Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.C([O-])(O)=O.[Na+].II.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl.O.CO>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4]1)=[O:1]
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: II
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 500-mL round-bottomed flask was charged a solution of benzyl 3-(hydroxymethyl)piperidine-1-carboxylate (8.94 g, 35.90 mmol, 1.00 equiv) in DCM (200 mL), NaHCO3 (9.05 g, 107.74 mmol, 3.00 equiv) in H2O (80 mL), I2 (18.24 g, 71.81 mmol, 2.00 equiv) and TEMPO (570 mg, 3.65 mmol, 0.10 equiv). The resulting mixture was stirred for 18 hours at room temperature. The reaction progress was monitored by TLC (DCM:MeOH=20:1). Upon completion, the reaction was then quenched by the addition of 10 mL of NaHSO3/H2O. The pH was adjusted to 8 with NaHCO3. The resulting solution was extracted with dichloromethane (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator to afford benzyl 3-formylpiperidine-1-carboxylate as brown oil (6.2 g, (70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH:10]1([CH2:13][OH:14])[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:14][CH2:13][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: OCC1CC1
Product: Fc1cc(Br)cnc1OCC1CC1

Procedure:
Following Typical Procedure 6, reaction of 5-bromo-2,3-difluoro-pyridine with cyclopropyl-methanol provided the subtitle compound. MS ESI+: m/z=246 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH2:22][CH2:23][N:36]4[CH2:37][CH2:38][C@@H:34]([F:33])[CH2:35]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: F[C@@H]1CCNC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CC[C@@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using (R)-3-fluoropyrrolidine in Step 2. LC-MS Method 2 tR=1.2 min, m/z=509.1; 1H NMR (CDCl3) 0.67-0.86 (m, 1H), 1.47 (d, 6H), 1.87-2.34 (m, 7H), 2.70-2.91 (m, 3H), 5.00-5.23 (d, 2H), 5.63 (m, 1H), 6.92-7.06 (m, 6H), 7.25 (m, 4H), 7.39 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].CI.[C:19](OCC)(=O)C>O1CCCC1.CN(C)C=O>[O:3]=[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[N:6]([CH3:19])[S:7]([CH3:10])(=[O:8])=[O:9])[CH3:2]
Reactant: CC(=O)c1ccccc1NS(C)(=O)=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1N(C)S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
2'-Acetylmethanesulfonanilide (1.0 g, 4.7 mmol) in 10 ml tetrahydrofuran is reacted with 0.23 g (4.8 mmol) of 50% sodium hydride dispersion in mineral oil at 5° C. for 15 min. Methyl iodide (1.5 g, 10.56 mmol) in 10 ml of dimethylformamide is added over 15 min at 0°-10° C. and stirred in cold for 15 min. Dimethylformamide (10 ml) is added, and the reaction is stirred for 2 days at room temperature. The reaction is taken up into ethyl acetate, the organic layer washed with water, sodium carbonate solution, water, and saturated sodium chloride successively. The dried organic layer is evaporated and the product crystallized from ether-pet. ether; m.p. 98°-99° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][C@@H:10]([O:18]C(=O)[C@@H](OC)C1C=CC=CC=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:18])[CH3:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H](C(=O)O[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(F)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C[C@@H](O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-methoxyphenyl acetic acid (1S)-2-(t-butoxycarbonyl-methylamino)-1-(4-fluorophenyl)ethyl ester (the compound of Preparation Example 35) (3.6 g) in methanol (17 mL) was added potassium carbonate (1.8 g) on an ice bath. After stirring at room temperature for 30 minutes, the colorless solid that was generated by diluting with water was collected by filtration. After washing with water, and then drying by aeration, the title compound (2.35 g) was obtained as a colorless solid. The NMR data matched the racemic mixture described in Preparation Example 32.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCCC1.C(O)(C)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=3)=[CH:12][C:13]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:14]2)=[CH:21][CH:20]=1
Reactant: COCOc1ccc(-c2cc(S(C)(=O)=O)nn2-c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc(-n2nc(S(C)(=O)=O)cc2-c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To the solution of 5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole (0.93 g) in a mixture of tetrahydrofuran (10 ml) and isopropyl alcohol (5 ml) was added hydrogen chloride aqueous solution (20%, 8 ml) at ambient temperature. The solution was stirred for 3 hours, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and evaporated to give 0.82 g of 4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]phenol (P0025).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:25]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
23.1 g of 9-(naphthalene-2-yl) anthracene was dispersed into 250 ml of DMF (dimethylformamide), and then 14.9 g of NBS (N-bromosuccinimide) in DMF solution (150 ml) was dropped therein. After stirred at room temperature for 7 hours, it was left over a night. 200 ml of water was added thereto, and then the crystal precipitated was separated by filtration. Subsequently it was washed by ethanol adequately, followed by drying, and 28.8 g of 9-bromo-10-(naphthalene-2-yl)anthracene of beige color crystal was obtained (Yield: 99%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH2:20])[C:17]=3[C:7]1=2.C(N(CC)CC)C>CN(C)C=O>[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH:20][C:1](=[O:3])[CH3:2])[C:17]=3[C:7]1=2
