Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH2:21].[Na]>ClCCl>[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH:21][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCCC1CCN
Reactant: O=Cc1cccc2ccccc12
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cccc2ccccc12

Procedure:
Experimental condition analogous to Example 5, from 1-naphthalencarboxaldehyde 0.15 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL dichloromethane. The crude material is 210 mg clear oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[Cl:21])[CH:11]=[CH:12][C:13](OCC)=[O:14].O.[OH-].[Na+]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[Cl:21]
Reactant: CCOC(=O)C=Cc1cc(Cl)c(Cl)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CCCO)cc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (1.2 g., 0.032 mole) is suspended in dry ether (100 ml.) in a flask equipped with a stirrer, upright condenser and dropping funnel and protected from moisture. To this is added dropwise with stirring a solution of ethyl 3,4-dichloro-5-methoxycinnamate (4.3 g., 0.0156 mole) in dry ether (150 ml.) over a twenty minute period. The mixture is stirred for an additional 30 minutes. Then with vigorous stirring, 1.2 g. of water is added carefully followed by 15% sodium hydroxide (1.5 ml.) and an additional 4.5 ml. of water. The ether solution is filtered from the granular inorganic salts which then are washed with additional ether. The combined ether solutions are washed with water and dried (Na2SO4). Upon evaporation of the ether 3-(3,4-dichloro-5-methoxyphenyl)propanol remains.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:25]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][CH:12]1[O:14][CH:13]1[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:25]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][CH:12]([OH:14])[CH2:13][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C2OC2CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(O)CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of methyl 4-[3-((3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-phenoxypentyl)oxiran-2-yl]benzoate from step D (410 mg, 0.7 mM) in 15 ml of methanol was added 100 mg of palladium on carbon (10%) and the suspension was set under 40 PSI of hydrogen gas and shaken for 2 h on the Parr shaker. The catalyst was filtered and the filtrate concentrated under reduced pressure to afford 378 mg of the title compound which was directly used for next step. LC-MS: m/z (ES) 488.21 (M-Boc+1).
Reaction SMILES: [NH:1]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O:24][C:25]1[C:26](=[O:57])[C:27](=O)[C:28]=1[NH:29][C:30]1[CH:31]=[N:32][N:33]([CH3:55])[C:34]=1[NH:35][C:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)C.C(N(CC)CC)C.C(OCC)C>C(Cl)(Cl)Cl>[CH3:55][N:33]1[C:34]([NH:35][C:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:30]([NH:29][C:28]2[C:25](=[O:24])[C:26](=[O:57])[C:27]=2[N:1]([CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:31]=[N:32]1
Reactant: CCOc1c(Nc2cnn(C)c2NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cn1ncc(Nc2c(N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)c(=O)c2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 9 h
Yield: 62.6 %

Procedure:
To a solution of di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (2.13 g) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (1.91 g) in chloroform (10 ml) was added triethylamine (0.558 ml), and the mixture was stirred under reflux. After 9 hours, additional di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (1.82 g) was added to the reaction mixture, and the mixture was stirred under reflux for 1 day. To the reaction mixture was added diethyl ether, and the solution was washed successively with 5% aqueous citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride/methanol (20:1) to give di-tert-butyl {[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxocyclobut-1-en-1-yl)imino]bis(2,1-ethanediyl)}biscarbamate (1.84 g) as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][CH2:21]3)[O:16][C:15]2=[O:32])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]3)[O:16][C:15]2=[O:32])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)CCN1CCN(CC2CN(C3CCN(C(=O)OC(C)(C)C)CC3)C(=O)O2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CC(CN3CCN(CCC(=O)O)CC3)OC2=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.8 g of 3-(1-BOC-4-piperidyl)-5-[4-(2-methoxycarbonylethyl)-piperazino]methyloxazolidin-2-one [obtainable according to Ex. 1] is suspended in 60 ml of methanol, and the mixture is treated with 4 ml of 2N NaOH solution and stirred at room temperature for 4 hours. After removal of the solvent, the residue is taken up in water, the pH is adjusted to 3 by addition of dilute HCl and the reaction mixture is filtered through an ion exchanger. The filtrate is dried over MgSO4. After removal of the solvent and subsequent freeze-drying, 3-(1-BOC-4-piperidyl)-5-[4-(2-carboxyethyl)piperazino]methyloxazolidin-2-one is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[C:12]2[N:13]([CH3:18])[O:14][C:15](=[O:17])[N:16]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.[Cu](I)I>[CH3:18][N:13]1[C:12](/[C:11](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10]\[O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:7]=2)=[N:16][C:15](=[O:17])[O:14]1
Reactant: C#Cc1ccccc1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1cccc(Br)n1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: Cn1oc(=O)nc1/C(=N\OCc1cccc(C#Cc2ccccc2)n1)c1ccccc1
Temperature: 120 °C
Yield: 54.5 %

