Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.CO.[C:17]([O-])([O-])=O.[Ca+2]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH3:17][O:13][C:11](=[O:12])[CH2:10][CH2:9][C:8]([O:3][CH:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])=[O:14]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)C(C)O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CCC(=O)OC(C)C(=O)OC
Temperature: 70 °C

Procedure:
Methyl lactate (14 mL, 0.147 moles), succinic anhydride (14.76 g, 0.147 moles), and 2 drops of concentrated sulfuric acid were mixed and heated to 70° C. for five hours. An NMR spectrum of a sample of the cooled reaction mixture showed quantitative conversion to succinic acid (ethyl-1-methoxycarbonyl) ester. Methanol (30 mL) and chloroform (20 mL) were added and heated to reflux in a soxhlet extractor containing silica gel in the receiver. The solution was refluxed for three hours, neutralized with CaCO3, filtered, and the volatile solvents removed under vacuum. The isolated yield of (i) was 29.56 g (98.5%).
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:43][O:44][CH3:45])[C:17]([NH:19][C@@H:20]2[C:41](=[O:42])[N:22]3[C:23]([C:38]([O-:40])=[O:39])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:37])[C:30]([NH:34]C=O)=[C:31]([CH3:33])[CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=O.Cl.C(OCC)C>CO>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:43][O:44][CH3:45])[C:17]([NH:19][C@@H:20]2[C:41](=[O:42])[N:22]3[C:23]([C:38]([O-:40])=[O:39])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:37])[C:30]([NH2:34])=[C:31]([CH3:33])[CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(C)c(NC=O)n3C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOCC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(C)c(N)n3C)CS[C@H]12)c1csc(N)n1
Reaction time: 4 h
Yield: 28.3 %

Procedure:
To a solution of trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2,4-dimethyl-3-formamido-1-pyrazolio)methyl-3- cephem-4-carboxylate (syn isomer) (3 g) in methanol (15 ml) was added concentrated hydrochloric acid (1.57 ml) at ambient temperature. After being stirred at the same temperature for 4 hours, the reaction mixture was added dropwise to diethyl ether, and the resulting precipitate was collected by filtration. The precipitate was dissolved in water, and the solution was adjusted to pH 2 with aqueous 5% sodium bicarbonate solution and subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20". The desired compound was eluted with aqueous 5% isopropyl alcohol solution. The objective fractions were collected and the isopropyl alcohol was evaporated. The resulting aqueous solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-amino-2,4-dimethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (763.5 mg).
Reaction SMILES: [CH3:1][I:2].[C:3]1([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[I-:2].[C:3]1([N+:9]2[N:10]=[CH:11][N:12]([CH3:1])[CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-n2cncn2)cc1
Reactant: CI
Solvent: CC#N
Product: Cn1cn[n+](-c2ccccc2)c1
Product: [I-]
Temperature: 80 °C
Yield: 41 %