Reactant: NCCC1=CCc2ccc3c(c21)CCO3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCC1=CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Acetyl chloride (0.24 g, 3.03 mmol) was slowly added dropwise to an ice-cooled solution of 2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (0.6 g, 2.52 mmol) and triethylamine (0.64 g, 6.31 mmol) in N,N-dimethylformamide (60 mL). After overnight stirring at room temperature, the reaction mixture was concentrated and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) and further recrystallized from ethyl acetate to give 425 mg (yield: 70%) of the target compound.
Reaction SMILES: CO[CH:3]=[C:4]([CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=O.Cl.[CH2:13]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[NH:23])=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH2:16][CH3:17].C[O-].[Na+].[Na].Cl>CO>[CH2:7]([C:4]1[CH:5]=[N:23][C:22]([C:21]2[CH:25]=[CH:26][C:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[N:24][CH:3]=1)[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CCCCCc1ccc(C(=N)N)cc1
Reactant: C=CCCCC(C=O)=COC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCCCc1cnc(-c2ccc(CCCCC)cc2)nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2.4 g of 3-methoxy-2-(4-pentenyl)acrolein and 3.4 g of p-pentylbenzamidine hydrochloride in 30 ml of methanol was treated dropwise while stirring with a sodium methylate solution prepared from 0.55 g of sodium and 5 ml of methanol. The reaction mixture was stirred overnight at 50° C. and then neutralized (pH 5) with 3N hydrochloric acid. The solvent was distilled off and the residue was taken up in diethyl ether and water. The aqueous phase was back-extracted with diethyl ether. The organic phase was phase was washed with water, dried over sodium sulphate and concentrated. Chromatographic separation of the residue on silica gel with hexane/ethyl acetate gave 5-(4-pentenyl)-2-(p-pentylphenyl)pyrimidine as a colourless liquid; m.p. (C-I) 8.0° C., cl.p. (N-I) -4.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[CH:6]=[N:7][N:8]([CH2:11][CH3:12])[C:9]=2[CH:10]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.[NH2:48][CH2:49][C:50]1[C:51](=[O:60])[NH:52][C:53]([CH3:59])=[CH:54][C:55]=1[CH2:56][CH2:57][CH3:58]>C(Cl)Cl>[CH3:59][C:53]1[NH:52][C:51](=[O:60])[C:50]([CH2:49][NH:48][C:13]([C:4]2[C:5]3[CH:6]=[N:7][N:8]([CH2:11][CH3:12])[C:9]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)=[O:15])=[C:55]([CH2:56][CH2:57][CH3:58])[CH:54]=1
Reactant: CCn1ncc2c(C(=O)O)cc(Br)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a stirred suspension of 6-bromo-1-ethyl-1H-indazole-4-carboxylic acid, 4 (450 mg, 1.67 mmol) in DCM (50 mL) were added EDC.HCl (384 mg, 2.00 mmol), HOBt.H2O (306 mg, 2.00 mmol) and then stirred for 15 min at RT. To the resulting mixture, DIPEA (1.2 mL, 5.59 mmol) followed by 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (301 mg, 1.67 mmol) were added and the contents stirred for 18 h at RT. The reaction mixture was diluted with DCM (50 mL) and washed with water (2×50 mL), 10% aq citric acid solution (2×50 mL), saturated aq NaHCO3 solution (2×30 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether (2×50 mL) to afford the title compound as a white solid (230 mg, 32%). 1H NMR (400 MHz, DMSO-d6): δ 0.83-0.79 δ (t, 3H), 1.38 (t, 3H), 1.55 (m, 2H), 2.15 (s, 3H), 2.49 (s, 2H), 4.38 (d, 2H), 4.43 (m, 2H), 5.90 (s, 1H), 7.64 (d, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 8.61 (m, 1H), 11.51 (bs, 1H). LCMS (ES+): m/z=431.15.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([I:12])[N:6]=1)=[O:4].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.ClCCl>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([I:12])=[CH:8][N:9]=1
Reactant: COC(=O)c1nc(I)cnc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ncc(I)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-amino-6-iodo-pyrazine-2-carboxylic acid methyl ester (45 g, 161 mmol) was dissolved in 750 ml of THF. 90 ml of water and 40 ml of a 4 M solution of lithium hydroxide in water was added. The mixture was stirred at room temperature for 2 hours or until TLC analysis showed only baseline material. A solution of 10% citric acid in water was added to adjust the pH to about 3-4. The mixture was diluted with dichloromethane and the organic phase was separated. The aqueous layer was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The residue was dried in vacuo to afford 37.0 g (140 mmol; 87% yield) of 3-amino-6-iodo-pyrazine-2-carboxylic acid as a yellow powder. 1H-NMR (d6-DMSO) δ: 11.70 s, weak, 8.44 [1H] s, 7.50 [2H] s, br. MS: m/z 266 [MH+].
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[N:9]=[CH:8][C:7]=1[C:20](=[O:22])[CH3:21]>CCO.O.[Fe]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:6]([CH3:5])=[C:7]([C:20](=[O:22])[CH3:21])[CH:8]=[N:9]2)=[CH:16][CH:15]=1
Reactant: CC(=O)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)c1cnn(-c2ccc(N)cc2)c1C
Temperature: 75 °C
Yield: 84.8 %

