Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH:46]([CH3:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[OH:57][CH2:56][CH2:58][NH:59][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH:22]([CH3:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:15]([CH3:30])([CH3:31])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:38][C:39]([CH3:54])([CH3:55])[N:40]([O:45][CH:46]([CH3:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]([CH3:43])([CH3:44])[CH2:42]2)[N:3]=1
Reactant: NCCO
Reactant: CC(ON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC(C)c4ccccc4)C(C)(C)C3)n2)CC1(C)C)c1ccccc1
Product: CC(ON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OC(C)c4ccccc4)C(C)(C)C3)n2)CC1(C)C)c1ccccc1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis{N-[1-(α-methylbenzyloxy)-2,2,6,6-tetramethylpiperidin-4-yl]butylamino}-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:11][C:12]([CH3:20])=[CH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>C(OCC)C.[Cu]I>[F:16][C:15]([F:18])([F:17])[C:14](=[O:19])[CH2:13][C:12]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:20])[CH3:11]
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(C)=CC(=O)C(F)(F)F
Agent: [Cu]I
Solvent: CCOCC
Product: COc1ccccc1C(C)(C)CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 2-methoxyphenylmagnesium bromide (131 mL, 65.7 mmol, 0.5M solution in THF) at 0° C. was added CuI (12.5 g, 65.7 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. A solution of 4-methyl-1,1,1-trifluoropent-3-en-2-one (10.0 g, 65.74 mmol) (made via procedure in PCT international application WO03/082280, Example 10), in diethyl ether (200 mL) was added and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with three 300 mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using 0%-5% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product-rich fractions gave 14 g (82%) of 1,1,1-trifluoro-4-(2-methoxyphenyl)-4-methylpentan-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=O)=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].O(Cl)Cl.[P+5]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:6]([CH:12]=[N:11][CH:10]=2)[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:23]
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(I)cc1F
Agent: ClOCl
Agent: [P+5]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 95 °C
Yield: 49.7 %

Procedure:
To a suspension of 2-(2-fluoro-4-iodophenylamino)-6-formylaminomethylnicotinic acid methyl ester (11.6 g, 27.4 mmol) in toluene (160 mL) was added phosphorous (V) oxychloride (5.1 mL, 54.8 mmol) and the reaction mixture heated at 95° C. for 1 hour. The reaction mixture was concentrated in vacuo and the resultant residue poured onto ice. The mixture was washed with aqueous saturated sodium hydrogen carbonate solution (40 mL) and the aqueous layer extracted twice with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-70% ethyl acetate in DCM) to yield the title compound as a brown oil (5.6 g, 50%). LCMS (Method B): RT=3.62 min, M+H+=412.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].BrBr>C(O)(=O)C>[CH2:1]([C:3]1[N:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)cn1-c1ccc(C2=NNC(=O)CC2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CCc1nc(C)cn1-c1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
Similarly, reaction of 4,5-dihydro-6-[4-(2-ethyl-4-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone with bromine in acetic acid as described in this Example gives 6-[4-(2-ethyl-4-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.[O:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=O)=[CH:10]1.BrC(Br)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[O:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[CH:4][CH3:5])=[CH:10]1
Reactant: CN(C)CCN(C)C
Reactant: CCOC(=O)c1ccoc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC=C(OCC)c1ccoc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
To 300 ml of THF was added with cooling (ice-bath) 300 ml (0.3 mol) of 1M TiCl4 in methylene chloride and the mixture was stirred for 10 min. To the above mixture was added at room temperature 90.5 ml (0.6 mol) of TMEDA, the mixture was stirred for 10 min, and then, 44.12 g (0.675 mol) of Zn dust was added with cooling to maintain the mixture at room temperature and stirred for 40 min. To the resulting reaction mixture was added dropwise a mixture of ethyl 3-furoate (10.5 g, 0.075 mol), 31 g (0.165 mol) of dibromoethane in 200 ml of THF, and the mixture was stirred at room temperature for 2.5 h. After adding 90 ml of aqueous potassium carbonate solution, the mixture was concentrated in vacuo, the residue was diluted with 20 g of basic alumina, passed through basic alumina column (ether/TEA 200:1), and the eluent was concentrated. The residue was triturated in ether (200 ml), filtered, and the filtrate was distilled (80°-95° C./25 mm) to afford 6.2 g of (54.3%) of 1-(3-furyl)-1-ethoxy-2-methylethylene (Formula III: R2 =CH3 ;R3 =H; R4 =CH3CH2O;R5 =3-Furyl; and Formula III: R2 =H;R3 =CH3 ;R4 =3-Furyl; R5 =CH3CH2O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1Br.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].C([O-])(=O)C.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:24]([O:23][C:19](=[O:22])/[CH:20]=[C:21]1/[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]/1=2)[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: Fc1ccc(Br)c(OCc2c(F)cccc2Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)/C=C1/c2ccc(F)cc2OCc2c(F)cccc21
Temperature: 120 °C
Yield: 68.2 %

