Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccco2)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b) (140 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. (Bromomethyl)benzene (170 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH (aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes). Yield 35%. MS M+H calculated 372.4, found 372.0.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:27][C:28]1[C:36]2[O:35][CH2:34][C:33](=[O:37])[C:32]=2[CH:31]=[CH:30][C:29]=1[O:38][CH3:39]>C1COCC1.O>[CH3:39][O:38][C:29]1[CH:30]=[CH:31][C:32]2[C:33](=[O:37])[CH2:34][O:35][C:36]=2[C:28]=1[CH2:27][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1CBr)OCC2=O
Reactant: CC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1CC(C(C)=O)C(C)=O)OCC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.3 %

Procedure:
A solution of acetylacetone (0.100 g, 1.00 mmol) in THF (2.5 mL) was added with a 1 M solution of tetrabutylammonium fluoride in THF (1.00 mL, 1.00 mmol) and water (1 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with a solution of 7-(bromomethyl)-6-methoxybenzofuran-3(2H)-one (0.257 g, 1.00 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added with a 1 M solution of tetrabutylammonium fluoride in THF (1.00 mL, 1.00 mmol), and the mixture was stirred at room temperature for additional 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 3[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]pentane-2,4-dione (0.0533 g, 19%).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>COCCO.[Pd]>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccnc2C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: COCCO
Product: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a solution of 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (5.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The reaction mixture was heated to 90° C. and stirred for 6 h under H2, then cooled to rt. The resulted mixture was poured into 100 mL of water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 1:2 (v/v) PE/EA) to give the title compound as colorless oil (3.00 g, 60.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 245.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.47-1.53 (m, 4H), 2.12 (s, 1H), 2.63-2.69 (m, 1H), 2.76-2.88 (m, 2H), 3.83 (d, J=8.2, 2H), 4.64 (s, 1H), 7.25-7.36 (m, 5H) ppm.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCC(NN)=O)=[O:11])[C@H:3]2[NH:22][C:23]([NH:25][C@@H:2]12)=[O:24].C(Cl)CCl.C1N(CCS(O)(=O)=O)CC[O:32]C1>CS(C)=O>[OH:32][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:25][C:23]([NH:22]2)=[O:24])[CH2:1][S:5]1)=[O:11]
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: NNC(=O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: ClCCCl
Solvent: CS(C)=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 20 h

