Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](B(O)O)[CH3:25].ClCCl>O1CCOCC1.O>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:4]1[CH:3]=[C:2]([CH2:24][CH3:25])[CH:7]=[CH:6][N:5]=1
Reactant: Fc1cccc(F)c1COc1cc(Br)ccn1
Reactant: CCB(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccnc(OCc2c(F)cccc2F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of 3.8 g (9.24 mmol, 73% purity) of 4-bromo-2-[(2,6-difluorobenzyl)oxy]pyridine (Example 145A) in 54 ml of 1,4-dioxane and 13 ml of water was degassed under argon for 10 minutes. The solution was admixed with 9.04 g (27.73 mmol) of caesium carbonate, 0.82 g (11.09 mmol) of ethylboronic acid (CAS: 4433-63-0) and 0.75 g (0.924 mmol) of (1,1)-bis(diphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (CAS: 95464-05-4). The reaction vessel was closed and the contents were stirred at 100° C. for 18 hours. The solvent was evaporated off and the residue was partitioned between water and ethyl acetate. The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane/ethyl acetate, gradient 0% to 5%), which gave 1.38 g (41% yield, 69% purity) of product.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36](O)=[O:37])[CH:27]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:36]([C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[O:37])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Product: COc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(C)sc2-c2cccc(F)c2)nc2ccccc12

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 4-methoxy-quinoline-2-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=517.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[F:11])=O.[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].CC(C)([O-])C.[Na+].[CH3:28][NH:29][NH2:30]>C(O)C>[F:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[C:2]1[N:29]([CH3:28])[N:30]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:1]=1
Reactant: CNN
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(F)cccc2F)n(C)n1
Reaction time: 1 h
Yield: 12.5 %

Procedure:
To a mixture of 2,6-difluoroacetophenone (4.7 g, 0.03 mol) and 1,2-diethyl ethanedioate (4.8 g, 0.033 mol) in ethanol (33 mL) was added sodium tert-butoxide (3.17 g, 0.033 mol). After 1 h, more ethanol (30 mL) was added to the reaction mixture and stirring was continued for 1 h. The reaction mixture was partitioned between hydrochloric acid (1 N) and diethyl ether. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to half its original volume. To the resulting mixture was added methylhydrazine (1.52 g, 0.033 mol) and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (5 to 20% gradient of ethyl acetate in methylene chloride as eluant) to provide the title compound as a solid (1.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.C(=O)(O)[O-:19].[Na+].ClC1C=CC=C(C(OO)=O)C=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:19]
Reactant: c1cnc(Sc2cccc3cccnc23)nc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(c1ncccn1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 ml. of tetrahydrofuran containing 170 mg. (0.71 m mole) of 8-(2-pyrimidylthio)quinoline was added 300 mg. of sodium bicarbonate and the mixture cooled to 0° C. m-Chloroperbenzoic acid (153 mg., 1.0 eg) in 5 ml. of the same solvent was added dropwise. After the addition was complete the reaction was allowed to warm to 25° C. and was stirred overnight. The reaction mixture was poured into a sodium bicarbonate solution and the product extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with a small amount of ethyl acetate and filtered, 84 mg., m.p. 152°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=[CH:16][O:17][CH3:18])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:19](/[CH:24](CO)[CH2:25][OH:26])=[CH:20]\[CH2:21][CH2:22][CH3:23].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[O:26][CH2:25][C@H:24](/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH3:23])[CH2:18][O:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC/C=C/C(CO)CO
Reactant: COC=C1CCC(c2ccc(C#N)c(F)c2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC/C=C/[C@H]1CO[C@H]([C@H]2CC[C@H](c3ccc(C#N)c(F)c3)CC2)OC1
Reaction time: 1 h

Procedure:
A mixture of 0.98 g of 2-fluoro-4-[4-(methoxymethylidene)cyclohexyl]benzonitrile (U.S. Pat. No. 4,784,471), 0.70 g of 2-(1E-pentenyl)-1,3-propanediol, 45 ml of toluene, 2 ml of water and 10 drops of 10 percent sulphuric acid was stirred at about 85° C. for 75 minutes, then heated to boiling for 1 hour, whereby moist solvent distilled off and was replaced by fresh toluene. The reaction mixture was treated with 12 drops of triethylamine and, after cooling, washed three times with 15 ml of water, dried over sodium sulphate, filtered and concentrated. Chromatography of the residue (1.86 g) on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) and two-fold recrystallization from 8 ml of hexane each time gave 0.65 g of pure 2-fluoro-4-[trans-4-[trans-5-(1E-pentenyl)-1,3-dioxan-2-yl]cyclohexyl]benzonitrile, m.p. (C-N) 91.2° C., cl.p. (N-I) 192.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(#N)C>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCc1ccc(OCCCBr)cc1
Temperature: 70 °C
Yield: 77.3 %