Procedure:
To a solution of 3-[(Z)-{[(6-bromopyridin-2-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (200 mg, 0.514 mmol, 1 eq) in degased THF (2 mL) was added in a microwave tube under argon tetrakis(triphenylphosphine)palladium (0) (59.4 mg, 0.051 mmol, 0.1 eq), copper iodide (14.6 mg, 0.077 mmol, 0.15 eq) N,N-diisopropylethylamine (0.358 ml, 2.06 mmol, 4 eq) and phenylacetylene (157 mg, 1.54 mmol, 3 eq). The mixture was heated in the microwave at 120° C. for 15 min. The mixture was concentrated, diluted with ethyl acetate and filtered over a celite cartridge. The solvent was evaporated and the residue was purified by chromatography on silica gel to afford 2-methyl-3-[(Z)-phenyl({[6-(phenylethynyl)pyridin-2-yl]methoxy}imino)methyl]-1,2,4-oxadiazol-5(2H)-one (115 mg, 52% yield).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH3:19])=[N+:17]([O-:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br>CO>[C:1]([C:9]1[C:18]([CH2:19][Br:22])=[N+:17]([O-:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CO
Product: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred suspension of 28 g. (0.10 mol.) of 2-benzoyl-3-methylquinoxaline 1,4-dioxide in 1,000 ml. of methanol was added 5.6 ml. (0.11 mol.) of bromine. The reaction mixture was refluxed for 2 hours and then an additional 5.6 ml. (0.11 mol.) of bromine was added. The mixture was refluxed for an additional 2 hours and then it was cooled to 25° C. The solid which had precipitated was collected by filtration, washed with methanol, and dried to affored 30.4 g. (85% yield) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide, m.p. 183°-185° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:24]([CH:26]=[C:27]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)#[N:25].N12CCCN=C1CCCCC2>C(#N)C>[C:24]([CH2:26][C:27]1([N:22]2[CH:23]=[C:19]([C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=34)[CH:20]=[N:21]2)[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)c(F)cnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3c(F)cnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of 5-fluoro-4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.02 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.168 g, 6.02 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8996 mL, 6.02 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc/hexanes) to give 3.05 g (96.3%) of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a colorless oil. LC/MS found: 527.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:15]([OH:17])=O)[CH2:14][CH2:13]2)=[CH:7][C:6]=1[F:18])=[O:4].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=C=S)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([NH:29][C:15]([C:12]2([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[C:6]([F:18])[CH:7]=3)[CH2:13][CH2:14]2)=[O:17])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(NC2(C(=O)O)CC2)cc1F
Product: CNC(=O)c1ccc(NC2(C(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)CC2)cc1F
Temperature: 140 °C
Yield: 12 %

Procedure:
A mixture of 1-(4-(methylcarbamoyl)-3-fluorophenylamino)cyclopropanecarboxylic acid (200 mg, 0.79 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (270 mg, 1.18 mmol) was heated at 140° C. for 3 h. The crude product was purified by silica gel chromatography (100-200 mesh silica, 5% acetone in DCM as eluant) to get 40 mg of 4-(1-(4-cyano-3-(trifluoromethyl)phenylcarbamoyl)cyclopropylamino)-2-fluoro-N-methylbenzamide, M+1: 421.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][N:15](C=CC)[C:16](=[O:17])[C:3]=12>CO.Cl>[OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:10])[CH3:11])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:3]=12
Reactant: CC=CN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Agent: Cl
Solvent: CO
Product: CC(C)n1c(=O)c(O)c2n(c1=O)CCNC2=O

