Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].CO.B(F)(F)F.C[CH2:40][O:41]CC>C(Cl)Cl>[CH3:40][O:41][CH2:31][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17]1
Reactant: CCOCC
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CO
Product: COCC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC
Reaction time: 3 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (454 g) was dissolved in methylene chloride (20 ml). To this solution were added methanol (5 ml) and then boron trifluoride etherate (0.124 g) under cooling at 0° C. The mixture was stirred for 3 hours at the same temperature and further stirred for 2 hours to 5° to 10° C. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and then with water, dried and the solvent was distilled off. The oily residue (25 g) was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was separated into each 50 ml fraction and the seventh and eighth fractions were combined. The solvent was distilled off to give oily methyl 2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[C:23]([C:27]([O:29]CC)=[O:28])[CH:24]=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1.Cl>CO>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: CCOC(=O)c1cncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C(=O)O)c2)c1
Temperature: 60 °C

Procedure:
Methanol (1.0 mL) and aqueous sodium hydroxide (4 M in H2O, 0.65 mL, 2.6 mmol) was added to a flask containing ethyl 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-3-carboxylate (210 mg, 0.052 mmol) and the reaction was heated to 60° C. for 1 hour. The mixture was allowed to cool to room temperature, acidified (2 N HCl) and the solid was isolated by filtration to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-3-carboxylic acid. MS ESI calc'd for C18H14F3N4O2 [M+H]+ 375. found 375.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]#[N:22])[CH:11]=1)=[O:8].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]([NH2:22])=[O:26])[CH:11]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 5-bromo-2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)benzamide (Preparation 15, 500 mg, 1.24 mmol) in DMSO (5 mL) was added K2CO3 (340 mg, 2.48 mmol) followed by H2O2 (50% by weight, aqueous solution, 1.69 mL, 24.9 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of saturated aqueous KHSO4 solution (5 mL) followed by water (15 mL) and EtOAc (40 mL). The mixture was filtered and separated. The organic layer was washed with brine (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was slurried in water and filtered to afford the title compound (457 mg, 88%).
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1.O.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C@@H:11]([NH:15][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: N[C@H](CCc1ccc(O)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (2R)-4-(4-hydroxyphenyl)-2-amino-butanoic acid hydrobromide (5.0 g, 18.18 mmol) and triethylamine (5.25 mL, 2 eq) in dioxane (50 mL) and water (50 mL) at 0° C. was added a solution of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitile (BOCON) (4.9 g) in dioxane (10 mL). The reaction mixture was allowed to warm up to room temperature and stirred for five hours when it became homogeneous: The reaction mixture was diluted with ethyl acetate (EtOAc) and the organic was seperated. The aqueous layer was acidified with citric acid (20%) and extracted with EtOAc. The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to give the desired material.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C@@H:8]1[CH2:17][N:16]2[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)C.Cl>CO>[C:19]1([CH2:18][N:9]2[C@H:8]([CH2:7][OH:6])[CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: OC[C@@H]1CN2CCOC[C@@H]2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (D126, 276 mg, 0.73 mmol) in MeOH (24 ml), cooled to 0° C., was added dropwise 12 N HCl (1.4 mL). The reaction mixture was stirred for 2 hrs at r.t., then it was put in the freezer for 12 hrs. The reaction mixture was warmed-up to r.t., further HCl was added (0.7 ml) and the reaction mixture was stirred for 2 more hrs. The mixture was filtered on a SCX cartridge washing with methanol and then with 2M methanolic ammonia. The fractions eluted with ammonia were combined and evaporated to dryness to give the title compound as a colourless oil (150 mg, y=78%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[ClH:20].[Cl:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2Cl)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Clc1cccc(COc2cnc(Cl)c(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 158 %

Procedure:
A solution of 3′-Chloro-6′-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (Compound I-3g) (40 mg, 0.091 mmol) in 1,4-dioxane (0.5 ml) at 23° C. was treated with HCl in 1,4-dioxane (4 M, 0.23 ml, 0.91 mmol). The resulting mixture was stirred at room temperature for 5 h (during which a precipitate appeared) and treated with ether. The solid was collected by filtration and washed with ether to afford the title compound 3-F (27 mg, 72%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])(=[O:23])C.[Na+]>CC(O)=O>[OH:23][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: CC(=O)[O-]
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c(CO)c(-c2ccc(O)cc2)oc2ccccc12
