Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].CC1(C)C(O)C(=O)OC1.C=O.[C-]#N>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Agent: C=O
Agent: CC1(C)COC(=O)C1O
Agent: [C-]#N
Product: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)O

Procedure:
Pantothenic acid can be prepared by chemical synthesis, or biotechnologically by fermentation of suitable microorganisms in suitable nutrient solutions. In the chemical synthesis, DL-pantolactone is an important precursor. It is prepared in a multi-stage process from formaldehyde, isobutylaldehyde and cyanide. In further process steps, the racemic mixture is separated, D-pantolactone is subjected to a condensation reaction with β-alanine, and D-pantothenic acid is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[CH2:16][CH3:17]>>[CH2:16]([O:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[CH3:17]
Reactant: CCI
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Product: CCOC1(c2ccc(I)cc2)CCOCC1

Procedure:
In the same manner as in Reference Example 2, tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (302 mg) and iodoethane (0.119 ml) were reacted to obtain 4-ethoxy-tetrahydro-4-(4-iodophenyl)-2H-pyran (269 mg).
Reaction SMILES: C1(O[N:8]=[C:9]([C:11]2[N:12]=[CH:13][N:14]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:15]=2[NH2:16])[NH2:10])CCCCC1.[C:26](=S)=[S:27]>C(N(CC)CC)C.CN(C)C=O>[CH:13]1[N:14]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:15]2[C:11](=[C:9]([NH2:10])[NH:8][C:26]([N:16]=2)=[S:27])[N:12]=1
Reactant: NC(=NOC1CCCCC1)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 65 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-cyclohexyl-oxime was dissolved in a mixture of 0.2 ml of triethylamine and 5 ml of N,N-dimethylformamide, and 0.5 ml of carbon disulfide was further added to the solution. The resulting mixture was allowed to react in an autoclave at 125° C for 5 hours under autogenous pressure (about 10 Kg/cm2) followed by working up in the same manner as described in Example 15 to obtain 0.26 g (yield, 65%) of 2-thioadenosine having a melting point of 197° C (with decomposition).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.Br[C:20]1[S:24][C:23]([C:25]2[S:26][C:27](Br)=[CH:28][N:29]=2)=[N:22][CH:21]=1.[F-].[K+]>CN(C)C=O.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:8][C:6]([C:20]1[S:24][C:23]([C:25]2[S:26][C:27]([C:6]([O:8][CH2:9][CH3:10])=[CH2:7])=[CH:28][N:29]=2)=[N:22][CH:21]=1)=[CH2:7])[CH3:10]
Reactant: Brc1cnc(-c2ncc(Br)s2)s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc(-c2ncc(C(=C)OCC)s2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.425 mL, 1.26 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (21.5 mg, 0.031 mmol) were added to a stirred solution of 5,5′-dibromo-2,2′-bithiazole (200 mg, 0.613 mmol) in dimethylformamide (4 mL) under nitrogen. The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled, diluted with ether and aqueous potassium fluoride (0.5 g in 5 mL of water). The mixture was vigorously stirred for 1 h at room temperature, both phases were filtered through CELITE® and then separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0 to 30% ethyl acetate in hexanes) to yield 5,5′-bis(1-ethoxyvinyl)-2,2′-bithiazole (181 mg, 0.587 mmol, 96% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2cccs2)c1Br
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (1 77 mg, 1.0 mmol) in dry tetrahydrofuran (THF, 2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1 ml) at 0-5° C. After stirring at 0-5° C. for 5 min., the reaction was stirred at room temperature for 10 min to complete the reaction. The reaction mixture was re-cooled to 0° C. and thiophene-2-sulfonyl chloride (200 mg, 1.1 mmol) dissolved in dry THF (2 ml) was added dropwise. Stirring was continued for 1 h; during this period the reaction mixture slowly attained ambient temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was adjusted to 10-11 by adding 5 N sodium hydroxide solution, and was extracted with ethyl acetate (3×10 ml) to remove the neutral impurities. The aqueous layer was acidified with concentrated HCl (pH 2-3) and extracted with methylene chloride (3×10 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide. The pure material was obtained by recrystallization using hexanes/ethyl acetate (110 mg, 34% yield), m.p. 125-127° C.
Reaction SMILES: [P:1]([O-:9])([O-:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[OH-].[Na+:11].C1[O:14][CH:13]1[CH2:15][OH:16].O1C[CH2:18]1>>[P:1]([O-:9])([O-:8])([O:3][CH:4]([CH2:5][CH2:6][CH2:7][CH3:18])[CH:13]([CH2:15][OH:16])[OH:14])=[O:2].[Na+:11].[Na+:11]
Reactant: OCC1CO1
Reactant: CCCCOP(=O)([O-])[O-]
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(OP(=O)([O-])[O-])C(O)CO
Temperature: 70 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
20 g (0.13 moles) of monobutyl phosphate having a purity of 99% (AV1=360.6, AV2=721.3) was charged into a reactor, to which 129 ml of 1N sodium hydroxide aqueous solution was added and agitated, followed by heating to 70° C. to make a uniform system. At this moment, the acid value of the reaction system was 46.7. While keeping the reaction system at 70° C., 42.7 g of glycidol (the oxirane value=683.7) was gradually dropped, followed by agitation at the temperature for 6 hours, at which the acid value of the reaction system was approximately zero, revealing that the conversion of phosphoric monoester was almost 100%. The reaction product was isolated from the reaction solution by HPLC and the solvent was distilled off under reduced pressure, thereby obtaining 26.5 g of sodium butylglyceryl phosphate (yield: 81.5%).
Reaction SMILES: [CH2:1]([CH2:4][NH:5][CH2:6][CH:7]([C:9]1([OH:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])[CH:2]=[CH2:3].[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([O:21][C:9]1([CH:7]([CH3:8])[CH2:6][NH:5][CH2:4][CH2:1][CH:2]=[CH2:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:24])[CH3:23]
Reactant: C=CCCNCC(C)C1(O)CCCCC1c1ccccc1
Reactant: CC(=O)Cl
Product: C=CCCNCC(C)C1(OC(C)=O)CCCCC1c1ccccc1