Procedure:
2 ml of acetic acid and 0.64 g of iron(0) are added to 0.94 g of 1-[5-methyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]ethanone (Journal of Chemical Research, Synopses (1986), (5), 166-7) in 60 ml of EtOH/water mixture (65/35; v/v). It is heated at 75° C. for 2 hours. It is concentrated, filtered on Celite®, the filtrate is neutralized with saturated Na2CO3 and it is extracted with DCM. The organic phase is washed with water, with brine, it is dried over Na2SO4 and evaporated. 0.70 g of yellow powder is obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][OH:9]>>[CH3:8][O:9][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: CO
Reactant: O=C1CCC(=O)O1
Product: COC(=O)CCC(=O)O
Temperature: 70 °C

Procedure:
To a single-necked, 100 mL round-bottom flask equipped with a teflon stirbar, is added 20 g succinic anhydride dissolved in 50 mL methanol. The flask is equipped with a reflux condenser topped with a septa and argon balloon, and the reaction mixture is heated to reflux (70° C.) in an oil bath (Dow Corning Fluid) for a 16 hr time period. The reaction flask is then allowed to cool to room temperature, the stirbar removed, and the excess methanol removed via rotary evaporator to give 26.4 g of succinic acid monomethyl ester. In the same 100 mL flask containing succinic acid monomethyl ester is added a teflon stirbar, 35 mg palladium dichloride, 1.31 g triphenylphosphine, and 38 mL acetic anhydride, respectively. The flask is equipped with a short-path distillation apparatus with a thermometer, argon balloon, and an attached 100 mL collecting flask in an ice-bath. The reaction flask is heated to a temperature of 230° C. in an oil bath over a 30-40 minute time period, distilling out the excess acetic anhydride, acetic acid byproduct, and methyl acrylate. The reaction is complete after approximately 30 min heating at 230° C. when no more product distills and the solution darkens to a black color due to inactivation of the catalyst. The distillate is then analyzed by NMR to verify the presence of methyl acrylate. The reaction flask is cooled and weighed to determine how much starting material was removed due to reaction (17.9 g, 68% conversion to methyl acrylate).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[NH:12])([O-:3])=[O:2].C(=O)([O-])[O-].[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.C(=O)=O>COCCOCCOC>[OH:23][C:18]1[N:13]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:12]=[C:20]([CH3:22])[CH:19]=1
Reactant: N=C(N)Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: COCCOCCOC
Product: Cc1cc(O)nc(Nc2ccccc2[N+](=O)[O-])n1