Procedure:
Methyl iodide (0.13 ml; 2 mmol) is added to a solution of 1-phenyl-1,2,4-triazole—which was obtained according to Antilla, J. C. et al., Journal of Organic Chemistry 2004, 69, 5578-5587—(0.15 g; 1 mmol) in 1 ml of acetonitrile. This mixture is heated at 80° C. for 16 hours, and is then evaporated to dryness. The residue obtained is recrystallized from a minimum amount of ethyl acetate, thus making it possible to obtain 0.12 g of the desired product (41%) whose characteristics are the following:
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:20]([NH2:23])(=[S:22])[CH3:21].C(Cl)Cl.CCCCCC>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]2[S:22][C:20]([CH3:21])=[N:23][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CSc1ccc(C(=O)C(Br)c2ccc(F)cc2)cc1
Reactant: CC(N)=S
Solvent: CCO
Solvent: CCCCCC
Solvent: ClCCl
Product: CSc1ccc(-c2nc(C)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl) ethanone from Step 2 (0.70 g, 2.10 mmol) in ethanol (20 mL) in a 50 mL round bottom flask was added thioacetamide (0.16 g, 2.10 mmol) and the mixture heated to reflux for 20 hours. The reaction was cooled to room temperature and concentrated in vacuo and dissolved in methylene chloride. This solution was washed with NaHCO3 saturated solution and dried over Na2SO4, filtered and reconcentrated in vacuo yielding a white crystalline solid. Flash chromatography of this solid (2:1 methylene chloride: hexane) yielded 5-(4-fluorophenyl)-4-(4-methylthiophenyl) -2-methylthiazole as a white solid (0.45 g, 68%): mp 104°-105° C. 1H NMR (CDCl3) 400 mHz δ7.39 (d, J=8.32, 2H), 7.28 (dd, J=8.80, 5.14, 2H), 7.15 (d, J=8.32, 2H), 7.00 (t, J=8.80, 2H), 2.74 (s, 3H), 2.47 (s, 3H). MS (EI): m/z 316 (M+H). HRMS Δ=0.000 mmu.
Reaction SMILES: [N+:1]([CH:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([O-:3])=[O:2].[CH3:15][OH:16]>O>[CH3:15][O:16][C:12]1([CH2:4][N+:1]([O-:3])=[O:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[O:13]1
Reactant: O=C1c2ccccc2C(=O)C1[N+](=O)[O-]
Reactant: CO
Solvent: O
Product: COC1(C[N+](=O)[O-])OC(=O)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2-nitroindane-1,3-dione (22.3g., 0.117 moles) and methanol (100 ml) was heated under reflux for 4 hours, cooled, poured into water (1 liter), allowed to stand overnight then filtered. The solid was extracted with 5% sodium bicarbonate solution (200 ml). The insoluble material was filtered off, dried, and recrystallised from ethanol to give the Ψ-ester, 3-methoxy-3-nitromethylphthalide, m.p. 113°-114°. Acidification of the sodium bicarbonate filtrate, filtration and recrystallisation from ethanol gave the α-methyl ester, 2-methoxycarbonyl-ω-nitroacetophenone, m.p. 108°-9°.
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)\[C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:13]([CH2:16]I)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[CH3:61][S:62][C:63]1[S:64][CH:65]=[CH:66][N:67]=1>C(Cl)Cl.C(Cl)(Cl)Cl.[B-](F)(F)(F)F.[Ag+]>[NH2:41][C:38]1[S:39][CH:40]=[C:36](/[C:5](=[N:4]/[O:3][CH2:1][CH3:2])/[C:6]([NH:8][CH:9]2[C:34](=[O:35])[N:11]3[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][N+:67]4[CH:66]=[CH:65][S:64][C:63]=4[S:62][CH3:61])[CH2:14][S:15][C@H:10]23)=[O:7])[N:37]=1
Reactant: CSc1nccs1
Reactant: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccsc3SC)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 145.6 %

Procedure:
To an ice-cooled solution of diphenylmethyl 7-[(Z)-2-(ethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VII-2] (517 mg, 0.55 mmole) and 2-methylthiothiazole (85.3 mg, 0.65 mmole) in CH2Cl2 (10 ml) was added AgBF4 (117 mg, 0.60 mmole) and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with CHCl3 (100 mL), and the resulting precipitate was recovered by filtration and washed with CHCl3 (100 mL). The filtrate and the washings were combined and washed with water, dried over MgSO4 and evaporated. The residue was triturated with ether (50 mL) to give an amorphous solid (433 mg), which was dissolved in 90% TFA. The mixture was allowed to stand for 45 minutes at room temperature and then evaporated in vacuo at 10° C. The residue was triturated with ether to give crude Id (291 mg) which was dissolved in a small amount of methanol and passed through an HP-20 (20 mL) column by eluting with 30% aqueous methanol, to give 63.3 mg (29%) of the title compound [Id]. Estimated purity 70%.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]#[N:10])[CH2:3]1.[CH2:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH2:13].C([BH3-])#N.[Na+]>>[CH2:15]([N:14]([CH2:11][CH:12]=[CH2:13])[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]#[N:10])[CH2:3]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CCNCCCCCCC
Reactant: N#CC1CCCCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C=CCN(CCCCCCC)C1CCCCC(C#N)C1