Procedure:
The procedure of Example I(c) is followed using 4.8 g of 1-(2-Allylmethylamino-1-methylethyl)-2-phenylcyclohexanol and 13 ml acetyl chloride to give 3.2 g pure product.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:21][C:22]([OH:24])=O)[C:9]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:41][C:42]([NH2:44])=[NH:43].C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:21][C:22]([NH:43][C:42]([NH2:44])=[NH:41])=[O:24])[C:9]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)N
Reactant: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)NC(=N)N)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 145.2 %

Procedure:
To a solution of 0.91 g (2.8 mmol) [2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetic acid in 28 mL anhydrous DMF was added 2.27 g (14 mmol) carbonyldiimidazole. The reaction was stirred at room temperature for 50 min, upon which time was added 2.52 g (14 mmol) guanidine carbonate, 0.17 g (1.4 mmol) 4-dimethylaminopyridine, and 2.83 g (28 mmol) triethylamine. The reaction was stirred at room temperature over 16 hr. The solution was filtered to remove the precipitate that formed, was diluted with ethyl acetate, and was washed three times with brine. Drying over MgSO4 and concentration afforded 1.49 g of N-{2-[2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetyl}-guanidine as a yellow-brown oil. The product was observed to contain DMF by 1H NMR. However, it was used in the next step without further purification.
Reaction SMILES: [O-][CH2:2]C.[Na+].[Na].C(C(CC)C([NH:11][CH:12]([C:16]([O-:18])=[O:17])[C:13]([O-:15])=O)=O)C.BrCC[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH3:2][O:18][C:16](=[O:17])[C@@H:12]([CH2:13][O:15][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:11]
Reactant: CCC(CC)C(=O)NC(C(=O)[O-])C(=O)[O-]
Reactant: CC[O-]
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COC(=O)[C@H](N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A solution of sodium ethoxide was generated by the addition of sodium metal (52.89 grams, 2.3007 mol) over 3 hours to ethanol (1500 mL). To the sodium ethoxide solution at ambient temperature was added a solution of diethylacetamidomalonate (499.75 grams, 2.3007 mol) dissolved in ethanol (225 mL). The reaction mixture was stirred for 1.5 hours at ambient temperature. 1-bromo-3-phenylpropane (458.07 grams, 2.3007 mol) was added over 15 minutes and the reaction mixture was refluxed until complete as determined by hplc (16 hours). The reaction mixture was concentrated to dryness and the residue partitioned between ethyl acetate (1×1500 mL and 2×500 mL) and water (1500 mL). The ethyl acetate layers were combined, washed with saturated sodium chloride solution (4×500 mL), dried using sodium sulfate, and concentrated to give 752.1 grams (98%) of the desired compound as a light yellow solid. A 1.0 gram sample was recrystallized from hexane:ethyl acetate (19:1, v:v) to give a mp 84-86° C. 1H nmr (CDCl3): δ1.18-1.23 (t, 6H), 1.37-1.50 (m, 2H), 2.02 (s, 3H), 2.34-2.41 (m, 2H), 2.58-2.62 (t, 2H), 4.16-4.24 (q, 4H), 6.76 (s, broad, 1H), 7.11-7.28 (m, 5H). 13C nmr (CDCl3): δ13.95, 23.03, 25.67, 31.85, 35.45, 62.46, 66.49, 125.40, 125.90, 128.27, 128.35, 141.77, 168.11, 168.94. MS (FIA) m/z 336.3 ([M+H]+). IR (KBr, cm−1) 1645.98 (amide), 1744.76 (C=O). Anal. Calcd. for C18H25NO5: C, 64.46; H, 7.51; N, 4.17. Found: C, 64.60; H, 7.37; N, 4.39.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[C:8](/[CH:11]=[C:12]2\[N:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14](=[O:21])[N:15]([CH2:18][O:19][CH3:20])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[OH-:37].