Procedure:
Natural GAGs (NAH, HS, HA, HEP, Ch, CS-A(S), CS-A(W), CS-B, CS-C, CS-D, CS-E, and KS) were dissolved in 0.1 M MES buffer (pH 5.5) to prepare 10 mg/ml GAG solutions. 25 μl of 20 mM biotin-LC-hydrazide (manufactured by Pierce Biotechnology) dissolved in dimethylsulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 1 ml of each GAG solution. Subsequently, 12.5 μl of a 100 mg/ml EDC (manufactured by Pierce Biotechnology) solution prepared with 0.1 M MES buffer (pH 5.5) was added thereto. The mixture was mixed well, and then allowed to react with stirring at normal temperature (15° C. to 25° C.) for 16 to 24 hours. After completion of the reaction, the reaction products were dialyzed by using a dialysis membrane (cutoff molecular weight: 10,000 or less) against phosphate buffered saline (pH 7.2 to 7.5, containing no divalent ions such as calcium ion: hereinafter, referred to as “PBS(−)”) as dialysis solution, to thereby sufficiently remove free biotin. After completion of dialysis, the concentration of Bi-GAG was adjusted to 5 mg/ml, followed by freeze preservation.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[NH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>CC#N.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[NH:10][C:11]2[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cccc(CO)c2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
4-Hydroxymethyl-2-(2-nitrophenyl)-benzimidazole 3 (2.69 g, 10 mmol) was dissolved in a mixture of CH3CN/CH2Cl2 (500 mL, v/v=4:1), and then manganese dioxide (10 g, 120 mmol) was added. The solution was stirred at room temperature and monitored by TLC. Once the reaction was complete, the reaction mixture was filtered through a pad of celite. The filtrate was washed with NaHCO3, and the water phase was extracted with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. Concentration by rotary evaporation and subsequent column chromatography on silica gel using hexane/ethyl acetate (1:1) as the eluent afforded 2-(2-nitrophenyl)-benzimidazole-4-carboxaldehyde (2.2 g, 82%) as a light-yellow solid. Rf=0.38 (hexane/ethyl acetate=1:1); 1H NMR (200 MHz, CDCl3) δ 7.47 (t, J=7.6 Hz, 1H), 7.63-7.82 (m, 3H), 7.94 (d, J,=7.5 Hz, J2=1.5 Hz, 1H), 8.05 (d, J1=7.7 Hz, J2=1.6 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 10.11 (s, 1H), 11.21 (broad s, 1H); HRMS: Calcd. for C14H9N3O3 267.0644, found 267.0648.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: O
Product: CC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
2-Hydroxy-5-aminobenzoic acid (20.0 g, 0.131 mole) was suspended in water (100 ml), and acetic anhydride (15.0 ml) was added. The reaction mixture was heated to 100° C., with stirring, for 10 minutes, cooled in an ice bath, and the product was isolated by filtration. After recrystallization from water, with activated carbon, analytically pure 2-hydroxy-5-acetamidobenzoic acid (17.0 g, 67%) was obtained, m.p. 218°-220° C. Found (Calc. for C9H9NO4) C 55.10 (55.38), H 4.61 (4.62), N 7.10 (7.18).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C@@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Temperature: 63 °C

Procedure:
To a solution of N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 1c (3.96 g, 9.08 mmol) in 30 mL DMF was added 4-(2-chloroethyl)-morpholine hydrochloride (5.07 g, 27.2 mmol) and K2CO3 (3.76 g, 27.2 mmol). The solution was heated to 63° C. for 24 hours. Additional K2CO3 (1.25 g, 9.08 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (1.69 g, 9.08 mmol) was added and the mixture heated for an additional 24 hours at 63° C. The mixture was then partitioned between ethyl acetate and H2O, and the organic was washed with sat'd NaCl (3×30 mL) and dried over MgSO4. After concentration in vacuo, the residue was purified by flash chromatography (20:80 hexane/EtOAc) to afford N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl)-N-[2-(4-morpholinyl)ethyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (5.21 g): MS MH+ calc'd for C28H41N2O5S2 : 549, found: 549. HRMS calc'd for C28H41N2O5S2 : 548.2379; found: 548.2384.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:28][C:29]([O:31]CC)=[O:30])([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:28][C:29]([OH:31])=[O:30])([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1(Cc2ccc(OCCCNc3ccccn3)cc2)CCCN(C(C)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCC(CC(=O)O)(Cc2ccc(OCCCNc3ccccn3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from STEP 10 (125 mg) was dissolved in 10 ml methanol and 10 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, then acidified with trifluoroacetic acid (0.77 ml), and concentrated. The residue was purified on reverse phase HPLC using acetonitrile gradient 10-50% in 30 min to yield 90.7 mg. MS: (M+1)=426.2. 1H NMR (CD3CN) δ1.39-1.76 (cmplx bnd, 4H); 2.15, 2.07 (s, 3H); 2.12 (p, 2H); 2.14, 2.10 (d, 1IH); 2.17, 2.28 (d, 1H); 2.68, 2.75 (d, 1H); 2.73, 2.77 (d, 1H); 3.23, 3.14 (ddd, 1H); 3.11, 3.28 (d, 1H); 3.54 (t, 2H); 3.76, 3.68, (d, 1H); 3.61, 3.86 (dd, 1H); 4.08 (t, 2H); 6.82 (t, 1H); 6.85, 6.87 (d, 2H); 7.01 (d, 1H); 7.17, 7.13 (d, 2H); 7.73 (d, 1H); 7.86 (t, 1H). Note: many signals are doubled due to restricted rotation about amide bond. Two chemical shifts are listed for protons which have different shifts in the rotamers, with chemical shift of major rotamer listed first. Anal Calcd. for C24H31N3O4 plus 2.2 CF3COOH: C, 49.77; H, 5.03; N, 6.13. Found: C, 49.47; H, 5.11; N, 6.49.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2OC)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C.[CH3:25][OH:26]>[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:26][CH3:25])=[CH:19][CH:18]=2)(=[O:15])=[O:16])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CO
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccccc2OC)CCN(CC)CC1
Agent: [Na+]
Agent: [OH-]
Product: CCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209° C.; MS: 328 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ccc2c(c1)CCNC2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ccccc4C3)n2)c1