Procedure:
In a manner similar to Preparation 8, react 3-oxocycloheptanecarbonitrile with N-(2-propenyl)heptanamine and sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]#N)[C:7]1=[O:15].S(=O)(=O)(O)[OH:21].[OH2:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]([OH:21])=[O:25])[C:7]1=[O:15]
Reactant: O
Reactant: Cc1ccn(Cc2ccc(Cl)c(Cl)c2)c(=O)c1C#N
Reactant: O=S(=O)(O)O
Product: Cc1ccn(Cc2ccc(Cl)c(Cl)c2)c(=O)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 11.5 g. (0.039 mole) of 1-(3,4-dichlorobenzyl)-3-cyano-4-methylpyrid-2-one in a mixture of 50 ml. of water and 100 ml. of conc. sulfuric acid heated overnight on a steam bath. Addition of the reaction mixture ot 3.1 of ice water results in the precipitation of product which is collected by filtration, washed with water and air dried at 40°-50° C. for 18 hr. to give 11 g. (90%) of product as a tan solid:m.p. 219°-221° C.; ν1710 cm. -1 (C=O); 8.19 (d, 1H, H6), 7.2-7.8 (m, 3H, phenyl protons), 6.59 (d, 1H, H5), 5.26 (s, 2H, benzyl methylene) and 2.51 (s, 3H, methyl).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH:22]1[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=S1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCS(=O)CC1
Yield: 37 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and thiomorpholine 1-oxide and purified by flash chromatography (ethyl acetate), yield 37%. White crystals, m.p. 156-157° C.; 1H NMR (CDCl3)δ 8.47-8.40 (s-like, 1H), 7.94-7.87 (dd-like, 1H), 7.24-7.13 (m, 4H), 7.06-6.99 (d-like), 4.31-3.91 (m, 4H), 2.97-2.87-2.75 (m, 2H+2H); IR (KBr): ν 1710 (C═O) cm−1.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.NCCO[CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[N:27]([CH2:30][CH2:31][CH2:32][NH:33][C:34]1[N:39]=[C:38](Cl)[N:37]=[C:36]([NH:41][CH2:42][CH2:43][OH:44])[N:35]=1)=[N+:28]=[N-:29]>C1COCC1>[N:27]([CH2:30][CH2:31][CH2:32][NH:33][C:34]1[N:35]=[C:36]([NH:41][CH2:42][CH2:43][OH:44])[N:37]=[C:38]([NH:3][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[N:39]=1)=[N+:28]=[N-:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: [N-]=[N+]=NCCCNc1nc(Cl)nc(NCCO)n1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOCCNc1nc(NCCO)nc(NCCCN=[N+]=[N-])n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
DIPEA (142 mg, 1.10 mmol), tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (273 mg, 1.10 mmol), and 2 (150 mg, 0.55 mmol) were dissolved in THF (5 mL). The mixture was stirred at 70° C. under N2 overnight. The solvent was removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent CH3OH/CH2Cl2=2/98) to give 3 as a white solid (124 mg, 47%): ESI-MS m/z 485.2 (M+H+) calculated for C19H37N10O5 485.3.
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19]N>CO.C(O)(C)=O.Cl>[Cl:18][C:16]1[CH:15]=[C:14]2[C:13](=[C:12]([Cl:11])[CH:17]=1)[NH:19][C:2]1[C:1](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: O=C1CCCCCC1=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 60 °C
Yield: 9.4 %

Procedure:
Cycloheptane-1,2-dione (1 g, 7.9 mmol) was dissolved in MeOH (25 mL) and (2,4-dichlorophenyl)hydrazine hydrochloride (1.86 g, 8.7 mmol) in AcOH—HCl (3.5:1, 45 mL) was added and heated to 60° C. for 18 h. MeOH was removed in vacuo, the reaction mixture was basified with aqueous NaHCO3 (pH-8) and then extracted with EtOAc (3×25 mL), The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatograph [EtOAc-hexane (9:1) as eluant] to give the title compound (0.2 g, 9.4%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.0 (br s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 3.11 (t, J=12.0 Hz, 2H), 2.90 (t, J=11.8 Hz, 2H), 2.13-2.20 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:21])=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH:41]=1)#[N:25]
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.63 g (2.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=615 ([M+H]+, 14), 229 (100), 109 (96); IR (KBr): 2167 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 65°-68° C. (ethanol/ether).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH2:31][CH:30]([C:32](Cl)=[O:33])[O:29][N:28]=2)[CH:22]=1>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH2:31][CH:30]([C:32]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:33])[O:29][N:28]=2)[CH:22]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CC(c2cccnc2)=NO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of 4-aminobenzoic acid (0.020 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine, (0.020 mol) in CH2Cl2 (100 ml) was cooled to 0° C. (±)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarbonyl chloride monohydrochloride (0.020 mol) was added. The resulting brown suspension was stirred overnight. The precipitate was filtered off, washed with CH2Cl2, then dried. The filtrate was evaporated under reduced pressure. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was stirred in methanol, filtered off, then dried, yielding 2.3 g of (±)-4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]benzoic acid (interm. 19).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[C:22]=1[C:23](O)=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[C:22]=1[C:23]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:24]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1c(F)cccc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.4 g, 1.549 mmol), 2-fluoro-6-iodobenzoic acid (0.374 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 507 (M+H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].[OH-].[K+].Cl.[C:29]([O-])([O-])=O.[K+].[K+].C(I)C>CN(C=O)C.O>[F:25][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH2:24][CH3:29])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Yield: 775.4 %

