Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 1.0E1 mmol) and Morpholine (0.962 g, 11.0 mmol) were dissolved in a solution of Acetic acid (0.500 mL, 8.79 mmol) and Methylene chloride (50.0 mL, 7.80E2 mmol). After stirring at room temperature for 15 minutes, Sodium triacetoxyborohydride (4.2 g, 2.0E1 mmol) was added and the reaction was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and reduced. TLC (visualized with iodine) showed evidence of a new product. Crude 3-Morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester (3.67 g) was used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].Cl[CH2:19]CC(Cl)=O.N1CCCC1>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:19]([CH2:12][CH2:11][N:13]3[CH2:16][CH2:17][CH2:15][CH2:14]3)=[N:1][C:2]=2[CH:6]=1
Reactant: CCN(CC)CC
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)CCCl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=c1[nH]c(CCN2CCCC2)nc2cc(Br)sc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (120 mg) produced in Example 1, step D, triethylamine (0.083 mL) and tetrahydrofuran (3.0 mL) was added 3-chloropropanoyl chloride (0.057 mL) with stirring at room temperature. After 10 min, pyrrolidine (0.23 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction system was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 1 hr. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (131 mg) as a pale-yellow solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][C@@H:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])[CH2:10][CH:9]=2)=[CH:6][C:5]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:4][N:3]=1.FC1C(C2CC[C@H](N3[C@@H](C4C=CC=CC=4)C(C)(C)[O:49]C3=O)CC=2)=CC(C2N=CC=CN=2)=CN=1.O1CCOCC1.Cl>O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([C@H:11]2[CH2:12][CH2:13][C:8]([C:7]3[C:2](=[O:49])[NH:3][CH:4]=[C:5]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:6]=3)=[CH:9][CH2:10]2)[C@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(c3cc(-c4ncccn4)cnc3F)CC2)[C@H]1c1ccccc1
Reactant: CC1(C)OC(=O)N([C@H]2CC=C(c3cc(-c4ncccn4)cnc3F)CC2)[C@H]1c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N([C@@H]2CC=C(c3cc(-c4ncccn4)c[nH]c3=O)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A resealable tube was charged with a mixture of (S)-3-((R)-4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and (S)-3-((S)-4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.090 g, 0.202 mmol), dioxane (3.0 mL), and water (1.0 mL). Concentrated HCl (37%) (0.25 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was washed and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford an off-white solid. This material was purified via SFC separation (Chiralpak AD-H column (2×15 cm), eluting with 25% MeOH (0.2% DEA)/CO2, 100 bar, 70 mL/min, 220 nM. Injection volume 0.5 mL, 9 mg/mL MeOH) to afford (S)-5,5-dimethyl-3-((S)-4-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)cyclohex-3-en-1-yl)-4-phenyloxazolidin-2-one (0.026 g, 0.059 mmol, 29% yield) as a white solid (first eluting peak, structure arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (s, 3H), 1.50 (s, 3H), 1.86-2.23 (m, 4H), 2.27-2.48 (m, 1H), 2.54-2.70 (m, 1H), 3.56-3.84 (m, 1H), 4.51-4.89 (m, 1H), 6.35 (br. s., 1H), 7.14-7.62 (m, 6H), 8.05-8.36 (m, 2H), 8.67-8.90 (m, 2H), 11.96 (br. s., 1H). m/z (ESI) 443 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>O1CCCC1.CO>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([OH:18])[CH2:13][CH2:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cc(OCc3ccccc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