Procedure:
B40 was prepared following the general procedure reported for B10 using A1 and 1,2,3,4-tetrahydroisoquinoline; yield: 23.6 mg (6%), colorless amorphous solid. MS (ES) C19H20N6O2S requires: 396. found: 397 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:13]2[CH:7]1[CH2:8][CH2:9][CH:10]([O:14][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][CH2:12]2)=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:13]2[CH:7]1[CH2:8][CH2:9][CH:10]([OH:14])[CH2:11][CH2:12]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C2CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCC21
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1C2CCC(O)CCC21
Temperature: 25 °C

Procedure:
A solution of Example 8D (2.2 g, 5.0 mmoles) was taken in ethanol (8 mL) and 12M HCl (1 mL) was added. The reaction was stirred at room temperature for twelve hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (hexanes; ethyl acetate 100:0 to 50:50) to obtain the titled compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:16]([S:18]C)=S)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]2=[O:15])[CH:4]=1.C>C(O)C.C(#N)C>[CH3:1][NH:2][C:16]([C:9]1([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]1=[O:15])=[S:18]
Reactant: CSC(=S)C1(c2cccnc2)CCCCS1=O
Reactant: CN
Solvent: CCO
Solvent: CC#N
Product: CNC(=S)C1(c2cccnc2)CCCCS1=O
Temperature: 22 °C
Reaction time: 0.58 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (10.2 cc) is added dropwise, in the course of 5 minutes, to a solution of methyl 2-(pyridin-3-yl)tetrahydrothiopyran-2-carbodithioate 1-oxide (a single stereoisomeric form; 10.2 g) in ethanol (150 cc), kept at between 25° and 30° C. The solution is then stirred for 1 hour and 35 minutes at a temperature of about 22° C. and a further amount of 33% (weight/volume) solution of methylamine in ethanol (1.5 cc) is then added. After it has been stirred for 1 hour at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) at 40° C. The product obtained (9.8 g) is dissolved in acetonitrile (15 cc) at a temperature of about 20° C. and the solution is kept at a temperature of about 5° C. for 1 hour. The resulting crystals are filtered off, washed twice with acetonitrile (10 cc in total) and dried under reduced pressure (25 mm Hg; 3.4 kPa) at 20° C. The product obtained (3.4. g), to which 0.8 g prepared under the same conditions has been added, is dissolved in boiling acetonitrile (80 cc); the solution is treated with decolourising charcoal (0.1 g) and filtered hot and the filtrate is then cooled at a temperature of about 5° C. for 2 hours. The resulting crystals are filtered off, washed twice with acetonitrile (10 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. This gives the A form of N-methyl-2-(pyridin-3-yl)tetrahydrothiopyran-2-carbothioamide 1-oxide (3.3 g) melting at 228° C. [Rf=0.22 (chromatography on a thin layer of silica gel; solvent: ethyl acetate/methanol (80/20 by volume)].
Reaction SMILES: [CH3:1][C:2]([O:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([O:19]C2CCCCO2)[CH2:14]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:19][C@H:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([CH2:12][O:11][C:2]([CH3:10])([CH3:1])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:14]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](OC2CCCCO2)C1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](O)C1
Reaction time: 96 h