Procedure:
A mixture of 4.1 g (0.001 mol) of product of Example 76, 0.62 g (0.011 mol) of KOH and 5 ml of H2O overnight. The reaction mixture was poured into 250 ml of H2O containing 50 ml of concentrated HCl, extracted with ether, dried (mgSO4) and concentrated in vacuo to 3.76 g of yellow air. This oil, 152 g (0.011 mol) of K2CO3 and 0.88 ml (0.011 mol) of ethyl iodide in 30 ml of DMF was stirred at room temperature overnight. The reaction mixture was poured into water extracted with ether, drid (MgSO4) and concentrated in vacuo to 3.64 g of yellow oil. Kugelrohr distillation at 53 Pa, pot temperature 103° C., afforded 2.98 g (70.5%) of product sa a light yellow oil which solidified; mp 37°-39° C.
Reaction SMILES: C[C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][OH:5].B(F)(F)F.CC[O:28][CH2:29][CH3:30].[OH2:31]>O1CCOCC1>[CH3:21][C:9]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH2:19][CH2:7][CH2:8][CH:9]([CH3:21])[CH3:10])=[CH:8][CH2:7][C:6]1[C:2]([OH:31])=[CH:3][C:4]([OH:5])=[CH:30][C:29]=1[OH:28]
Reactant: O
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1COCCO1
Product: CC(=CCc1c(O)cc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Yield: 32 %

Procedure:
3,7,11,15-Tetramethyl-2-hexadecen-1-ol (14.8 g;50 mmole) in dioxane (10 ml) was dropwise added to 16.2 g (100 mmole) of 1,3,5-benzenetriol·dihydrate and 4.3 g (30 mmole) of boron trifluoride ethyl etherate in dioxane (35 ml) at room temperature over one hour. After stirring the resulting reaction solution at that temperature overnight, it was further stirred at 50° C. for additional 3 hours, then poured into 150 ml of water and was extracted with 150 ml of isopropyl ether. The extract was washed twice with 150 ml of water and once with 150 ml of saturated aqueous solution of sodium chloride followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resultant residue to silica gel column chromatography. Thus, 6.4 g of the title compound was recovered from the fractions eluted with hexane-ethyl acetate (2:1). Yield=32%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:13](=[O:14])[CH2:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].CN([CH:18]=[O:19])C>>[O:8]=[C:7]1[NH:9][C:10](=[O:11])[CH:12]([CH:18]=[O:19])[C:13](=[O:14])[NH:6]1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1C(=O)NC(=O)NC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
9.03 ml of phosphoryl chloride are added dropwise to 2 ml of dry DMF with ice-cooling. 1.5 g of barbituric acid are subsequently added, and the mixture is stirred at 100° for 4 h. The mixture is cooled, poured into ice-water, the precipitate is separated off, rinsed with water and dried at 45°, giving 2.5 g of “1”.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-c2ccccc2)cc1NC(=O)c1ncc[nH]1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a suspension of 0.31 g of imidazole-2-carboxylic acid (2.76 mmol) in 14 ml DMF was added 0.448 g of CDI (2.76 mmol), 0.38 ml triethylamine (2.76 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 0.5 g of 5-phenyl-o-anisidine (2.5 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with methylene chloride. The combined organic phases were tried on sodium carbonate, evaporated and the residue was stirred in hot ethyl acetate. After filtration and drying, 0.11 g 1H-imidazole-2-carboxylic acid (4-methoxy-biphenyl-3-yl)-amide (14%) were obtained as a light yellow solid; M.p.: 276° C. 0.1 g of 1H-Imidazole-2-carboxylic acid (4-methoxy-biphenyl-3-yl)-amide (0.36 mmol) was taken up in toluene (5.0 ml) and treated with 0.435 g of Lawesson reagent (1.0 mmol). The reaction mixture was heated to reflux for 16 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with dichloro methane. The combined organic phases were dried on sodium carbonate, evaporated and the residue triturated in methanol. 0.08 g of 1H-imidazole-2-carbothioic acid (4-methoxy-biphenyl-3-yl)-amide (73%) were obtained as a yellow solid; M.p.: 223–226° C.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCCO2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCCO2
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (11.58 g) in 1,4-dioxane/water (600 ml/180 ml), cooled in ice, was treated with an aqueous solution of osmium tetroxide (4% w/v, 25 ml) and sodium periodate (43 g). This mixture was allowed to warm to room temperature and after 7 hours under stirring the mixture was evaporated to dryness and azeotroped with 1,4-dioxane. Silica gel, 1,4-dioxane and chloroform were added and the mixture was evaporated to dryness overnight, then added to a silica column (400 g) and chromatographed, eluting with chloroform then 0-100% ethyl acetate in hexane, to afford a white solid (7.55 g, 64%).