Procedure:
Degas a mixture of 1-bromo-2-(2-bromo-6-fluoro-benzyloxy)-4-fluoro-benzene (886 mmol, 335 g), ethyl acrylate (931 mmol, 101 mL, 1.05 eq), Pd(OAc)2 (22.2 mmol, 4.97 g), tetrabutylammonium bromide (886 mmol, 286 g), and sodium acetate (4.40 mol, 363.5 g) in N-methylpyrrolidinone (3.3 L) by evacuating and back-filling with nitrogen five times. Heat the mixture to 120° C. for 2 h. Cool to 35° C. and add water (5.5 L) over 40 min. Filter the precipitate, rinse with water (2×500 mL) and air dry for 30 min. Reslurry the in isopropanol (1 L) for 2 h and cool on ice for one hour. Collect the dark gray solid by filtration, rinse with cold isopropanol (5×100 mL) and dry at 50° C. in vacuo to obtain the title compound (191 g, 68%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Reactant: O=C=NCc1ccccc1
Product: COc1cc2c(NC(=O)NCc3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 35 °C

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to 35° C. for 16 hours, benzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (DMSOd6): 1.3-1.5 (m, 2H), 1.8-1.9 (m, 4H), 1.95 (t, 1H), 2.2 (s, 3H), 2.8 (br d, 2H), 3.9 (br s, 3H), 4.0 (br d, 2H), 4.5 (br d, 2H), 7.2-7.3 (m, 2H), 7.3-7.4 (m, 4H), 8.0 (br s, 1H), 8.55 (br s, 1H), 10.2-10.5 (br s, 1H), 10.4 (t, 1H); Mass Spectrum: M+H+ 436.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dichlorobenzyl 4-(tert-butoxycarbonylamino)piperidine-1-carboxylate (step 1)(5.3098 g, 13.17 mmol) in DCM (20 ml) was added 4M HCl in dioxane (33 ml, 132 mmol) and the mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford the title product as hydrochloride salt;
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]4[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=4)=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCc1ccc(-n2c(CCC3CCCC3)nc3cccnc32)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(CCC4CCCC4)nc4cccnc43)cc2)cc1
Yield: 43.1 %

Procedure:
4-[2-(2-Cyclopentylethyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.22 g, 0.658 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.266 g, 0.656 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.209 g, 0.283 mmol).
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[CH:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]([Cl:14])=[CH:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(OC=C(Cl)Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OC=C(Cl)Cl)cc1

Procedure:
A mixture containing 27.8 g. of 4-(2,2-dichlorovinyloxy)benzoic acid and 278 ml. of thionyl chloride was stirred and refluxed on a steam bath for 3 hours. The excess thionyl chloride was distilled off, first at atmospheric pressure and then at reduced pressure. Ethylene dichloride was added to the liquid residue and the solution evaporated in vacuo to remove the ethylene dichloride and remaining traces of thionyl chloride. There was thus obtained a quantitative yield of 4-(2,2-dichlorovinyloxy)benzoyl chloride as a pale yellow, non-volatile liquid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:7])=[O:4].[CH3:15][C:16]([O:27][Si](C)(C)C)([CH3:26])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([Zn]CC)C.Cl>C(OC(C)C)(=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][C@@:18]([OH:19])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][C:16]([OH:27])([CH3:26])[CH3:15])[CH3:7])=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)CBr)c1ccc(Br)cc1
Reactant: CC(C)(CC(=O)c1ccccc1)O[Si](C)(C)C
Agent: CC[Zn]CC
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: C[C@H](NC(=O)C[C@](O)(CC(C)(C)O)c1ccccc1)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A flask is charged with 1 (120.0 g, 0.366 mol), 2 (120.0 g, 0.479 mol) and NiCl2(dppe) (1.93 g, 3.66 mmol). The flask is purged with nitrogen and charged with DME (240 mL). The resultant slurry is cooled to about −20° C. and treated with diethylzinc (30 wt. % solution in toluene, 477 mL, 1.097 mol) at a rate to keep the temperature of the reaction mixture between −15 to −5° C. The reaction mixture is then stirred at −5 to 0° C. for 2 hours, treated with 6N aqueous HCl (600 mL), and stirred for 15 minutes. The reaction mixture is treated with isopropyl acetate (120 mL), stirred at 25° C. for 30 minutes, cooled to 10° C., and held at 10° C. for 30 minutes. The resultant solids are collected by filtration, and washed with water, toluene, and heptane. The solid is then dried at 70° C. for 18 hours to provide 3 as a white solid. Yield: 98.3 g, 62.1%; 97.1 wt. % purity. Diastereomeric ratio: 98.9:1.1. Melting point: 150-152° C. LC-MS: 419.8/421.8 (100%, 95%); calculated exact mass: 419.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
To 6-chloropyridin-2-amine (20.0 g, 156 mmol) and triethylamine (23.7 mL, 171 mmol) in 100 mL toluene at 50° C. was added pivaloyl chloride (19.6 mL, 163 mmol) dropwise via syringe. The reaction mixture was allowed to stir, and eventually became a solid mass. 50 mL toluene was added. The reaction mixture was heated overnight, and cooled to ambient temperature. The reaction mixture was quenched with 400 mL 2N aq. HCl, and diluted with 300 mL EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated to a solid. The solid was dissolved in a min. volume of hot MTBE (50° C.), and approx. 300 mL hexanes was added with swirling. On standing, crystals form, which were collected by filtration, rinsing with hexanes to give a total of N-(6-chloropyridin-2-yl)pivalamide. MS (ESI) m/z: calculated: 212.1; Observed: 213.2 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:2])=[N:14][C:13]=2[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cnccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cnccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyrazin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.086 mmol), β-alanine (768 mg, 8.62 mmol) and NaOMe solution (13 mL, 6.47 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4, and the resulting precipitate was isolated by filtration to give 33 mg of the title compound as a light yellow solid. MS: (+) m/z 522.29 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:9]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13]>CN(C=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:9]2[NH:10][C@@H:11]([CH3:14])[CH2:12][O:13][C:8]=2[C:18]=1[F:19]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1COc2c(ccc(F)c2F)N1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To DMF (2 ml) was added potassium tertiary-butoxide (110 mg) under ice-cooling. Next, a solution of the compound (100 mg) obtained in Example 51 in DMF was dropped thereinto and the obtained mixture was stirred for 30 minutes. After treating in a conventional manner, the mixture was subjected to silica gel column chromatography to give 72 mg (79%) of the title compound. The optical purity determined by HPCL was >94% ee. Various spectral data was identical with those of a specimen synthesized separately.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][OH:9])[N:4]=[C:3]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=[O:9])[N:4]=[C:3]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: Cc1c(CO)nc(-c2ccc(C(F)(F)F)cc2)n1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)nc(-c2ccc(C(F)(F)F)cc2)n1C
Yield: 100.8 %