2,3-Dihydro-5-(phenylmethoxy)-1H-inden-1-one (1.3 g, 5.46 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and methanol (10 mL), sodium borohydride (0.41 g, 11 mmol) was added, and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.16 g, yield 89%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH:12]1(O)[CH2:16][CH2:15][CH:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH:16]1([O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC1C=CCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1C=CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (1.48 g), 2-cyclopenten-1-ol (662 mg) and triphenylphosphine (2.47 g) in THF (25.0 ml) diethylazodicarboxylate (1.48 ml) was added at 0° C. After stirring at room temperature overnight the reaction mixture was diluted with methylene chloride and washed with 10% aq. KHSO4. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by chromatography to give the desired product.
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].OCC[C:13]#[C:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.C(=O)(O)[O-:26].[Na+]>C(O)C1C=CC=CC=1.[Hg]=O>[CH2:18]([O:17][C:15]1[CH2:14][CH2:13][O:7][C:8](=[O:26])[CH:9]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(C#CCCO)OCc1ccccc1
Reactant: O=C([O-])O
Reactant: CCOCC
Agent: FB(F)F
Agent: O=[Hg]
Agent: [Na+]
Solvent: OCc1ccccc1
Product: O=C1C=C(OCc2ccccc2)CCO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A heterogeneous mixture of benzyl alcohol (2.65 mole, 274.4 mL), mercury(II) oxide (red) (13.26 mmol, 2.87 g) and boron trifluoride diethyl etherate (0.133 mole, 16.3 mL) was heated at 60° C. for 3 hours (eventually turned homogeneous). A solution of the product from Example 31C (90.17 g, 0.442 mole) in benzyl alcohol (91.5 mL) was added at ambient temperature, and the reaction mixture was stirred at 70° C. for 4 hours and again at ambient temperature overnight. It was poured into an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified via flash chromatography (silica, hexane to hexane:ethyl acetate, 30:1 to 1:2) to provide the title compound as a white solid (49.6 g, 55%). 1H NMR (300 MHz, CDCl3) δ 2.60 (t, 2H), 4.38 (t, 2H), 4.95 (s, 2H), 5.28 (s, 1H), 7.32-7.46 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 35.5 g of methyl 4-hydroxybenzoate and 50.2 g of methyl 2-chloro-5-nitrobenzoate dissolved in 500 ml of N,N-dimethylformamide (DMF), was added 48.4 g of anhydrous potassium carbonate, and the mixture was stirred for 3 hours at 80° C. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was recrystallized from methanol to yield 67.7 g of methyl 2-(4-methoxycarbonylphenoxy)-5-nitrobenzoate (melting point: 103-105° C.) (Reaction Scheme (24) described below).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:11]=[C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].FC(F)(F)S(O[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[C:18]1([C:12]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:11][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccccc2)OC2C=Cc3ccccc3N2c2ccccc21
Yield: 77 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and ethyl 2-oxo-2-phenylacetate (0.134 g, 119 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=90/10) of the crude reaction mixture afforded ethyl 5-phenyl-5H,6aHbenzo[4,5][1,3]oxazino[3,2-a]quinoline-5-carboxylate as a white solid (0.147 g, 77% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: Cl.Br.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:14])[C:11]=2[NH2:13])[CH2:6][CH2:5][NH:4]1.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[NH:13]1[C:11]2[C:12]3[CH2:3][NH:4][CH2:5][CH2:6][C:7]=3[CH:8]=[CH:9][C:10]=2[NH:14][C:16](=[O:17])[C:15]1=[O:19]
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2c(c1N)CNCC2
Agent: Br
Agent: Cl
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Temperature: 90 °C
Yield: 81.5 %

