylene chloride (3×100 ml.), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-8-chloro-5-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline as whitish yellow solid with a melting point of 105°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=[N:30][OH:31])[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: CC(=O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Yield: 79.8 %

Procedure:
1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone (0.87 g, 2 mmol), hydroxylamine hydrochloride (0.28 g, 2.05 mmol) and sodium acetate (0.33 g, 2.06 mmol) were dissolved in ethanol (9.0 mL) and heated to reflux for 2 h. After cooling to ambient temperature water (20 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (silica gel, ethyl acetate) to yield the title compound as a colorless foam (0.74 g, 82%). ES-MS m/e: 437.5 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[Cl:24][C:17]1[CH:18]=[C:19]([CH3:23])[C:20]([F:22])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][O:29][C:30]3=[O:34])=[CH:3][C:4]=2[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1cc(Cl)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)cc1F
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)CC2)cc1F
Yield: 26 %

Procedure:
To a mixture of 1-Boc-piperazine (1.9 g), 1-bromo-2-chloro-5-fluoro-4-methylbenzene (2.2 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg) and sodium tert-butoxide (1.4 g) was added toluene (20 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform). The obtained compound was dissolved in chloroform (3 mL), 4N hydrogen chloride/ethyl acetate (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-chloro-5-fluoro-4-methylphenyl)piperazine hydrochloride (2 g). To a mixture of 1-(2-chloro-5-fluoro-4-methylphenyl)piperazine hydrochloride (1.1 g), 4-bromo-2-methanesulfonylbenzoic acid (1.1 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (50 mL), methanol (50 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give (4-bromo-2-methanesulfonylphenyl)[4-(2-chloro-5-fluoro-4-methylphenyl)piperazin-1-yl]methanone (1.9 g). To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(2-chloro-5-fluoro-4-methylphenyl)piperazin-1-yl]methanone (1.9 g), oxazolidin-2-one (418 mg), potassium carbonate (1.7 g) and copper (I) iodide (152 mg) were added toluene (4 mL) and N,N′-dimethylethylenediamine (180 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (0.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1(=O)Cc2ccccc2C12CCNCC2
Yield: 95 %

Procedure:
170 mg (0.5 mmole) of 1'-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4'-piperidine]-2,2-dioxide [prepared as described in step (a) above] were dissolved in 3 ml of methylene chloride, and 1 ml of a 4 N solution of hydrogen chloride in dioxane was added, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling, for 1 hour, after which the crystals which deposited were collected by filtration, to give 131 mg (yield 95%) of the title compound as white crystals.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH3:15])[OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([C:15]([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])[CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:11][OH:12])([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCC(CO)(CO)CO
Reactant: CCOC(=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(=O)C(CC(CO)(CO)CO)(C(=O)C(=O)OCC)C(=O)C(=O)OCC
Yield: 106.2 %

Procedure:
A reaction vessel equipped with a stirrer, a condenser and a decanter was charged with 500 g (3.42 mol) of diethyl oxalate, 31.3 g (0.23 mol) of trimethylolpropane and 1 g (0.0053 mol) of p-toluenesulfonic acid monohydrate, and mixed at 130° C. for 5 hours. After removing 32.3 g of ethanol, it was then cooled and excess amount of diethyl oxalate was evaporated to obtain 106.1 g of crude triethoxalyltrimethylolpropane (yield 85%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(CCCCNCc2ccccc2)cc1
Product: CCOC(=O)CCN(CCCCc1ccccc1)Cc1ccccc1

Procedure:
Starting from N-(4-phenylbutyl)-N-benzylamine and ethyl acrylate, ethyl 3-[N-(4-phenylbutyl)-N-benzylamino]-propionate is obtained analogously to Example 1 and is hydrolyzed with hydrochloric acid to give 3-[N-(4-phenylbutyl)-N-benzylamino]-propionic acid hydrochloride, melting point 145°-147°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([C:32](=[O:34])[CH3:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[C:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:27][CH2:26]1)(=[O:34])[CH3:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(=O)N1CCCNCC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1-(1,4-diazepan-1-yl)ethanone (101 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (87.7 mg, 78%). 1H NMR (DMSO-d6) [1:1 ratio of rotamers: δ: 10.93 (s, 1H); 10.91 (s, 1H)], 7.99 (d, J=8.3 Hz, 2H), 7.62 (dd, 2H), [1:1 ratio of rotamers: 7.13 (s, 1H); 7.07 (s, 1H)], [1:1 ratio of rotamers: 6.19 (s, 1H); 6.18 (s, 1H)], [1:1 ratio of rotamers: 4.37 (t, J=5.6 Hz, 2H); 4.20 (t, J=5.4 Hz, 2H)], [1:1 ratio of rotamers: 4.03 (t, J=5.6 Hz, 2H); 3.97 (t, J=5.9 Hz, 2H)], 3.63-3.78 (m, 2H), [1:1 ratio of rotamers: 3.58 (t, J=5.9 Hz, 2H); 3.52 (t, J=5.8 Hz, 2H)], 2.37 (s, 3H), [1:1 ratio of rotamers: 2.03-2.11 (m, 2H); 1.94 (quin, J=5.9 Hz, 2H)], [1:1 ratio of rotamers: 2.02 (s, 3H); 1.89 (s, 3H)], 1.46 (s, 6H); ESI-MS: m/z 451.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(/C=C/c2ccccc2)nc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(C(=O)OC)c1c(C)nc(CCc2ccccc2)nc1-c1ccccc1
Yield: 99.7 %