Procedure:
29 g of tert-butyl 2-methyl-2-[(1R,3S)-3-(tetrahydropyran-2-yloxy)cyclohexylmethoxy]-propionate are dissolved in 150 ml of isopropanol, and 2.3 g of toluenesulfonic acid monohydrate are added. After the toluenesulfonic acid has completely dissolved, the solution is left to stand for 4 days and then mixed with saturated sodium bicarbonate solution and partly concentrated. The residue is taken up MTBE/water, the phases are separated, the aqueous phase is extracted with MTBE, and the combined organic phases are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel with heptane/ethyl acetate 3:1, resulting in 13.8 g of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpropionate as yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.CC(N=C=NC(C)C)C.[NH2:15][C:16]1[CH:17]=[C:18]([S:22]([NH:25][C:26]2[C:35]([NH:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=3)=[N:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:23])(=[O:24])[NH:25][C:26]2[C:35]([NH:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=3)=[N:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH:17]=1)=[O:5]
Reactant: O=C(O)CBr
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)cc(OC)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)CBr)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL round-bottom flask was added 2-bromoacetic acid (1.87 g, 13.5 mmol), N,N-diisopropylcarbodiimide (860 mg, 6.8 mmol) and 10 mL DCM. To this mixture was added 3-amino-N-(3-(3,5-dimethoxyphenylamino) quinoxalin-2-yl)benzenesulfonamide (2.03 g, 4.5 mmol), prepared using procedures similar to those in Example 168. The reaction was stirred overnight at room temperature. Complete consumption of the starting aniline was confirmed by LCMS. The solvent was evaporated off to yield the crude product (2-bromo-N-(3-(N-(3-(3,5-dimethoxyphenylamino) quinoxalin-2-yl)sulfamoyl)phenyl)acetamide). This was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH3:12])([CH2:10][OH:11])[C:6]1=[O:13])=[O:4].[CH3:22][O:23][CH2:24]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:10][O:11][CH2:22][O:23][CH3:24])([CH3:12])[C:6]1=[O:13])=[O:4]
Reactant: COCOC
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCOCC1(C)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Reaction time: 0.17 h

Procedure:
1-(4-Chlorobenzyl)-3-methyl-3-hydroxymethyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XI), R1=CH3, R2=CH3, Ym=4-Cl) (186 mg, 0.60 mmol) was dissolved in methylene chloride (5.6 ml), and dimethoxymethane (2.8 ml) was added. This was cooled in a water bath, diphosphorus pentoxide (372 mg) was added and vigorous stirring was conducted at room temperature for 10 minutes. After completion of the reaction, saturated brine was combined with the reaction solution, and extraction with diethyl ether was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away and dried under reduced pressure to obtain a crude 1-(4-chlorobenzyl)-3-methoxymethoxymethyl-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (X), R1=CH3, R2=CH3, Ym=4-Cl, G=CH2OCH2OCH3) (195 mg). From this, an aliquot (188.8 mg) was dissolved in isopropanol (0.53 ml), a 2M aqueous solution of sodium hydroxide (0.53 ml, 1.12 mmol) was added, and stirring was conducted at 60 degrees C. for 1 hour. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=7:1) to obtain the desired substance as a mixture of two isomers (Isomer (a):Isomer (b)=36:65).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([NH:13]C(OC(C)(C)C)=O)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:5](=[CH:6][CH:7]=[C:8]([F:10])[CH:9]=1)[C:11]([NH2:13])=[O:12]
Reactant: COC(=O)c1cc(F)ccc1C(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(F)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-tert-butoxycarbonylaminocarbonyl-5-fluoro-benzoic acid methyl ester (4.5 g, 15.13 mmol) plus regioisomer in CH2Cl2 (25 mL) is added TFA (2.0 mL, 25.96 mmol). The reaction mixture is stirred at room temperature for 3 hours and concentrated under reduced pressure to afford 5-fluoro-phthalamic acid methyl ester plus regioisomer (2.24 g, 75%).