Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.CC(C)=O.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](=[O:22])[CH3:21]>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH2:8]([O:7][C:3](=[O:10])[CH2:21][C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH3:9]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 25 °C

Procedure:
To a vigorously stirred suspension of NaH (60% dispersion in mineral oil, 2.28 g, 56.6 mmol, 2.9 equiv.) and diethyl carbonate (4.7 mL, 38.83 mmol, 1.99 equiv.) in dry toluene (30 mL) was added drop wise (over a period of 1 h) a solution of the methyl ketone, 1-furan-2-yl-ethanone, (2.14 g., 19.51 mmol) in toluene (5 mL) under reflux. After addition, the mixture was stirred at reflux for 0.5 h. The mixture was cooled to RT and was acidified with glacial acetic acid. After adding cold water, the mixture was extracted 3 times with ethyl acetate. Combined organic extract was washed with water and brine. After drying over MgSO4, solvent was evaporated to furnish the crude β-ketoester, 3-furan-2-yl-3-oxo-propionic acid ethyl ester. To the crude product was added absolute ethanol (10 mL) and hydrazine hydrate (1 mL). The mixture was kept under reflux for 3 h. Solvent was evaporated in vacuo. The crude mass was purified by flash chromatography (EtOAc). The solid obtained was stirred in EtOAc for 15 min., filtered and dried to furnish the pyrazolone (VIb) (1.23 g, 42%). 1H-NMR (DMSO-d6) δ 12.1 (br s, 1H), 9.5 (br s, 1H), 7.64 (s, 1H), 6.63 (s, 1H), 6.51 (s, 1H), 5.64 (s, 1H). MS: 151 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15]Cl)(=[O:3])[CH3:2].[CH3:18][NH:19][CH3:20]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15][N:19]([CH3:20])[CH3:18])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)Nc1cc2c(cc1C(=O)CCl)OCO2
Product: CC(=O)Nc1cc2c(cc1C(=O)CN(C)C)OCO2

Procedure:
2'-Acetylamino-4',5'-methylenedioxy-2-chloroacetophenone, prepared in Example 1, part (B), is reacted with an excess of dimethylamine under similar conditions as taught in Example 1, part (H), to yield 2'-acetylamino-4',5'-methylenedioxy-2-dimethylaminoacetophenone which is turn is deprotected by the procedure of Example 1, part (E), to yield 2'-amino-4',5'-methylenedioxy-2-dimethylaminoacetophenone.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][OH:6])[CH3:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCC(CO)OCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCC(COS(=O)(=O)c1ccc(C)cc1)OCC

Procedure:
2-Ethoxyhexadecyl p-toluenesulfonate was prepared by treating 2-ethoxyhexadecanol (1.72 g) with p-toluenesulfonylchloride (1.5 g) in pyridine (2.3 ml) at room temperature over night. There was obtained 2.47 g of a crude product, which by thin layer chromatography was shown to contain very small amounts of impurities.
Reaction SMILES: [ClH:1].Cl.O1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Cl:30]C1[S:32]C2C=CC=CC=2N=1>>[ClH:30].[ClH:1].[S:32]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1

Procedure:
The procedure for 3-benzoxazol-2-yl-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine dihydrochloride except using 2-chlorobenzothiazole in place of 2-chlorobenzoxazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.22 (m, 2H), 2.27 (d, J=13.5 Hz, 2H), 3.07-3.18 (m, 2H), 3.43 (d, J=13.2 Hz, 2H), 4.47-4.57 (m, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.55-7.61 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 8.16 (d, J=7.7 Hz, 1H), 8.21 (br. s., 1H), 8.33 (s, 1H), 8.50 (d, J=2.2 Hz, 1H). MS (ES+): m/z=376.80 [MH+]. HPLC: tR=2.02 min (ZQ2, polar—5 min).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[N:19]1([CH2:18][CH2:17][CH2:16][C:14]2[N:15]=[C:10]([CH2:9][OH:8])[CH:11]=[CH:12][CH:13]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CCCN2CCOCC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Then, to a solution of 760 mg of 4-{3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]propyl}morpholine in 4 mL of THF at ice temperature, 4.34 mL of a solution of TBAF/THF (1 mol/L) was added dropwise. After stirring the solution at room temperature for 2 hours, the solvent was removed, and the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 495 mg of [6-(3-morpholin-4-ylpropyl)pyridin-2-yl]methanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:8]1[N:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Cc1cc2nccn2cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2ncc(Br)n2cn1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 84.7 %