[Na+].CO.Cl>C1COCC1>[CH2:2]([C:6]1[N:7]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=2)[C:8](/[CH:11]=[C:12](\[N:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]([NH:15][CH2:18][O:19][CH3:20])=[O:21])/[C:16]([OH:17])=[O:37])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(COC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ncc(/C=C(/C(=O)O)N(CCCC)C(=O)NCOC)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[3-butyl-1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate monohydrochlorde. (0.100 g, 0.193 mmol) in THF was added 1N NaOH (0.22 mL, 0.22 mmol) and then methanol (2 mL). The yellow solution was stirred for 1.5 hours and then 1N HCl (0.22 mL, 0.22 mmol) was added. The reaction mixture was evaporated in vacuo to a white solid. This solid was dissolved in ethyl acetate and water. The organic layer was dried briefly over MgSO4 and then concentrated to 1/6 original volume. An equal volume of hexane was added and the solid collected.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:8]2.[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.O>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: Cc1ccc(CNc2ccc3c(CCl)cccc3n2)o1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2ccc3c(CS(=O)(=O)c4ccc(Cl)cc4)cccc3n2)o1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(5-Chloromethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (55 mg, 0.192 mmol) were dissolved in 1 mL dimethylformamide and 4-chlorobenzenesulphinic acid sodium salt (47 mg, 0.237 mmol) was added. The reaction mixture was stirred at 60° C. for 3 h. Water was added until a suspension was formed and the mixture was stirred for 15 min. The solid was filtered off and dried. The title compound was obtained as a brown solid (53 mg, 65%), MS: m/e=427.4 (M+H+).
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[CH3:41])[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[CH3:41])[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:30])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3C)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1C)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Yield: 88.8 %

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chloro-2-methylphenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate (60 mg, 0.10 mmol, 1 equ.) was dissolved in methanol/tetrahydrofuran (2/1) (0.8 ml). A solution of sodium hydroxide (12 mg, 0.30 mmol, 3 eq.) in water (0.3 ml) was added and reaction mixture heated to 40° C. for 2 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[acetyl(4-chloro-2-methylphenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid (50 mg, 89%).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1.[C:17](O)(=O)[CH3:18].[H][H]>O>[CH2:17]([NH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:18]
Reactant: [H][H]
Reactant: Nc1ccc2nc(S(N)(=O)=O)sc2c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCNc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (378 mg, 0.01 mole) and 6-amino-2-benzothiazolesulfonamide (459 mg, 0.002 mole) are ground together, then added very slowly over 1 hr. to glacial acetic acid (5 ml.) with stirring under nitrogen at 20° C. After the vigorous evolution of hydrogen has subsided, the reaction mixture is stirred at 20° C. for 3 hrs, treated with H2O, filtered, and made basic with 10N NaOH solution. Neutralization with aqueous HCl followed by extraction with EtOAc and concentration to dryness gives 6-ethylamino-2-benzothiazolesulfonamide. ##STR11## NMR (d6 -DMSO) δ1.21 (3H, t, CH3CH2 --), 3.11 (2H, q, CH3CH2), 3.44 (1H, br s, NH), 6.94 (1H, dd, J=9 Hz, J=3 Hz, Hb), 7.11 (1H, d, J=3 Hz, Hc), 7.79 (1H, d, J=9 Hz), Ha), 8.07 (2H, br s, SO2NH2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[CH2:14]C(C)(C)N[C:17](=O)[C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+].[OH2:40]>C1COCC1>[CH3:5][C:6]1([CH3:23])[NH:7][C:14](=[O:40])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([C:28]5[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: O
Reactant: CC1(C)Cc2sc(N3CCOc4ccc(Br)cc43)nc2C(=O)N1
Reactant: Cc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Temperature: 25 °C
Yield: 29 %