Procedure:
A solution of 9-hydroxy-7-isopropyl-2-(1-propenyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (1.8 g, 6.4 mmol) in MeOH (15 mL) and 6 N aqueous HCl (10 mL) was heated to reflux for 1 h. The solvents were removed in vacuo and the residue was triturated in MeOH to give the title compound as a solid. HPLC RT=2.14 min (Method A); ES MS (M+H)=240; 1H NMR (400 MHz, DMSO-d6) δ 11.5 (v broad s, 1H), 9.19 (s, 1H), 5.04 (septet, J=7 Hz, 1H), 3.87 (t, J=7 Hz, 2H), 3.46 (m, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: O[C:2]([C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])[CH3:3].C(N(S(F)(F)[F:25])CC)C>C(Cl)Cl>[F:25][C:2]([C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(C)(C)O)COC1(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C(C)(C)F)COC1(C)C
Temperature: -78 °C
Yield: 51.5 %

Procedure:
tert-Butyl (4R)-4-(1-hydroxy-1-methylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.80 g, 14.7 mmol), prepared by the method of Joullie, Tetrahedron, 52, pp. 11673-11694, (1996) was dissolved in 90 mL of anhydrous CH2Cl2. The solution was cooled to −78° C. under an atmosphere of N2. (Diethylamino)sulfur trifluoride (DAST) (2.25 mL, 17.0 mmol) was added and the reaction was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated NaHCO3 solution and the layers were separated. The organic portion was washed successively with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography (SiO2, 7% EtOAc/hexanes) gave tert-butyl (4R)-4-(1-fluoro-1-methylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.98 g) as a nearly colorless liquid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[CH:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C1CCN(C2CC2)c2cc(F)c(F)cc21
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Product: O=c1ccn(C2CC2)c2cc(F)c(F)cc12
Yield: 86.8 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydro-4-oxoquinoline(10 g) and p-chloranil (22 g) were reacted in the same method as described in Preparation 1-B to give the white above-indicated compound(8.6 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:31]5[CH:27]([CH3:26])[CH2:28][CH2:29][C:30]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)nn2)CC1
Yield: 11.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and 5-methylpyrrolidin-2-one (30 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (14 mg) was obtained.
Reaction SMILES: [CH:1]1([CH:6]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4[C:24]5[CH:37]=[CH:36][S:35][C:25]=5[C:26](=[O:34])[NH:27][C:28]=4[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[CH:18][CH:17]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:38]>CCOCC>[ClH:38].[NH2:8][CH2:7][CH:6]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3[C:24]4[CH:37]=[CH:36][S:35][C:25]=4[C:26](=[O:34])[NH:27][C:28]=3[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])=[CH:20][CH:21]=1)[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C2CCCC2)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN)C2CCCC2)cc1
Yield: 69 %

Procedure:
Following General Procedure D, tert-butyl 2-cyclopentyl-2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (50 mg, 0.10 mmol) was reacted with HCl in ether (5 mL) to afford the desired product (29 mg, 69%) as an off-white solid: ESI MS m/z 419 [C25H26N2O2S+H]+; 1H NMR (500 MHz, DMSO-d6) δ 7.59 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.44-7.36 (m, 2H), 7.45-7.35 (m, 2H), 7.28-7.19 (m, 2H), 7.28-7.19 (m, 2H), 5.72 (d, J=5.4 Hz, 1H), 5.72 (d, J=5.4 Hz, 1H), 3.70 (s, 3H), 3.33-3.20 (m, 2H), 2.84 (td, J=9.2, 6.0 Hz, 1H), 2.20-2.03 (m, 1H), 1.98-1.84 (m, 1H), 1.76-1.35 (m, 5H), 1.28 (dq, J=18.0, 8.9 Hz, 1H), 1.18-1.02 (m, 1H). HPLC >99% (AUC), tR=12.45 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH2:19]=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][O:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: C=O
Reactant: COc1ccc(Nc2ccccc2)c(C(=O)O)c1
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)OCN2c1ccccc1
Temperature: 0 °C
Yield: 83 %