Procedure:
To a solution of 7-methylimidazo[1,2-c]pyrimidine (0.3404 g, 2.56 mmol) in acetic acid (10 ml) was added sodium acetate (0.3132 g, 3.82 mmol), then, dropwise over 7 min, a solution of bromine (66.0 μl, 1.28 mmol) in acetic acid (2 ml). The solution was stirred at room temperature for 20 min, then more bromine (19.7 μl, 0.382 mmol) in acetic acid (0.6 ml) was added over 4 min. The solution was stirred at room temperature for a further 15 min, then partitioned between saturated aqueous NaHCO3 (200 ml) and ethyl acetate (200 ml). The aqueous layer (pH 9) was further extracted with ethyl acetate (200 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to afford 0.2298 g (42%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 2.57 (3H, s), 7.29 (1H, s), 7.56 (1H, s), 8.91 (1H, s); MS (ES+) m/z 212/214 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5](Br)=[CH:6][CH:7]=1.CN1C(=O)CCC1.[CH3:22][S-:23].[Na+]>O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:23][CH3:22])=[CH:6][CH:7]=1
Reactant: Cc1c(Br)ccc(Br)c1C1=NOCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
25 g (0.075 mol) of 3-(3,6-dibromo-2-methylphenyl)-4,5-dihydroisoxazole are initially charged in 12 mol of NMP. At a temperature of 100° C. and at a reduced pressure of 100 mbar, 29.3 g (0.09 mol) of a 21.5% strength methanolic solution of sodium thiomethoxide are added dropwise over a period of 40 min. The reaction mixture is stirred at 100° C. for 3 h and then stirred into 250 ml of water and extracted three times with 100 ml of toluene. The combined organic phases are washed once with 100 ml of water and then concentrated under reduced pressure. This gives 17.5 g of a dark oil. GC/MS shows, in addition to other isomers, 52.3% of the desired product. MSm/z: 287.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:19]([NH:26][CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:19]([N:26]([CH2:1][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1[nH]cnc1C=O
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1[nH]cnc1CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methyl 4-formyl-1H-imidazole-5-carboxylate (1.68 mmol, 1 equiv.) was taken up in dry THF (10 ml). Dry Na2SO4 (15.53 mmol, 9.2 equiv.) and N-benzylethanolamine (1.99 mmol, 1.18 equiv.) were added, and the mixture was stirred for 1 h at 25° C. under nitrogen. NaBH(OAc)3 (2.36 mmol, 1.4 equiv.) was then added in portions, and the reaction mixture was stirred for 16 h. Then water (5 ml) was added, and the mixture was neutralised with sat. NaHCO3 solution (10 ml). Extraction with DCM (2×20 ml) was carried out, and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 5-10% MeOH in DCM), and the desired product was thus obtained in the form of a white solid. Yield: 99%
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>CCO.N1CCCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: COc1cc(C=O)ccc1F
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)ccc1F

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (3 mL) and 4-Fluoro-3-methoxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-fluoro-3-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25].P(OP(O)(O)=O)(O)(O)=O.[OH-].[Na+]>O>[Br:1][CH:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1)=[O:14].[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Fe+2]
Agent: O=P(O)(O)OP(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(Br)CCCCCCCCCC(=O)[c-]1cccc1
Yield: 178.9 %

Procedure:
10.61 g of 11-bromoundecanoic acid, 1.86 g of ferrocene, and 50 g of pyrophosphoric acid were added and stirred while heating at 50° to 60 ° C. for 5 hours, and then poured into water, made to be basic with sodium hydroxide, subjected to extraction with methylene chloride, and dried. Then, the unreacted ferrocene was removed with column chromatography, to obtain 4.00 g of 10 -bromoundecanylferrocenyl ketone represented by the formula (C) in a yield of 92.3%. The proton nuclear magnetic resonance (1H--NMR) spectrum of the product was shown in FIG. 3. The result showed that the resulting product was the desired compound (10-bromoundecanylferrocenyl ketone). ##STR10##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1>[N:16]1([S:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:14])=[O:13])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1

