Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:38])([CH3:37])[CH2:7][CH2:8][CH:9]([OH:36])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[S:48](Cl)([C:51]1[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=1)(=[O:50])=[O:49]>ClCCl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:38])([CH3:37])[CH2:7][CH2:8][CH:9]([OH:36])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][S:48]([C:51]2[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OS(=O)(=O)c1ccc(C)cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(OS(=O)(=O)c1ccc(C)cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (8E,12E,14E)-7-acetoxy-3,6,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (52.3 mg, 97.4 μmol) in dichloromethane (1.0 mL) was ice-cooled, and dimethylaminopyridine (37.4 mg, 306.1 μmol) was added thereto. After stirring for about 30 min., tosyl chloride (28.6 mg, 150.0 μmol) was added and the temperature was raised to room temperature. After stirring for 4 hours, the reaction mixture was diluted with ethyl acetate (10 mL), and washed with distilled water (2 mL) for two times and with brine (2 mL). The organic layer obtained was dried over anhydrous sodium sulfate, filtered and then concentrated. The crude product was purified by medium pressure column chromatography (toluene:acetone=10:1, MERCK Lobar, LiChroprepSi 60, 4 ml/min.) and a thin layer chromatography (MERCK Silicagel 60 F254, 0.5 mm, developing solution; ethyl acetate) to obtain the title Compound (8.8 mg, 12.7 μmol, 13.0%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1CO
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
(2R,4R)-1-t-Butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) and potassium thioacetate (KSAc) are dissolved in dimethylformamide (DMF), and the mixture is stirred. The conditions for this reaction are shown in Table 1, Step A-5. The reaction mixture is diluted with ethyl acetate, and ice water is added. The organic layer is taken, successively washed with aqueous sodium hydroxide, hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2R,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].[CH:29](=O)[CH2:30][CH3:31].C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH2:29][CH2:30][CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)(C)CCN2C(C)C
Yield: 17.9 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 60.3 mg, 0.1585 mmol), propionaldehyde (36.4 mg, 0.792 mmol), sodium cyanoborohydride (49.77 mg, 0.792 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.44) to give the title compound (12.0 mg, 18%) as a solid:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:16])[C:12]([CH2:14][OH:15])=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:16])[C:12]([CH2:14][O:15][C:18]3[CH:50]=[CH:49][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:24]4=[O:48])=[CH:20][CH:19]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1ccc2nc(CO)n(C)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 85.8 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.33 g 5-isopropoxy-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 102), 0.69 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 0.38 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.85 g of the title compound, melting at 90-100° C. (softening).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:15][CH3:16])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoate (1.06 g, 3.36 mmol), THF (10 mL) and MeOH (10 mL). To the solution was added aq. LiOH (1.0 M, 5.04 mL). The mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuo, and the resulting aqueous solution was acidified with aq HCl (1.0 M) and then transferred to a separatory funnel. The solution was twice extracted with EtOAc and the combined organics were dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid as a colorless solid foam (1.00 g, 99% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[O:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:11]=1)=[O:6].C(N(CC)CC)C.N1C=CC=CC=1S(O)(=O)=O>CS(C)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH:2]=[O:1])[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc(C(=O)CCCO)oc2-c2ccc(C)cc2)cc1
