Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].[CH:29]([NH2:31])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:29]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=1)#[N:31]
Reactant: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Br)cc1
Reactant: NC=O
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-Bromo-4-nitro-4'-(N,N-diethylamino)azobenzene (1.9 parts), copper (I) iodide (0.95 parts), anhydrous sodium acetate (1.2 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperatures is maintained at 110° C. for 31/2 hours when reaction is adjudged complete by thin layer chromatography. The solvent is removed at 80° C. under reduced pressure and the residue is slurried in water (250 parts), collected and dried. 2-Cyano-4-nitro-4'-(N,N-diethylamino)azobenzene is obtained in 75% yield and requires no purification.
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][OH:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCc1ccccc1O
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccccc1OCc1ccccc1
Yield: 82.3 %

Procedure:
To a solution of sodium ethoxide (10.8 g) in ethanol (500 ml), 2-(2-hydroxyphenyl)ethanol (20.0 g) and benzyl bromide (24.8 g) were added and the mixture was refluxed under heating for 2 hours. The solvent was distilled away under reduced pressure, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a 2M aqueous potassium hydroxide solution and a saturated brine and dried over sodium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (27.2 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[C:14](=[O:22])[CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[F:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CN2c3c(c(F)c(F)c(F)c3C1=O)CCN2C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(NCc4ccccc4)c3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.6 %

Procedure:
62 mg of the compound (198) obtained in Example 69 and 50 mg of benzylamine were added to 2 ml of toluene, and the solution was heated at 80° C. for 24 hours. The reaction solution was added to chloroform and was washed with aqueous 5% citric acid solution. After drying over magnesium sulfate, the solvent was removed by distillation. Obtained solids were dispersed in ether and filtered off to obtain 59 mg of the subject compound (200) in a 74% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:10]=1.[CH2:27]([N:29]([CH2:44][CH3:45])[CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])[CH3:33])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([CH2:34][N:32]([CH2:31][CH2:30][N:29]([CH2:44][CH3:45])[CH2:27][CH3:28])[CH3:33])[CH:36]=2)=[C:3]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[N:12]=[CH:13][N:14]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 6-(2-amino-5-chlorophenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 65b (200 mg, 0.53 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (130 mg, 0.49 mmol, 1.00 equiv), HATU (300 mg, 0.79 mmol, 1.50 equiv), and N,N-diisopropylethylamine (270 mg, 2.09 mmol, 5.00 equiv). The resulting solution was stirred for 2 days at 25° C. in an oil bath. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of saturated NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.1 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.73 (s, 1H), 8.60 (d, J=9.3 Hz, 1H), 8.41 (s, 1H), 8.19 (m, 1H), 7.92 (m, 3H), 7.64 (m, 7H), 7.14 (s, 1H), 4.73 (d, J=5.7 Hz, 2H), 3.35 (s, 2H), 3.14 (d, J=6.9 Hz, 4H), 1.18 (t, J-7.2 Hz, 6H). MS (ES, m/z): 625 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:25][CH:24]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COc1ccc(N(Cc2ncc[nH]2)[C@H]2c3cc([N+](=O)[O-])ccc3O[C@@](C)(C(OC)OC)[C@@H]2O)cc1
Yield: 86.8 %