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (4.37 g, 31.0 mmol) and potassium carbonate (6.55 g, 47.0 mmol) in acetonitrile (62.0 mL) was added 1,3 dibromopropane (31.0 mL, 316 mmol). The reaction mixture was heated to 70° C. for 12 hours and then cooled to room temperature, filtered and concentrated under vacuum. The resulting oil was purified by silica gel chromatography using a mixture of 4:1 hexanes and ethyl acetate to give the title compound (6.21 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.C(OC(=O)C)(=O)C.[N:21]1C=CC=CC=1.CC1C=C(OC(=O)C)C(C(OC)=O)=C(OC(=O)C)C=1.[Cl:46]CCl>>[ClH:46].[NH2:21][CH2:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([OH:12])[CH:11]=1
Reactant: c1ccncc1
Reactant: COC(=O)c1c(O)cc(C)cc1O
Reactant: ClCCl
Agent: COC(=O)c1c(OC(C)=O)cc(C)cc1OC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(O)cc(CN)cc1O
Product: Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
Methyl 4-methyl-2,6-dihydroxybenzoate (14.0 grams, 76.8 mmoles) was dissolved in anhydrous dichloromethane (250 mL) and acetic anhydride (21 mL, 223 mmoles) and anhydrous pyridine (18 mL, 223 mmoles) were added carefully. The solution was refluxed under dry nitrogen for 30 hours, then cooled to room temperature. The solution was washed twice with 1M aqueous hydrochloric acid (200 mL portions) and then with saturated aqueous sodium chloride (200 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to an off-white solid. This crude product was flash chromatographed on silica gel (250 grams) using hexanes:ethyl acetate (70:30 [v/v]) as the eluting solvent. Fractions containing the major product (Rf =0.3) were pooled and evaporated to dryness to afford 19.0 grams (98% yield) of a white solid of methyl 4-methyl-2,6-diacetoxybenzoate (m.p. 70°-71° C., open capillary, uncorrected).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27].ClCCl>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:27]#[C:26][CH2:25][OH:28])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(C#CCO)c21

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)palladium(II) chloride (0.012 g), and propargyl alcohol (0.035 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Dichloromethane followed by hexanes is added to the reaction mixture. The resulting solid is filtered, washed thoroughly with hexanes, and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 0.5% MeOH:CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L), 1.5% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (1 L), 3% MeOH:CH2Cl2 (1 L)) affords the title compound as a yellow solid (0.13 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]3[C:10]([NH:15][C:16](=[O:25])[C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:24])=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCCl>[C:26]([N:3]1[C:2](=[NH:1])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([NH:15][C:16](=[O:25])[C:17]4[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=4[Cl:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4]1)(=[O:28])[CH3:27].[C:26]([NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]3[C:10]([NH:15][C:16](=[O:25])[C:17]4[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=4[Cl:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1)(=[O:28])[CH3:27]
Reactant: Nc1n[nH]c2c1cnc1c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Nc1n[nH]c2c1cnc1c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Product: CC(=O)n1[nH]c2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc32)c1=N
Temperature: 25 °C

Procedure:
To a suspension of 3-amino-6-(2,6-dichlorobenzoylamino)-1H-pyrazolo[4,3-c]quinoline (200 mg) in 1,2-dichloroethane (2 ml) was added acetic anhydride (302 mg), and the reaction mixture was refluxed for 12 hours. The solution was allowed to cool to ambient temperature and the solvent was evaporated in vacuo. The residue was triturated with water-ethanol, and the precipitate was collected. The crude product was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 2-acetyl-6-(2,6-dichlorobenzoylamino)-2,3-dihydro-3-imino-1H-pyrazolo[4,3-c]-quinoline as a yellow crystal (60 mg) and 3-acetamido-6-(2,6-dichlorobenzoylamino)-1H-pyrazolo[4,3-c]quinoline as a white crystal (30 mg). 2-Acetyl-6-(2,6-dichlorobenzoylamino)-2,3-dihydro-3-imino-1H-pyrazolo[4,3-cilquinoline
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:32]([CH:34]2[CH2:39][N:38]([C:40](=[NH:42])[CH3:41])[CH2:37][CH2:36][N:35]2C(OC(C)(C)C)=O)=[O:33])[CH:3]=1.CO>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:32]([CH:34]2[CH2:39][N:38]([C:40](=[NH:42])[CH3:41])[CH2:37][CH2:36][NH:35]2)=[O:33])[CH:3]=1
Reactant: CC(=N)N1CCN(C(=O)OC(C)(C)C)C(C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=N)N1CCNC(C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4 N Hydrochloric acid in 1,4-dioxane (10 mL) was added to crude (1-tert-butoxycarbonyl-4-acetimidoylpiperazin-2-ylcarbonyl)-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (D) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 10 min, methanol (2 mL) was added until insoluble materials were disappeared. After stirring for 1 hr, the solvents were removed in vacuo. The residue was purified by HPLC (Shiseido, Capcell Pak C18 UG120, 3 cm×25 cm, 0.02 N hydrochloric acid:methanol=70:30 to 60:40, v/v) and freeze-dried from water to afford the title compound (37 mg) as a pale yellow powder. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, D2O) δ 1.78-2.00 (2H, m), 2.26 and 2.32 (each s, total 3H), 2.20-2.43 (m, 1H), 2.52-2.66 (m, 2H), 3.18-3.72 (m, 6H), 3.87-4.13 (m, 3H), 4.30-4.44 (m, 2H), 4.52-4.66 (m, 1H), 4.73-4.82 (m, 1H), 7.04-7.27 (m, 5H), 7.77 (t, J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 8.00-8.12 (m, 2H), 8.91 (s, 1H), and 9.25 (s, 1H); IR (KBr) 3064, 1658, 1612, 1571, 1550, 1494, and 1454 cm−1; mass spectrum (FAB+) m/e 572 (M+1); Anal.Calcd for C31H37N7O4.3HCl.6.1H2O: C, 47.07; H, 6.65; N, 12.40. Found: C, 46.68; H, 6.11; N, 12.02.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>O1CCOCC1.O>[C:7]1([CH:2]([NH:1][S:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])(=[O:26])=[O:25])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium hydroxide and 1.95 g of 2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are gradually added, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 100 ml of water, extracted twice with EtOAc and acidified to pH=2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40° C. 2.09 g of the expected product are obtained, m.p.−218-219° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:44]2[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:43])[N:23]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:43])[N:23]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.42 g, 64%).
Reaction SMILES: [CH2:1]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][NH:8][C:7](=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].CCCCCC.CCOC(C)=O.O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([C:5]1[CH:6]=[C:7]([Cl:32])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(=O)[nH]nc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCc1cc(Cl)nnc1-c1ccccc1
Temperature: 85 °C