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.50 g, 1.5 mmol) and sodium acetate (1.24 g, 15.0 mmol) in AcOH (20 mL) was heated to reflux for 15 h. AcOH was removed and the residue was poured into water and extracted with EtOAc (100 mL). The organic phase was further washed with brine and dried over sodium sulfate. The residue was mixed with potassium carbonate (0.52 g) and MeOH (10 mL) and stirred for 2 h. AcOH (1.0 mL) was added and MeOH was removed. The residue was poured into water and the solid was washed additionally with water and hexane to give 3-(hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.265 g, 62.6%). MS (ES) m/z: 269.94 (M+1), 268.94 (M); Mp. 234-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CCN(CC)CC.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:23])[CH3:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred solution of 2-amino-5-chloropyridine (0.645 gm 5.0 mmol) in CH2Cl2 (15 mL) was added Et3N (0.80 mL, 6.0 mL, 1.2 eq) followed by addition of ethyl chlorooxoacetate (0.56 mL, 5.0 mmol, 1.0 eq). The mixture was stirred at rt for 2 h. It was diluted with EtOAc; washed with H2O and brine; dried (Na2SO4); and purified by silica gel chromatography to give pure N-(5-chloro-pyridin-2-yl)-oxalamic acid ethyl ester as a white solid (389 mg, yield: 34%). 1H NMR (400 MHz, methanol-d4) δ 8.16 (d, J=2.4 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 7.66 (dd, J=8.9, 2.6 Hz, 1H), 4.19 (q, J=6.6 Hz, 2H), 1.20 (t, J=6.6 Hz, 3H) ppm. MS (ESI) 227.0 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH3:19][N:20]([CH2:22][CH2:23]Cl)[CH3:21].Cl>O1CCCC1>[CH3:1][C:2]1([CH3:16])[C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([O:15][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])=[C:5]2[CH2:4][O:3]1
Reactant: CN(C)CCCl
Reactant: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1c2c(nc3ccccc13)C(C)(C)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound of formula VI, 3,4-dihydro-3,3-dimethylfuro[3,4-b]quinolin-9(1H)-one (8.0 g, described in Example 8), in tetrahydrofuran (80 ml) is slowly added over one hour to a suspension of 55% sodium hydride (4 g) in tetrahydrofuran (80 ml) at 20° to 30° C. The mixture is stirred at room temperature for one hour and dimethylaminoethyl chloride (prepared from 20 g of the hydrochloride) is added. The mixture is heated at reflux for 18 hours, filtered and the filtrate is evaporated. The residue is crystallized from acetonitrile to give the title compound, mp 92°-93° C. Treatment of the title compound with a solution of hydrogen chloride in ether gives the hydrochloride salt of the title compound, mp 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: Fc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a flask was added 4-chloro-1,2-difluorobenzene (8.97 g, 60.4 mmol), followed by adding 98% con. H2SO4(16.1 mL, 302 mmol) and 65% con. HNO3 (5.0 mL, 66.4 mmol) at 0° C. The mixture was stirred at rt for 5 hours, then poured into ice water (500 mL). The resulted mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase were washed with saturated aqueous NaHCO3 solution (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound as yellow liquid (11.31 g, 96.7%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C:12]1([C:11](=[O:24])[NH:10][C:9](=[O:25])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:20]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)NC(=O)N1Cc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of (±)-3-benzyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step C (80 mg, 0.24 mmol) in EtOAc (1.5 mL) and MeOH (1.5 mL) was added 10% Pd/C (5 mg) and the reaction mixture was stirred vigorously under hydrogen (ca. 1 atm). After 18 h, the catalyst was filtered off and the filtrate was concentrated to yield the title compound as a pale brown solid. MS: m/z=308 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(Cc4ccc(F)cc4F)C3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol), 2,4-difluorobenzaldehyde (64 μL, 0.59 mmol) and 4 Å molecular sieves in chloroform (7 mL) was heated to reflux for 3.5 hours. After cooling sodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added and the mixture was stirred at RT overnight. Aqueous saturated sodium bicarbonate solution was added and the phases were separated. The aqueous phase was extracted with 10% MeOH/DCM (×4) and the combined organic phase was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 50-100% EtOAc in cyclohexane) to give 372 (122 mg, 50%). LCMS: RT=8.65 min, [M+H]+=494. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=2.33 Hz), 7.90 (1 H, s), 7.33 (1 H, q, J=7.71 Hz), 7.14 (1 H, dd, J=8.27, 2.33 Hz), 7.01 (1 H, d, J=8.26 Hz), 6.86-6.74 (2 H, m), 5.94-5.84 (1 H, m), 4.37 (2 H, t, J=5.06 Hz), 3.83-3.73 (3 H, m), 3.68 (2 H, s), 3.39 (2 H, t, J=5.07 Hz), 3.29-3.23 (2 H, m), 1.61 (6 H, d, J=6.65 Hz)