Procedure:
A solution of Example 29 (01.27 g, 0.96 mmol) in 25 mL 3 N HCl, was treated with oxalic acid (0.15 g, 1.2 mmol) and heated at reflux for 4 h. The mixture was cooled in an ice bath and the precipitate collected by filtration and washed with 3 N HCl, water and then diethyl ether consecutively. After air drying, the solid was suspended in 10 mL water and heated at approximately 90° C., basifyed with ammonium hydroxide solution to pH 8, and filtered hot. The solid was washed first with water, then with diethyl ether and then dried in a vacuum oven to give an off-white solid (0.17 g, 81% yield) mp=294-297° C. MS (CI) M+1, 218; IR 1691, 1659 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:17]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC2CC2)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CC2CC2)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-cyclopropylmethyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=465.1 [M+H]+.
Reaction SMILES: [NH2-].[Na+].[C:3]1([C:9]#[CH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N.[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>C1COCC1>[OH:18][C:15]1([C:10]#[C:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:17][C:12](=[O:19])[CH:13]=[CH:14]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C#Cc1ccccc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Temperature: -78 °C

Procedure:
Sodium amide (0.35 g, 0.009 mole), dry THF (25 mL), and phenylacetylene (0.92 g, 0.009 mole) were placed in a 100 mL, three-necked round-bottomed flask under nitrogen. The reaction was heated at reflux while nitrogen was blown through the flask until ammonia evolution ceased. The reaction slurry was cooled to -78° C., then added to a mixture of benzoquinone (0.97 g, 0.009 mole) in THF (50 mL) at about -108° C. The reaction mixture was allowed to warm to -30° C., then quenched into a saturated solution of ammonium chloride and extracted with ether. The ether extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed as in Example 3 to yield 0.05 g (2.6%) of the title carbinol.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)CCC.Cl[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>>[N+:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)([O-:27])=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: O=[N+]([O-])c1ccsc1-c1cscn1

Procedure:
4-(3-Nitrothiophen-2-yl)thiazole was prepared from 4-(tributylstannyl)thiazole (0.51 g, 1.31 mmol) and 2-chloro-3-nitrothiophene (0.21 g, 1.31 mmol) according to protocol E. Retention time (min)=2.012, method [1], MS(ESI) 212.9 (M+H).
Reaction SMILES: [N:1]#[N:2].Cl.C[O:5][C:6](=[O:31])[C@H:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10].C(OCC)C.[CH2:37]([NH2:41])[CH2:38][CH2:39][CH3:40]>C(O)(=O)C>[N:1]#[N:2].[C:6]([OH:31])(=[O:5])[CH3:7].[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:9]([NH:8][C@H:7]([C:6]([NH:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:5])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])(=[O:11])=[O:10])[CH:21]=[CH:20]2
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Reactant: CCCCN
Agent: Cl
Agent: N#N
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 48 h
Yield: 74 %

Procedure:
A 1.0 gram amount of N2 -(6-methoxy-2-naphthalene-sulfonyl)-L-arginine methyl ester hydrochloride was dissolved in 2 ml of butylamine with vigorous agitation. After the resulting solution was allowed to stand at room temperature for 2 days, the butylamine was removed in vacuo and the residual syrup was washed well with 5 ml of water to obtain a powdery product. And then this powder was dissolved in minimum volume of acetic acid. To this solution ethyl ether was added to precipitate the viscous oily product. Reprecipitation from ethanol-ethyl ether gave N2 -(6-methoxy-2-naphthalenesulfonyl)-N-butyl-L-argininamide acetate in a powder form in 74% yield.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[N:7]([C@@H:8]2[O:16][C@H:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]2[F:22])[CH:6]=[N:5][C:4]=1[C:23]([OH:25])=O>O1CCCC1>[C:12]([O:11][C@@H:10]1[C@@H:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:16][C@@H:8]([N:7]2[C:3]([N:2]=[CH:6][N:7]([CH3:8])[CH3:3])=[C:4]([C:23]([Cl:1])=[O:25])[N:5]=[CH:6]2)[C@@H:9]1[F:22])(=[O:14])[CH3:13]
Reactant: [Cl-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@H](F)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O

Procedure:
In step 12, compound (18) is dissolved in tetrahydrofuran and reacted with N,N-dimethylchloroforminium chloride under ice-cooling, whereby 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-ribofuranosyl)-5-(dimethylaminomethyleneamino)imidazole-4-carbonyl chloride [compound (19)] is produced.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.Cl.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[NH:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>C(#N)C.O>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[NH:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:21]=2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: N=C(N)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1ccccc1-c1c[nH]c(-c2ccc(F)cc2)n1
Yield: 255.8 %