Procedure:
A mixture of 15.0 g (0.062 mole) of 5-methoxy-2-(phenylamino)benzoic acid and 75 ml of 37% aqueous formaldehyde solution in 75 ml of ethanol was heated on the steam bath for 75 minutes. The mixture was cooled and added to 400 g ice/water. The crude oxazine product was filtered, stirred in 75 ml of 5% aqueous sodium bicarbonate, and refiltered to yield 13.0 g (83% yield) of the product, mp 99.5°-101° C. A sample recrystallized from hexane was analytically pure, mp 100°-102° C.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.O>ClCCl.CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=3)[N:26]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CSc1ccc(NN)cc1
Reactant: CCOC(C)=NC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(-n2nc(C)nc2-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 66005.5 %

Procedure:
N-(1-ethoxy-ethylidene)-4-bromo benzamide 565 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and (4-methylsulfanyl-phenyl)-hydrazine hydrochloride 439 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=1:1). As a result, 5-(4-bromo-phenyl)-3-methyl-1-(4-methylsulfanyl-phenyl)-1H-[1,2,4]triazole (497 g, yield: 66%) was obtained as a liquid phase.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])[NH:17][CH:16]2[C:38](O)=[O:39])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:47][C@@H:46]([CH2:48][CH2:49][NH2:50])[CH2:45][O:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:47][C@H:46]([CH2:45][OH:44])[CH2:48][CH2:49][NH:50][C:38]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:41])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH2:36][CH3:37])([CH2:32][CH3:33])[CH2:34][CH3:35])[NH:17]1)=[O:39]
Reactant: CCC(CC)(CC)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(CC)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 69.1 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 106c (0.5 g, 0.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.35 g, 2.4 mmol), HATU (0.55 g, 1.4 mmol) and iPr2NEt (0.7 mL, 4 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.33 g, 70%).
Reaction SMILES: [F:1][C:2]1([F:13])[C:4]2([CH2:9][CH2:8][N:7](C(O)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:14]>ClCCl.O1CCOCC1>[ClH:14].[F:1][C:2]1([F:13])[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3]1
Reactant: O=C(O)N1CCC2(CC1)CC2(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC1(F)CC12CCNCC2
Reaction time: 4 h

Procedure:
1.2 g of tert-butyl ester of 1,1-difluoro-6-aza-spiro[2.5]octane-6-carboxylic acid is put in 24 mL of dichloromethane. 24 mL of 4M hydrochloric acid in dioxane is added at room temperature. The solution is stirred for 4 h and is evaporated to dryness. 1 g of 1,1-difluoro-6-aza-spiro[2.5]octane hydrochloride is obtained.
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Br:16])([Br:15])[Br:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S([N:27]=[N+:28]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>C(#N)C>[N+:27](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH:8]([C:13]([Br:14])([Br:15])[Br:16])[CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[N-:28]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=CC(OC(=O)CC(=O)C=[N+]=[N-])C(Br)(Br)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-1-tribromomethyl-2-butenyl acetoacetate (8.32 g, 0.0198 mole) and tosyl azide (3.9 g, 0.0198 mole) in 40 ml of acetonitrile was added dropwise over a period of 35 minutes a solution of triethylamine (2.0 g, 0.020 mole) in 10 ml of acetonitrile. The resulting mixture was stirred at room temperature for 21/2 hours to give 3-methyl-1-tribromomethyl-2-butenyl diazoacetoacetate. Then 60 ml of 1N aqueous sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with ether, the organic phase was separated, the aqueous phase was extracted with ether, and the organic phases were combined. The ethereal solution was washed with three successive portions of 3% aqueous potassium hydroxide containing sodium chloride, then three times with saturated aqueous sodium chloride. The washed ethereal solution was dried over magnesium sulfate and treated with active charcoal. Evaporation of the ether afforded an oily residue. 3-Methyl-1 -tribromomethyl-2-butenyl diazoacetate (5.78 g, 71% yield) was isolated therefrom by column chromatography.