Procedure:
2-(4-Nitro-phenyl)-ethanesulfonyl chloride (from Example 33 (A), 300 mg) was suspended in 5 mL of THF. To the stirring solution was added morpholine (1 mL) dropwise at r.t. After 5 hours the solvent was evaporated. The nitro product was purified by flash chromatography (CH2Cl2/CH3OH 10:1 v/v) and was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (167 mg, 52%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.01 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.72 (t, J=4.7 Hz, 4H), 3.23 (t, J=4.7 Hz, 4H), 3.11 (m, 2H), 2.98 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH:30](=O)[CH:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)C=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Product: CC(C)CN1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for example 26 using (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) and iso-butyraldehyde as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [CH3:1][C:2]([CH:4]([OH:23])[CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]\[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]/[CH2:13][O:14]C1CCCCO1)=[CH2:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:14][CH2:13]/[CH:12]=[C:11](\[CH3:21])/[CH2:10][CH2:9]/[CH:8]=[C:7](/[CH3:22])\[CH2:6][CH2:5][C:4](=[O:23])[C:2]([CH3:3])=[CH2:1]
Reactant: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C/COC1CCCCO1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0016 mol) of (6Z,10E)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol dissolved in 15 ml of methylene chloride is treated with 10 g of manganese dioxide. The suspension is stirred at room temperature for 18 hours under argon. After filtration and removal of the solvent the residue is chromatographed on silica gel with ether-hexane 10:1. The product, containing (6Z,10E)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-one, is dissolved in 10 ml of tetrahydrofuran and 2.6 ml of water and treated with 118 mg of pyridinium p-toluenesulfonate. The solution is boiled at reflux for 17 hours. After cooling 100 ml of water and 200 ml of ether are added thereto. The organic phase is neutralized with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (6Z,10E)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one which exhibits the following absorption bands in the IR spectrum: 3389 cm-1, 1675 cm-1, 1626 cm-1, 1413 cm-1, 1382 cm-1, 1000 cm-1, 948 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, 2H, J=8.4 Hz), 6.99 (d, 1H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 6.71 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4, 2.4 Hz), 4.16 (t, 2H, J=6.0 Hz), 3.21 and 3.11 (d of Abq, 2H, J=14.0 Hz), 2.98 (t, 2H, J=6.0 Hz), 2.91 (tt, 1H, J=11.4, 3.2 Hz), 2.31 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.06-2.02 (m, 2H), 1.85-1.79 (m, 2H), 1.73-1.68 (m, 1H), 1.62-1.51 (m, 2H), 1.42-1.22 (m, 3H), 1.39 (s, 3H). IR (KBr) 3500, 2935, 1735, 1612, 1513, 1249, 1178 cm−1. HRMS (ES+) m/z exact mass calcd for C30H38NO5 492.2750, found 492.2751.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[C:7]([O:19]C)(=[O:18])[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C1(C)C=CC=CC=1.[OH-].[K+:29]>CO>[C:12]([O:14][CH3:15])(=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([C:7]([O-:19])=[O:18])=[CH:9][CH:10]=1.[K+:29]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)[O-])cc1
Temperature: 67.5 °C
Reaction time: 0.5 h

Procedure:
To a three-necked 50 ml round bottom flask equipped with a mechanical stirrer, reflux condenser and an addition funnel topped with a drying tube containing indicating Drierite® were added 2.70 gm (0.0139 mole) of dimethyl terephthalate (ex Aldrich Chemical Co.) and 15 ml of toluene. A solution containing 0.76 gm (0.0136 mole) of potassium hydroxide and 10 ml of methanol was added dropwise to the diester solution. The mixture formed an immediate emulsion. The emulsion was heated to 65-70° C. and soon thereafter a precipitate began to form. After 30 minutes the reaction was complete. The mixture was cooled to room temperature and the solid collected on a Buchner funnel. The filter cake was washed several times with warm toluene and ether; thereupon the cake was dried in a vacuum oven at 60° C. The yield was 2.85 gm (96%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[N:12]([C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=1[NH2:24])[CH2:13][CH2:14][CH3:15])(C)(C)C.Cl.O1CCOCC1.CO.C(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:13][CH2:14][CH3:15])[C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=2[N:24]=1
Reactant: CCCN(C(=O)CCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCn1c(CCCN)nc2ccc(C#N)cc21
Reaction time: 0.33 h
Yield: 124.6 %