Procedure:
121 g (0.5 mol) of 2-nitrophenyl-guanidine-carbonate, 100 g of ethyl acetoacetate and 200 ml of diethylene glycol dimethyl ether are heated first to 65° and, when the evolution of CO2 has ceased, to 140°. In the course of this ethanol and water are distilled off. After 31/2 hours the suspension is cooled, water is added and the pH is adjusted to 4-5 with concentrated hydrochloric acid. The yellow precipitate is filtered off, washed with water and dried in vacuo at 80° C. 80.3 g (65.2% of the theoretical amount) of the title compound of formula ##STR17## (compound No. 2.071) are obtained in the form of crystals having a melting point of 240°-242°.
Reaction SMILES: [CH2:1]([C@H:8]([NH:38]C(=O)OC(C)(C)C)[C@@H:9]([OH:37])[CH2:10][N:11]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][CH:26]=1)[NH:12][C:13](=[O:23])[C@@H:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:38][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:37])[CH2:10][N:11]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:29][CH:30]=1)[NH:12][C:13]([C@@H:14]([NH:18][C:19](=[O:20])[O:21][CH3:22])[CH:15]([CH3:16])[CH3:17])=[O:23]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
A solution of Example 18C (0.11 g, 0.18 mmol) in THF (2 mL) was treated with 4N HCl (0.3 mL), stirred at 60° C. for 3 hrs and cooled to room temperature. The mixture was concentrated, neutralized with 10% sodium bicarbonate, and extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated to give 92 mg (100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[I:18]I.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([I:18])=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H -imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 95° for 1.5 hours with 8.88 g (35 mmol) of iodine in 25 ml of N,N-dimethylformamide. The reaction mixture was then poured into 300 ml of water, decolorized with sodium thiosulfate solution and extracted four times with methylene chloride. The organic extracts were washed three times with water, dried over magnesium sulfate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 187-188°.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12](=[CH:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[C:4]1([C:3]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCC=C(Br)C(=O)OCC
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCc1c(-c2ccccc2)noc1C(=O)OCC
Reaction time: 24 h
Yield: 2.6 %

Procedure:
To a solution of (Z)-N-hydroxybenzimidoyl chloride (770 mg, 4.95 mmol) and ethyl 2-bromohex-2-enoate (1.09 g, 4.95 mmol) in DCM (15 mL) was added triethylamine (2.07 mL, 14.85 mmol) over 5 minutes. After ˜50% of the addition was complete, a precipitate formed. Stirring was continued for 24 hr at rt. The reaction mixture was partitioned between Et2O (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated to afford a yellow oil. This oil was chromatographed on a 5×15 cm silica gel column, eluting with a 0-8% EtOAc/Hex gradient. The product containing fractions were concentrated to afford 343 mg of a waxy, white solid. This material was triturated with heptane. The solid contained no product. The mother liquor was concentrated to afford a partially purified semisolid residue. The portion of the residue that dissolved in ˜3 ml of hexane was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-1% EtOAc/Hex gradient. Fractions containing the product were concentrated to afford ethyl 3-phenyl-4-propylisoxazole-5-carboxylate (34 mg, 0.131 mmol, 2.65% yield) as a colorless oil. HPLC retention time=1.91 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=260.23. 1H NMR (500 MHz, chloroform-d) δ ppm 0.90 (t, J=7.4 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 1.53 (m, 2H), 2.80 (m, 2H), 4.46 (q, J=7.2 Hz, 2H), 7.45 (m, 1H), 7.50 (m, 2H), 7.59 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][C:6]1=[O:22])[CH3:4].[CH3:23][O:24][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C=O)C>[CH3:23][O:24][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH2:3][CH3:4])[C:6]1=[O:22]
Reactant: CCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O
Reactant: COC(=O)CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(-c2ccccc2)c(-c2ccccc2)n(CCCCCCCCCCC(=O)OC)c1=O

Procedure:
The product is produced as described in example 1 from 0.45 g of NaH (80% suspension in mineral oil), 4 g of 1-ethyl-4.5-diphenyl-4-imidazolin-2-one, 30 cc. of DMF, 4.2 g of 11-bromoundecanoic acid methyl ester and 0.45 g of NaJ.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23].O1CCCC1>CO>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1C
Yield: 96.4 %

Procedure:
To a mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (2.52 g, 0.00789 mol), tetrahydrofuran (50 ml), methanol (50 ml) and washed Raney nickel (0.5 g) was initially applied 48.6 psi of hydrogen gas at 30.2° C. in a shaker for 4 hours 48 minutes. The mixture was filtered and the filtrate concentrated in vacuo to afford 2.20 g of a salmon-colored amorphous solid; 96% yield; 1H-NMR (400 MHz; DMSO) δ7.84 (s, 1H), 7.04 (d, 1H, J=7.1 Hz), 6.98 (d, 1H, J=1.2 Hz), 6.95-6.91 (m, 1H), 6.68-6.64 (m, 1H), 6.40-6.36 (m, 1H), 5.39 (s, 2H), 4.73 (s, 2H), 3.66 (s, 3H), 2.21 (s, 3H); 19F-NMR (376 MHz; DMSO) δ−139.66 (s).