Procedure:
The title compound (446 mg, 86%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (300 mg, 1.06 mmol) and 4-methoxyphenyl-1H-imidazol-2-ylmethylamine (216 mg, 1.06 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:29])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]>C(OCC)(=O)C>[CH3:29][C:5]1([CH3:4])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: CC(C)=CC1C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Product: CC1(C)C(C=O)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Ozone gas was bubbled at -78° C. into a solution of 3.50 g (10.0 mmol) of 3-phenoxyphenylmethyl 2,2-dimethyl- 3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 2, in 20 ml of ethyl acetate. The subsequent operation was conducted in the same manner as those in Reference Example 5, whereby 2.66 g of 3-phenoxyphenylmethyl 2,2-dimethyl-3-formylcyclopropanecarboxylate was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CNCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1CN(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.150 g, 0.56 mmol) and N-methyl-phenethylamine (0.10 mL, 0.67 mmol) were combined in MeOH and stirred at room temperature overnight. Once no starting material was seen by analytical LCMS, sodium borohydride (0.064 g, 1.69 mmol) was added and the reaction was stirred at room temperature for 1 hour. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]=O.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][CH2:9][NH2:10].Cl.[OH-].[Na+]>O.C(OCC)(=O)C.CN(C=O)C>[S:3]1[C:4]2[CH2:8][CH2:9][NH:10][CH2:1][C:5]=2[CH:6]=[CH:7]1
Reactant: C=O
Reactant: NCCc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cc2c(s1)CCNC2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Formaldehyde (37% in H2O, 3.82 g, 47 mmol) was added dropwise to a flask equipped with a magnetic stirring bar containing neat 2-(thiophen-2-yl)ethanamine (5 g, 39.3 mmol). The mixture was heated to 90° C. for 2 h and then allowed to cool down to room temperature. The reaction was then diluted with water and ethyl acetate. The organic layer was collected and dried with sodium sulfate, reduced in vacuo to give a thick oil. The thick oil was dissolved in anhydrous DMF (25 mL) and added dropwise to a DMF solution saturated with HCl gas (HCl gas was bubbled in DMF for 15 min at 10° C.). The reaction was stirred for 1 h and then poured unto crushed ice and rendered basic (pH 10) with 5 N NaOH. The mixture was extracted three times with dichloromethane. All the organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and placed on a vacuum line to give a thick oil. Yield 5.47 g. MS (M+H)+ 140.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][C:12]([F:16])([F:15])[CH2:13][OH:14])[N:10]=1)([O-:5])=[O:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)C>C1COCC1>[N+:3]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][C:12]([F:16])([F:15])[CH2:13][O:14][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1nc(CC(F)(F)CO)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COCC(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Temperature: -50 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a suspension of sodium hydride (500 mg, 20.8 mmol) in dry THF (20 ml) which was cooled at -50° C., a solution of 3-(2'-nitroimidazolyl)-2,2-difluoropropanol (2.0 g, 9.6 mmol) in dry THF (10 ml) and then a solution of ethyl bromoacetate (2.4 g, 14.4 mmol) in dry THF were dropwise added. Then, the reaction mixture was gradually warmed to a room temperature and stirred for 4 hours at the temperature. After the reaction, the mixture was cooled by ice. Ethanol (2 ml) was added to the mixture, concentrated and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain ethyl 2-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropoxy]acetate (2.4 g)
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. p-Toluenesulfonyl chloride (available from Sigma-Aldrich; 103 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 12% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (76 mg, 46%) as a white solid. MS cald. for C24H25FNO4S [(M+H)+]: 456, obsd. 456.4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([NH:36][CH:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[CH2:31][CH2:32]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: NC1CCN(c2ccc(F)cc2)CC1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1nc(NC2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 52.5 %

Procedure:
To a chloroform solution (1.1 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (59 mg, 0.23 mmol) synthesized in Reference Synthesis Example 11, potassium carbonate (80 mg, 0.58 mmol) and 1-(4-fluorophenyl)piperidine-4-amine (66 mg, 0.34 mmol) synthesized in Reference Synthesis Example 83 were added and the resultant mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, water was added to the reaction solution and extraction with chloroform from the resultant reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/5→0/1 and next, ethyl acetate/methanol=19/1 (v/v)) to obtain the title compound (50 mg, yield: 52%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:22].Br.CCN(C(C)C)C(C)C.[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36]>CN(C=O)C>[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH:1][C@H:2]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[CH:20][CH:21]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:36].[BrH:22]
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
1 g (2.19 mmol) of H-L-Arg-pNA.2HBr is dissolved in 10 ml of DMF, and 0.854 ml (6.57 mmol) of DIEA is then added. In another vessel, a solution of 4.71 mg (2.19 mmol) of Boc-L-Pro-OH in 50 ml of DMF is neutralized with 0.285 ml of DIEA. The two solutions are mixed and 970 mg of Bop are then added while the resulting mixture is kept at RT, with stirring, the pH being kept at between 7.0 and 8.0 throughout the reaction by the addition of small portions of DIEA. After one hour, the reaction is complete and the reaction mixture is evaporated to dryness under vacuum; the evaporation residue is taken up with an AcOEt/MeOH mixture and extracted with a 0.5 M aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, concentrated and precipitated in ether (MeOMe or EtOEt) to give 877 mg (yield: 70%) of the expected product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl[CH2:26][CH:27]1[CH2:29][CH2:28]1.[I-].[K+].Cl>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][CH:27]5[CH2:29][CH2:28]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: ClCC1CC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CC4CC4)CC3)c(F)cc2c1=O
Yield: 15.6 %