Procedure:
To a suspension of (E)-methyl 2-(4-methyl-6-phenyl-2-styrylpyrimidin-5-yl)pentanoate (91 mg; 0.235 mmol) in ethanol (2 mL) was added 10% Pd/C. The solution was deoxygenated and back filled with a nitrogen atmosphere twice. The solution was then degassed, back filled with hydrogen gas and allowed to react at room temperature overnight. The reaction mixture was filtered using a syringe filter and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-30%) in heptane to give 91 mg of the title compound which was immediately used in the next step. ESI/APCI(+): 389 (M+H).
Reaction SMILES: [OH-].[Li+].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=1)[C:15](=[O:29])[CH2:14][CH2:13]2>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=1)[C:15](=[O:29])[CH2:14][CH2:13]2
Reactant: COC(=O)c1ccc(CN2C(=O)CCc3c(CC4SC(=O)NC4=O)ccc(OC)c32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(C(=O)O)cc1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
35 ml of an aqueous 1 N-lithium hydroxide solution was added to a mixed ethanol (200 ml) and THF (200 ml) solution of 4.0 g of 5-[8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, hydrochloric acid was added to the residue, and the insoluble matter thus formed was collected by filtration. The collected insoluble matter was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→1:3), and recrystallized from ethyl acetate, giving 3.75 g (97% yield) of 5-[8-methoxy-1-(4-carboxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2.C(O[C:14]1[O:15][CH2:16][CH2:17][N:18]=1)C.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:14]1[O:15][CH2:16][CH2:17][N:18]=1)[CH2:6]2
Reactant: CCOC1=NCCO1
Reactant: Fc1cccc2c1CNC2
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: Fc1cccc2c1CN(C1=NCCO1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoroisoindoline (400 mg), 2-ethoxy-2-oxazoline (400 mg), and β-naphthylsulfonic acid (30 mg) in 50 ml of toluene was stirred at 100° C. for 1 hour. The solvent as removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 1-4% methanol in ethyl acetate, to give 4-fluoro-2-(oxazolin-2-yl)isoindoline, a compound of Formula (IB), m.p. 125°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(OCC)(=O)C>[Br:23][CH2:24][CH2:25][CH2:26][C:27]([N:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:28]
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: O=C(Cl)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCCBr)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Yield: 93.2 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-3,4-dihydro2H-1,4-benzothiazine (1.08 g), ethyl acetate (20 ml) and aqueous sodium hydrogen carbonate solution (20 ml) is added dropwise a solution of 4-bromobutyryl chloride (0.97 g) in ethyl acetate (5 ml) with stirring under ice cooling. The ethyl acetate layer is washed, dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 4-(4-bromobutyryl)-2-(4-chlorophenyl)-3,4-dihyro-2H-1,4-benzothiazine (1.58 g, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:31])[F:32])=[CH:25][CH:26]=2)[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(C)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.135 ml of 4-(trifluoromethoxy)-benzenamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 210 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[N:33]([CH3:34])[C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:26]1[C:25]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:24][C:23]([C:29]2[N:33]([CH3:34])[C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:30]=2[CH3:39])=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)n1C
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)n1C
Temperature: 97.5 °C
Yield: 62.4 %

Procedure:
4-aminosulfonylbenzene boronic acid (0.72 g, 3.57 mmol) and potassium carbonate (0.89 g, 6.50 mmol) were added to a solution of methyl 5-(3-bromo-4-methoxyphenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (10a, 1.1 g, 3.25 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0) palladium (0.18 g, 0.16 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in DCM (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound 10b (0.84 g, 62.6%).