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=CC(C5NN=CC=5)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:41]([O:45][C:46](=[O:76])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:59](=[O:75])[C:60]4[C:61]([O:67][C:68]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[C:62](Cl)[N:63]=[CH:64][CH:65]=4)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42].[CH3:77][N:78]1[CH:82]=[C:81](B2OC(C)(C)C(C)(C)O2)[CH:80]=[N:79]1>>[C:41]([O:45][C:46](=[O:76])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:59](=[O:75])[C:60]4[C:61]([O:67][C:68]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[C:62]([C:81]3[CH:80]=[N:79][N:78]([CH3:77])[CH:82]=3)[N:63]=[CH:64][CH:65]=4)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Product: Cn1cc(-c2nccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cn1
Yield: 97 %

Procedure:
Following the procedure used to prepare (1-{-4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound (28.7 mg, 97%). LCMS (Method H): RT=4.04 min, [M+H]+=549.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[O:31]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][CH2:33][CH2:34][C:35]1=[O:37]
Reactant: O=C(O)CCCC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 50 h
Yield: 65.2 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.087 g, 0.27 mmol) and diisopropylethylamine (0.079 ml, 0.46 mmol) were added sequentially at ambient temperature to a stirred solution of 4-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]butyric acid (0.08 g, 0.21 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 50 hours, then it was added dropwise to ice-cold water (10 ml). The resulting solid was collected by filtration and dried in vacuo to give 1-[2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperidine-2,6-dione (0.05 g) as a white solid, m.pt. 259–263° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.8–2.1 (m, 2H) (—CH2CH2CH2—), 2.7–2.9 (m, 4H) (—CH2CH2CH2—) 4.35 (s, 2H) (ArCH2—), 7.1–7.35 (m, 2H) (2×ArH), 7.4–7.5 (m, 1H) (ArH), 7.8–8.05 (m, 3H) (3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+ 366, 100% purity.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=O.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][N:41]([CH2:17][CH2:16][N:3]4[C:4]5[C:9](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CC=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1 mL of a chloroform solution containing methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate, 26.5 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 6.9 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 24.2 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 9.3 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]1(Br)[CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C=O.CO>[CH:8]1([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrC1CCCC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: c1cn(C2CCCC2)cn1
Reaction time: 0.25 h

Procedure:
Imidazole (6.8 g, 0.1 mole) was dissolved in 100 ml of dry dimethylformamide (DMF). Sodium hydride, 50% dispersion in oil, (4.8 g, 0.1 mole) was added in small portions and the mixture was allowed to stir for 15 minutes. Cyclopentyl bromide (14.9 g, 0.1 mole) dissolved in 100 ml dry DMF was then added dropwise to the mixture which was kept under nitrogen and at about room temperature. Allowed to stir for a further 1 hour. When t.l.c. showed no further reaction, the mixture was poured onto approximately equal volume of water and shaken well. The product was then extracted with chloroform (3×200 ml) and dried over anhydrou MgSO4. The dry extract was evaporated down under vacuum. The DMF was then distilled off at 15 mmHg pressure to leave a yellowish oil. T.l.c. showed that the mixture was mainly product and an imidazole impurity, about 10 g nn on silica gel column with MeOH/EtOAC 1:9. Product fractions were combined and evaporated. Residual oil obtained was distilled under vacuum. B.pt. 67°-68° C./0.2 mm. Yield 2.0 g.
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH2:32]([OH:35])[C:33]#[CH:34]>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C(OCC)(=O)C.O>[CH3:5][C:4]([CH3:7])([CH3:6])/[CH:3]=[CH:2]/[C:34]#[C:33][CH2:32][OH:35]
Reactant: C#CCO
Reactant: CC(C)(C)/C=C/I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)/C=C/C#CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.63 g of (E)-1- iodo-3,3-dimethyl-1-butene [see J. Org. Chem., 43, 4424 (1978)] was dissolved in 10 ml of tetrahydrofuran, and 31 mg of triphenylphosphine, 29 mg of copper(I) iodide, 11 mg of palladium chloride, 1.5 ml of n-butylamine and 0.35 ml of propargyl alcohol were added. The mixture was stirred overnight at room temperature, and then water and ethyl acetate were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=2/1] to give 0.27 g of the captioned compound as a pale brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:62][CH3:63])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53](=[O:60])[N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([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)=[O:14])[CH:9]=1)[CH3:2].[CH3:64][CH:65]([S:67](Cl)(=[O:69])=[O:68])[CH3:66].S(Cl)(Cl)(=O)=O>>[CH2:62]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53]([N:54]3[CH2:59][CH2:58][N:57]([S:67]([CH:65]([CH3:66])[CH3:64])(=[O:69])=[O:68])[CH2:56][CH2:55]3)=[O:60])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:63]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCN(S(=O)(=O)C(C)C)CC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 262b according to the procedure described in Example 290 using propane-2-sulfonyl chloride as the sulfonyl chloride. MS (ES, m/z) 983.9 [M+H]+.