Procedure:
A mixture of 2-bromo-2′-methoxy-acetophenone (514 mg), 4-fluorobenzamidine hydrochloride (392 mg) and potassium carbonate (930 mg) in acetonitrile (5 ml) was refluxed for 2 hours. After cooling, to the reaction mixture were added chloroform and water, the organic layer was collected and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from methanol to obtain 2-(4-fluorophenyl)-4-(2-methoxyphenyl)imidazole (1.54 g) as pale yellowish crystal. This compound was treated with hydrogen chloride-ethanol solution to be converted into a hydrochloride salt form.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]([N+:20]([O-])=[O:21])([CH3:19])[CH3:18]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N+:20]([C:17]([CH3:19])([CH3:18])[CH3:16])[O-:21])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: CCCCCI
Product: CCCCCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 2 using 4-hydroxybenzaldehyde, 1-iodopentane and 2-methyl-2-nitropropane. The title compound was isolated in 75% overall yield as a solid, m.p. 43.2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]2[CH:21]=[C:2]([NH:1][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 20 °C
Reaction time: 336 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are suspended in 60 ml of absolute methylene chloride, treated with 2.1 g of powdered potassium carbonate and 1.6 ml of dimethylcarbamoyl chloride and stirred at 20° C. for 14 days. The mixture is then poured on to a mixture of ice and water, extracted with methylene chloride and the organic phase is washed 2-3 times with water, dried with sodium sulphate, filtered and concentrated. The residue is purified on a 200 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/petroleum ether. There is obtained 3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1,1-dimethylurea which crystallises with 0.5 mol of ethanol and melts at 97° C. with decomposition.
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:2].CN(C)C=O.[CH:27]([C:29]1[CH:36]=[CH:35][C:32](CCl)=[CH:31][CH:30]=1)=[CH2:28].[C:37](=O)(O)[O-].[Na+]>O>[C:20]([C:3]([C:1]#[N:2])=[C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH:27]([CH:28]=[CH2:37])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:35][CH:36]=3)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:21]
Reactant: O=C([O-])O
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)O)cccc21
Reactant: C=Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(OC(=O)c1cccc2c1-c1ccccc1C2=C(C#N)C#N)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a 1 liter round bottomed flask were added 60.0 grams of 9-dicyanomethylenefluorene-4-carboxylic acid, 700 milliliters of N,N-dimethylformamide, 67.1 grams of 4-vinylbenzyl chloride, and 37.0 grams of sodium bicarbonate, and the resulting mixture was stirred at 40° C. for 48 hours. The mixture was poured into 1,500 milliliters of distilled water with vigorous stirring, and the resulting aqueous mixture was extracted with 1,000 milliliters of dichloromethane. The organic layer was separated and was further washed with 1,500 milliliters of distilled water and dried over anhydrous magnesium sulfate. Subsequently, the organic solvent was removed by means of a rotary evaporator and the residue was recrystallized from a mixture of dichloromethane and methanol (2:1 by volume) to give vinylbenzyl 9-dicyanomethylenefluorene-4-carboxylate after filtration and drying in a vacuo for 48 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][CH2:15][O:16][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1cc(CCCO)c2cc(Br)ccc2[nH]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCCc1cc(=O)[nH]c2ccc(Br)cc12)(c1ccccc1)c1ccccc1

Procedure:
6-Bromo-4-(3-hydroxypropyl)quinolin-2(1H)-one (4.7 g, 16.67 mmoles), imidazole (2.84 g, 41.7 mmoles) and tert-butyldiphenylsilyl chloride (5.14 mL, 20 mmoles) were stirred in dimethylformamide (60 mL) overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to provide the title compound.