Procedure:
3.3 g (10 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 90° in 50 ml of dimethylformamide with 1.8 g (20 mmol) of chloromethylcyclopropane, 3.3 g (20 mmol) of potassium iodide and 2.1 g of triethylamine for 5 hours. The solution is poured into 40 ml of water, the pH is brought to 5 with 2N hydrochloric acid and the precipitate is filtered off with suction and recrystallized from methanol. 0.6 g of 1-cyclopropyl-7-(4-cyclopropylmethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 279°-282° (with decomposition) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[NH:25][C:24](C)=[N:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[N:25]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2)c(=O)[nH]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 25.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.70 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.62 g of 2-(4-chlorophenyl)-5-methyl-3(2H,4H)-1,2,4-triazolone, 0.28 g of 2-(4-chlorophenyl)-4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH:6]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[O:18][CH3:19])([CH3:8])[CH3:7]>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[C:11]([O:18][CH3:19])[CH:12]=1
Reactant: COc1cc(C=O)ccc1OC(C)C
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 100.5 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (0.1 g, 154.5 mmol) and PP3 (40.5 g, 159.4 mmol) in CH2Cl2 (350 ml) maintained at 0° C. on an ice-salt bath. This suspension was allowed to warm to room temperature and then stirred at for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and vanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. and allowed to stir at room temperature for 1 h. After dilution with hexane (200 ml) the resulting mixture was filtered through a sintered glass funnel and the filtrate concentrated on to silica gel (30 g). The resulting solid was added to the top of a flash chromatography column (silica gel: 20 cm long×10 cm wide) which was subjected to gradient elution (2:1, 1:1 and then 1:2 hexane/CH2Cl2). Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) then afforded the title compound (27.2 g, 99.8%) as white crystalline masses, m.p. 36-38° C. IR(KBr disc, cm−1) 2976, 2973, 1599, 1510.1464, 1418, 1383, 1373, 1267, 1235, 1141, 1110, 1036. 1H NMR (300 MHz, CDCl3) δ7.41 (s, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.07 (dd, J=2.1, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz), 4.58 (septet J=6.0 Hz, 1H), 3.87 (s, 3H), 1.39 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ149.7 (C), 147.7 (C), 136.5 (CH), 127.9 (C), 121.9 (CH), 114.4 (CH), 111.8 (CH), 87.1 (CH), 71.1 (CH), 56.0 (CH3), 22.1 (CH3). MS (70 eV) m/z(%): 352 (28), 350 (49), 448 (31) (M+•), 310 (51), 308 (100), 306 (54) M+•−CH2CHCH3), 295 (34), 293 (38), 291 (36) (M+•−CH2CHCH3—CH). Anal. Calcd for C12H14O2Br2, 41.17; H. 4.03; Br, 45.65. Found: C, 41.21; H, 3.92; Br, 45.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH3:16])=[N:10]1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:14]([C:12]2[C:11]([CH3:16])=[N:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:13]=2)[OH:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccccc1-n1cc(C=O)c(C)n1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccccc1-n1cc(C(O)C2CCCCC2)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution (15 mL) of 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (11.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.1 g, 53%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1(O)[C:12]2([CH3:13])[C:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH2:5][CH:4]1[CH3:16])#[CH:2].[OH-:18].[Na+]>CC1C=CC=CC=1C>[CH3:16][C:4]1[CH2:5][CH:6]=[C:7]2[C:12]([CH3:13])([CH2:11][CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[C:3]=1[CH2:1][CH:2]=[O:18]
Reactant: C#CC1(O)C(C)CC=C2C(C)(C)CCCC21C
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC1=C(CC=O)C2(C)CCCC(C)(C)C2=CC1
Temperature: 145 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
A solution of 1-ethynyl-2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-1-naphthalenol (4.00 g; 17.2 mmol) in o-xylene (60 ml) was treated with [V2O6SiPh2]n, (400 mg) [Tetrahedron Lett. 1976, 17, 2981] and heated at reflux (145° C.). After 17 hours, the rearrangement was completed. The reaction mixture was poured into 5% aqueous NaOH. The product was extracted twice with Et2O and washed successively with H2O and twice with satured aqueous NaCl, dried (Na2SO4) and evaporated. Bulb-to-bulb distillation (125° C. (oven temp.)/0.04 mbar) afforded 97% pure (2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)acetaldehyde (3.42 g; yield=83%).