Procedure:
A stirred solution of Example 39 (0.090 g, 0.23 mmol), 2-methylpyridine-5-boronic acid (0.094 g, 0.69 mmol), Na2CO3 (0.073 g, 0.69 mmol) and tetrakis-(triphenylphosphine)palladium(0) (0.026 g, 0.02 mmol) in THF (3 mL) was heated to 160° C. under microwave irradiation for 30 minutes. After cooling to r.t., water (10 mL) was added and the resulting precipitate filtered off, washed with water (3×20 mL) and dried in vacuo. The solid was then triturated with EtOAc (3×20 mL) and DCM (2×20 mL), then concentrated in vacuo to give the title compound (0.027 g, 29%) as an off-white solid. δH (CDCl3) 8.71 (1H, d, J 2.3 Hz), 8.22 (1H, d, J 2.1 Hz), 7.75 (1H, dd, J 8.1 and J 2.4 Hz), 7.29 (1H, dd, J 7.9 and J 2.3 Hz), 7.22 (1H, d, J 7.9 Hz), 7.05 (1H, d, J 8.5 Hz), 5.30 (1H, br. s), 4.43-4.37 (2H, m), 4.22-4.16 (2H, m), 2.89 (2H, s), 2.60 (3H, s), 1.40 (6H, s). LCMS (ES+) 407.0 (M+H)+, RT 1.99 minutes (Method 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27]=[C:28]1[O:32][C:30](=[O:31])[CH2:29]1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:30](=[O:31])[CH2:29][C:28]([CH3:27])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: C=C1CC(=O)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.41 g) synthesized in Example 303-2 was dissolved in N,N-dimethylformamide (43 mL), and diketene (0.75 g) was added dropwise under ice-cooling. After warming to room temperature, the mixture was stirred for one hour. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.4 g) as a colorless oil. The present compound was used in the next step without particular purification. The present compound (1.0 g) was dissolved in ethanol (10 mL), hydrazine monohydrate (0.103 g) was added thereto at room temperature, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), diphosphorus pentasulfide (0.459 g) and sodium carbonate (0.437 g) were added thereto, and the mixture was heated under reflux for 2 hr. The solvent was evaporated, and the residue was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 1:2) to give the title compound (0.54 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:10]=2[N:11]=1.[C:20](=O)([O-])O.[Na+].CI>CN(C)C=O.CCOCC>[F:19][C:2]([F:1])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:20])=[O:17])=[CH:12][C:10]=2[N:11]=1
Reactant: O=C(O)c1ccc2oc(SCCC=C(F)F)nc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(SCCC=C(F)F)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To a stirred solution of 2-(4,4-difluorobut-3-enylthio)benzoxazole-5-carboxylic acid (400 mg) in dimethylformamide (5 cm3) was added sodium hydrogen carbonate (224 mg) and methyl iodide (284 mg). The reaction mixture was stirred at the ambient temperature for 1 hour. The reaction mixture was filtered through High-flo to remove solid material and the filtrate evaporated to give a yellow oil. This oil was taken up in ether and washed with water. The ether was dried (MgSO4) and evaporated to give a yellow oil when crystallised on standing. Recrystallisation from hexane gave methyl 2-(4,4-difluorobut-3-enylthio)benzoxazole-5-carboxylate as a white solid (31 mg). 1H NMR (CDCl3): δ8.29(1H,d); 8.03(1H,dd); 7.48(1H,d); 4.32(1H,ddt); 3.94(3H,s); 3.36(2H,t); 2.58(2H bq).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]([N:13]1[C:17]2=[N:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:16]2[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH:11]([N:13]1[C:17]2=[N:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:16]2[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:12]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCNC(=O)OC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCN)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 129.9 %

Procedure:
To a solution of diethyl 1-{4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (1.20 g, 2.77 mmol) in CH2Cl2 (16 mL) is added TFA (4 mL). The mixture is stirred at room temperature for 3 hr. The mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4) and concentrated in vacuo to afford the title compound (1.20 g, >99%) which is used in the next step without purification. LCMS: 334.75 (M+H+).