Procedure:
The compound (0.375 g) obtained in Example 46-3 was dissolved in ethyl acetate (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (1.09 ml). The whole was stirred for 20 minutes and added with methanol (8.0 ml), followed by distillating off the solvent. The concentrate was added with chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, and the aqueous layer was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off, thereby obtaining a crude product (0.314 g) containing the subject compound as an amber liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[SH:11][CH2:12][C:13]([OH:15])=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:15])[CH2:12][S:11][C:9]2=[S:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CS
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: O=C1CSC(=S)N1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 27 g. (0.16 m.) of p-chlorophenyl isothiocyanate, 33 ml. (42.5 g., 0.475 m.) of mercaptoacetic acid and 5 drops of triethylamine is heated in a pressure bottle at 120°-130°C. for 21/2 hours. The reaction mixture is allowed to stand at room temperature overnight and filtered. The crude product is recrystallized from ethanol to give 3-(4'-chlorophenyl)-rhodanine, m.p. 124.5°-126°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:26]([OH:28])=[O:27])[CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]3)[CH2:9][N:8]=[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:6]=2[CH:35]=1.[N+](=[CH2:38])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:26]([O:28][CH3:38])=[O:27])[CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]3)[CH2:9][N:8]=[C:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6]=2[CH:35]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CCN1CCN(CCO)CC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: COC(=O)C(CCN1CCN(CCO)CC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-3-[4-(2-hydroxyethyl)piperazino]propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-3-[4-(2-hydroxyethyl)piperazino]-propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C=C(OP(O)(O)=O)C(O)=O.C([O-])(=O)C(C)=O.CC(O[CH2:52][C:53]1[CH2:72][S:71][C@@H:56]2[C@H:57]([NH:60][C:61]([CH2:63][CH2:64][CH2:65][C@@H:66]([NH2:70])[C:67]([OH:69])=[O:68])=[O:62])[C:58](=[O:59])[N:55]2[C:54]=1[C:73]([OH:75])=[O:74])=O>>[CH3:52][C:53]1([CH3:72])[S:71][C@@H:56]2[C@H:57]([NH:60][C:61]([CH2:63][CH2:64][CH2:65][C@H:66]([NH2:70])[C:67]([OH:69])=[O:68])=[O:62])[C:58](=[O:59])[N:55]2[C@H:54]1[C:73]([OH:75])=[O:74]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)CCC[C@H](N)C(=O)O)C(=O)N2[C@H]1C(=O)O

Procedure:
Five μmoles of adenosine triphosphate (ATP), 10 μmoles of phosphoenol pyruvate, and 100 μgrams of pyruvate kinase were incubated for three hours at 25° C. at a pH of 7.2 with 100 μg of "LLD" and 1.0 ml of mutant M-0198 extract produced in accordance with the procedure set forth above. The reaction mixture showed the presence of antibiotic activity equivalent to 2.3 μg/ml using the β-lactam antibiotic, cephalosporin C, as standard i.e. 2.3 units/ml. One unit of antibiotic activity is that which produces the same size inhibitory zone as does 1 μg of cephalosporin C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](C([Sn](Cl)(Cl)Cl)=C(CCCC)CCCC)[CH2:15]CC.N#N>CN(C=O)C>[F:9][C:4]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:2]([CH:14]=[CH2:15])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1F
Reactant: CCCCC(CCCC)=C(CCCC)[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: CN(C)C=O
Product: C=Cc1ccc(N)c(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
4-Bromo-2-fluoro-3-trifluoromethylaniline described above (5.0 g, 19.4 mmol) and tributylvinyltin chloride (7.1 g, 20.4 mmol) are added to anhydrous DMF (100 mL). The solution is degassed with N2, palladium tetrakistriphenylphosphine (1.5 g, 1.3 mmol) is added, and the reaction is heated at 120° C. for 18 hours. After cooling, the reaction mixture is partitioned between Et2O and saturated aqueous NaCl. The separated ether layer is washed with fresh saturated aqueous NaCl (2×), dried with Na2SO4, and concentrated under reduced pressure. The residue is purified by flash chromatography eluting with 5, then 10, then 20% EtOAc in hexanes to give the desired product, 2-fluoro-3-trifluoromethyl-4-vinylaniline.