Procedure:
5-butyl-6-phenyl-2H-pyridazin-3-one (3.6 g, 15.8 mmol)) is dissolved in POCl3 (40 mL) and the solution is heated at 85° C. for 3 hours. The excess POCl3 is evaporated in vacuo and the residue is partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL). The organic layer is washed with water (35 mL), brine (35 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatograph (silica gel, 4:1 hexane, EtOAc) provides a light yellow oil. LC-MS (M+1) 247. 1H NMR (δ, CDCl3) 7.47 (s, 5H), 7.42 (s, 1H), 2.62 (t, J=7.2 Hz, 2H), 1.43-1.53 (m, 2H), 1.18-1.31 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28](OC)=[O:29])[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=2[O:17][C:16]([CH3:33])([CH3:32])[C:15]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH:37][C@@H:38]1[C@@H:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][N:40]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:39]1)[CH3:36]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28]([N:37]([CH2:35][CH3:36])[C@@H:38]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:42][CH2:41][N:40]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:39]3)=[O:29])[C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:18]=2[O:17][C:16]([CH3:32])([CH3:33])[C:15]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Reactant: COC(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)OCc1ccccc1
Product: CCN(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)OCc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1

Procedure:
Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3R,4R)-3-(ethylamino)-4-phenylpiperidine-1-carboxylate, the title compound (60.4 mg) was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [Mg+2].[Br-].[Br-].[O:4]=[C:5]1[C:10]2=[CH:11][C:12]([CH:14]=[O:15])=[N:13][N:9]2[CH2:8][CH2:7][O:6]1.[N+:16]([C:19]1[CH:37]=[CH:36][C:22]([CH2:23][O:24][C:25]([C:27]2[N:28]3[C@H:31]([S:32][CH:33]=2)[C@@H:30]([Br:34])[C:29]3=[O:35])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(#N)C.C1COCC1>[C:45]([O:15][CH:14]([C:12]1[CH:11]=[C:10]2[C:5](=[O:4])[O:6][CH2:7][CH2:8][N:9]2[N:13]=1)[C:30]1([Br:34])[C:29](=[O:35])[N:28]2[C@@H:31]1[S:32][CH:33]=[C:27]2[C:25]([O:24][CH2:23][C:22]1[CH:36]=[CH:37][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)=[O:26])(=[O:47])[CH3:46]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=CS[C@@H]2[C@@H](Br)C(=O)N12
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc2n(n1)CCOC2=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)OC(c1cc2n(n1)CCOC2=O)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Temperature: -20 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
To a solution of MgBr2 (0.46 g, 2.52 mmol) in acetonitrile (13 ml) under nitrogen was added 4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carbaldehyde (0.14 g, 0.84 mmol) at room temperature with stirring. A solution of (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (0.32 g, 0.84 mmole) in THF (13 ml) was then added, and the mixture was cooled to −20° C. Triethylamine (0.35 ml, 2.52 mmol) was introduced, and the mixture was stirred at −20° C. in the dark for 4 hr. It was then treated with acetic anhydride (0.2 ml, 2.0 mmol), and 4-N,N-dimethylaminopyridine (12 mg, 0.1 mmol), and kept at 0° C. for 18 hr. The mixture was concentrated and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% citric acid, saturated sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was chromatographed with silica gel (EtOAc-CH2Cl2/1:5) to give 0.27 g of an off-white solid; mp 107–110° C.; MS m/e 595 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:6]3=[C:5]([CH3:17])[C:4]=2[CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[ClH:1].[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:6]2[C:7](=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: Cc1c2c(nc3ccc(Cl)cc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3ccc(Cl)cc3c(C)c2CC1
Product: Cl
Yield: 65 %

Procedure:
9-Chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 9-chloro-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.