Agent: O=S(=O)(O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc(C(=O)CCC=O)oc2-c2ccc(C)cc2)cc1
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of 4-hydroxy-1-[4,5-bis(4-methylphenyl)oxazol-2-yl)butan-1-one (0.78 g) and triethylamine (2 ml) in DMSO (10 ml) was added a solution of pyridinesulfonic acid (1.16 g) in DMSO (4 ml) at room temperature. After being stirred for 20 minutes at the same temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1M-HCl, water and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[4,5-bis(4-methylphenyl)oxazol-2-yl)butan-1,4-dione (0.22 g). MS (m/z): 334 (M+ +1) IR (Nujol): 1735, 1690 cm-1NMR (CDCl3, δ): 2.38 (3H, s), 2.40 (3H, s), 2.97 (2H, t, J=6.4 Hz), 3.47 (2H, t, J=6.4 Hz), 7.17-7.26 (4H, m), 7.53-7.59 (4H, m), 9.88 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:15])[CH2:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:16][C:17]1[C:22]2[NH:23][C:24](Cl)=[N:25][C:21]=2[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1>O1CCOCC1>[Br:16][C:17]1[C:22]2[N:23]=[C:24]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH2:10][C@H:11]3[CH3:15])[NH:25][C:21]=2[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1

Procedure:
A mixture of the piperazine from step (a) above (148 mg, 0.6 mmol) and 7-bromo-2-chloro-5-trifluoromethyl-1H-benzoimidazole (150 mg, 0.5 mmmol, Example 6b) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. Mp: 135-137° C. MS (ESI, pos. ion) m/z: 510 (M+1)
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH2:23]([O:25][P:26]([CH2:31][CH2:32][NH2:33])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24].[Cl:34][C:35]1[CH:36]=[C:37]([CH:51]=[CH:52][C:53]=1[Cl:54])[CH2:38][N:39]([CH3:50])[C:40]([C:42]1[CH2:43]N(C)[C:45](=[O:48])[C:46]=1[OH:47])=[O:41]>C(Cl)Cl.CCCCCC>[CH2:28]([O:27][P:26]([CH2:31][CH2:32][N:33]1[CH2:43][C:42]([C:40](=[O:41])[N:39]([CH2:38][C:37]2[CH:51]=[CH:52][C:53]([Cl:54])=[C:35]([Cl:34])[CH:36]=2)[CH3:50])=[C:46]([OH:47])[C:45]1=[O:48])(=[O:30])[O:25][CH2:23][CH3:24])[CH3:29]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CCOP(=O)(CCN)OCC
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOP(=O)(CCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OCC
Yield: 44 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and (2-aminoethyl)phosphonic acid diethylester as described in the preparation of Compound 12. Trituration with CH2Cl2/hexane gave the title compound (106 mg, 44% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (d, 1H, J=8.05), 7.35 (s, 1H), 7.10 (dd, 1H, J=8.05, J=1.47), 4.60 (s, 2H), 4.25 (s, 2H), 4.11 (m, 4H), 3.77 (m, 2H), 3.02 (s, 3H), 2.17 (m, 2H), 1.31 (t, 6H, J=7.32). HRMS (M−H) calcd for C19H24PN2Cl2O6: 477.0749. found: 477.0749.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[N:14][N:15]=[C:11]3[N:10]3[N:16]=[CH:17][N:18]=[C:9]3[C:8]=2[CH2:19][CH2:20][OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>N1C=CC=CC=1.C(Cl)Cl>[C:22]12([C:32]([O:21][CH2:20][CH2:19][C:8]3[C:9]4[N:10]([N:16]=[CH:17][N:18]=4)[C:11]4[N:12]([N:13]=[N:14][N:15]=4)[C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:33])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12)C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To a solution containing 1.4 g of 5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine-6-ethanol (0.005 mole) dissolved in 12 ml of pyridine is added 1.0 g of 1-adamantanecarbonyl chloride (0.005 mole). The reaction mixture is stirred for one hour and then allowed to stand overnight at room temperature. The reaction mixture is evaporated to dryness yielding a residue. The residue is taken up in methylene chloride, extracted with water, dried over sodium sulfate and evaporated to dryness yielding a crude product. The crude product is chromatographed on silica gel to yield 2-(5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidin-6-yl)ethyl tricyclo[3.3.1.13,7 ]decane-1-carboxylate having the structural formula ##STR25## and the azido tautomer thereof as a white solid having a melting point of 129°-130° C. and the following elemental analysis:
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C@@:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C@:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 48F (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1 H) 0.78 m, 10 H) 1.59 (s, 3 H) 2.08 m, 1 H) 2.23 (td, J=12.78, 4.60 Hz, 1 H) 7.07 m, 2 H) 7.53 m, 2 H) 7.77 (m, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 13.58 (s, 1 H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:14])[C:5](CC)(Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:15]([NH2:18])(=[S:17])[CH3:16]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[S:17][C:15]([CH3:16])=[N:18][C:4]=1[OH:14])=[O:7])[CH3:10]
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Br)(CC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(C)nc1O
Yield: 28.9 %

Procedure:
A mixture of ethyl 2-bromo-propanedioic acid diethyl ester (32.0 g, 133.2 mmol) and thioacetamide (10.0 g, 133.2 mmol) in toluene (130 ml) is refluxed for 4 h and then cooled. The insoluble material is filtered off and the filtrate is concentrated. The residue is suspended in diisopropyl ether and collected by filtration to give the 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (7.2 g, 38.5 mmol, 29%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCC.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.CCCCCC>[C:5]([C:4]1[CH:3]=[C:2]([B:14]([OH:15])[OH:13])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
In 100 ml of anhydrous tetrahydrofuran, was dissolved 20 g of 3-bromobenzonitrile. To the resulting solution, was added 37.6 ml of triisopropoxyborane under a nitrogen atmosphere. The formed solution was cooled to −78° C., and 98.3 ml of a 1.6 M solution of n-butyllithium in hexane was dropped thereinto under stirring for about 30 minutes. After stirring the resulting mixture at room temperature for 30 minutes, the mixture was then cooled to 0° C., and 220 ml of a 4 M sulfuric acid was added. The prepared solution was refluxed overnight and subsequently recooled to 0C. To the cooled solution, was added 340 ml of a 5 M aqueous solution of sodium hydroxide. The resulting solution was extracted with 200 ml of diethyl ether, and an aqueous layer was separated. To the aqueous layer, was added a 6 M hydrochloric acid until pH attained 2. The resulting mixture was extracted with 300 ml of ethyl acetate twice. The extract was dried over magnesium sulfate, and the solvent was then evaporated. The resulting crude product was recrystallized from dimethylformamide-water to provide 11.6 g (72%) of the title compound as a needlelike light-yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of 2-chloro-4-methoxybenzaldehyde (1.55 g, 9 mmol) in methanol (20 mL) was added under ice-cooling sodium borohydride (378 mg, 10 mmol) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in 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 an almost pure title compound (1.5 g, 97%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].[ClH:26]>CO.O>[ClH:26].[N:18]1([CH2:17][CH2:16][O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 70 %

Procedure:
A suspension of ester 12 (1.02 g, 3.20 mmol) in MeOH (8 mL) was treated with a solution of NaOH (150 mg, 3.75 mmol) in water (4 mL) and heated at reflux for 3 h. After cooling to room temperature, the solution was adjusted to pH 6 with 1 M HCl and the solvent was removed under reduced pressure. The residue was dissolved in MeOH, 1 M HCl was added dropwise and the formed precipitate was collected by filtration to give 13 (727 mg, 70%) as a brown solid. Purification of the residue obtained by evaporation of the mother liquor using column filtration on silica gel (MeOH, 1% conc. HCl) provided a second batch of 13 (232 mg, 22%). 1H NMR (300 MHz, DMSO-d6): δ=3.07-3.61 (m, 6 H, 2′-H2, 3″-H2, 5″-H2), 3.76-4.06 (m, 4 H, 2″-H2, 6″-H2), 4.43 (t, J=5.0 Hz, 2 H, 1′-H2), 6.98 (dd, J=8.9, 2.3 Hz, 1 H, 6-H), 7.01 (d, J=1.8 Hz, 1 H, 3-H), 7.20 (d, J=2.3 Hz, 1 H, 4-H), 7.37 (d, J=8.9 Hz, 1 H, 7-H), 11.39 (sbr, 1 H, NH+), 11.65 (s, 1 H, NH), 12.85 (sbr, 1 H, CO2H) ppm; 13C NMR (50.3 MHz, DMSO-d6): δ=51.6 (C-3″, C-5″), 54.9 (C-2′), 62.8 (C-1′), 63.1 (C-2″, C-6″), 103.9 (C-4), 106.9 (C-3), 113.5 (C-7), 115.9 (C-6), 127.0 (C-2), 129.0 (C-3a), 133.0 (C-7a), 152.0 (C-5), 162.6 (C═O) ppm; MS (70 eV, EI): m/z (%)=290 (6) [M-Cl]+, 100 (100) [CH2N(CH2)4O]+; C15H19ClN2O4 (326.78): calcd. C, 55.13; H, 5.86; found C, 54.96; H, 5.81.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.CC([O-])=[O:17].[Na+]>CO>[O:17]=[CH:3][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=O)ccc1O
Reaction time: 0.25 h

Procedure:
Metabolites of trans-ferulic acid, including the CoASH thioesters, were analysed and quantitated by HPLC using a Lichrosorb RP-18 column (20 cm×4.6 mm; Capital HPLC, Broxburn, West Lothian, UK) with a multiphasic gradient; solvent “A” was 20 mM NaOAc, adjusted to pH 6.0 and solvent “B” was MeOH; the flow rate was 1.2 ml/min; the proportion of solvent “B” rose linearly from 0% at 0 min to 10% at 15 min and thence to 50% at 40 min and 70% at 45 min, finally decreasing to 0% at 50 min. Detection was with a Spectra Focus detector (Thermo Separation Products, Stone, Staffs. UK), which permitted u/v spectral analysis of each eluting component. Typical approximate retention times were: CoASH, 3 min; vanillic acid, 7 min; trans-ferulic acid, 19 min; acetyl SCoA, 22 min; HMPHP SCoA, 29 min; vanilloyl SCoA, 31 min; vanillin, 31.5 min; trans-feruloyl SCoA, 34 min.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:6][C:7]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Yield: 87.2 %

Procedure:
About 2.05 g of compound 3a (m=6) was dissolved in a mixture of methanol (90 ml) and water (10 ml). About 1.6 g of solid potassium carbonate (K2CO3) was added and the reaction mixture was refluxed for 2.5 h. After removal of most of the methanol, 50 ml of 1N HCl was added to the reaction mixture. The precipitate formed was filtered and washed with water, yielding the phenol 4a (1.34 g, 87%).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=S)[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].[NH3:19].O=O>O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:18][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[NH:19]
Reactant: N
Reactant: Cc1ccccc1NC(=S)Nc1ccccc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Product: Cc1ccccc1NC(=N)Nc1ccccc1C
Yield: 93.2 %

Procedure:
0.1 mol of di-o-tolylthiourea, 3 mol of ammonia, and 0.1 mmol of Cu(OAc)2 are reacted in 130 g water with oxygen. The reaction temperature is 80° C. and the oxygen pressure 3 bar. Di-o-tolylguanidine is obtained in 93.2% yield after a reaction time of 3 hours.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].FC1C=CC=CC=1CBr.[CH3:16][O:17][C:18]1[C:23](C)=[CH:22][C:21]([N:25]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[C:38]([F:39])=[CH:37][C:36](F)=[CH:35][C:34]=3F)[C:28]3[CH:42]=[CH:43][CH:44]=[CH:45][C:27]=3[S:26]2(=[O:47])=[O:46])=[CH:20][C:19]=1C>CN(C=O)C>[CH3:1][O:2][C:19]1[CH:20]=[C:21]([N:25]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[F:39])[C:28]3[CH:42]=[CH:43][CH:44]=[CH:45][C:27]=3[S:26]2(=[O:46])=[O:47])[CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: O=C([O-])[O-]
Agent: Fc1ccccc1CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3ccccc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (64 mg, 0.14 mmol) was prepared from (IntA1) (67 mg, 0.20 mmol), K2CO3 (83 mg, 0.60 mmol) and 2-fluorobenzyl bromide (45 mg, 0.24 mmol) in DMF (2 mL) using the methods of (115).