Procedure:
A mixture of 1,5-dimethyl-4-hydroxymethyl-2-(4-trifluoromethylphenyl)imidazole (0.5 g) and manganese dioxide (2 g) in 20 ml of chloroform was refluxed for 24 hours. A further 2 g of manganese dioxide was added, and the mixture refluxed for a further 3 hours. The mixture was cooled, the solid material filtered off, and washed with methylene chloride. The solvent was removed from the filtrate under reduced pressure, to yield 0.5 g of 1,5-dimethyl-4-formyl-2-(4-trifluoromethylphenyl)imidazole, m.p. 144° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8](=[O:10])(=[O:9])[NH2:11])[CH:6]=[CH:7][C:2]=1[NH:16][CH2:17][C@H:18]1[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][CH2:23]1)([O-:14])=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CC[C@H](CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To 4-fluoro-3-nitrobenzenesulfonamide (0.265 g) and trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride in tetrahydrofuran (5 mL) was added N,N-diisopropylethylamine (0.526 mL) and the reaction was stirred at room temperature. After stirring overnight the reaction was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 0.5% to 3.5% methanol/dichloromethane over 30 minutes to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
1,4-Dibromobenzene (2.36 g), diethyl phosphite (1.52 g) and triethylamine (1.53 ml) were dissolved in toluene, tetrakis(triphenylphosphine)palladium(0) (578 mg) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.16 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH:9]1([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:42])=[C:19]([C:24]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[CH2:25])[C:20]=3[O:22][CH3:23])[C:15](=[O:43])[C:14]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:13]2)[CH2:11][CH2:10]1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH:9]1([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:42])=[C:19]([C:24]4([C:26]([O:28][CH:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:27])[CH2:4][CH2:25]4)[C:20]=3[O:22][CH3:23])[C:15](=[O:43])[C:14]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:13]2)[CH2:10][CH2:11]1
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1OC
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(C3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 26.9 %

Procedure:
160 mg of 60% sodium hydride was suspended in 18 ml of N,N-dimethylformamide and 877 mg of trimethylsulfoxonium iodide was added thereto under ice-cooling. After stirring at room temperature for 40 minutes, 1.80 g of ethyl 1-cyclopropyl-7-(l-diphenylmethoxycarbonylvinyl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate was added thereto and the resulting mixture was stirred at 50° C. for 3 hours. To the reaction mixture, 30 ml of ethyl acetate and 15 ml of water were added and the pH value of the mixture was regulated to 1 with 2N hydrochloric acid. Then the organic layer was collected, successively washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue thus obtained was crystallized by adding ethyl acetate/n-hexane and the crystals were collected by filtration. Thus 497 mg of ethyl 1-cyclopropyl-7-(1-diphenylmethoxycarbonylcyclopropyl)-6- fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate was obtained (yield: 26.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:9]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-chloro-2-(ethoxycarbonylamino)benzonitrile (K. O. Geolotte et al, J. Heterocyclic Chem., 1990, 27, 1549) and 2-bromoacetophenone.