Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:40]4[C:39](=[CH:38][CH:37]=[C:36]([O:35][C:34]([F:45])([F:44])[F:33])[CH:41]=4)[NH:42][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 578.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[N:17]=2)=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:41][CH:42]=4)[CH:19]=3)[N:17]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2nc(-c3cccc(N)c3)cn3ccnc23)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3)cn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of 4-[6-(3-aminophenyl)imidazo[1,2-a]pyrazin-8-ylamino]benzoic acid ethyl ester (19) (44.2 mmol), triethylamine (66.4 mmol), and tetrahydrofuran (140 mL) is treated dropwise with a solution of 4-t-butylbenzoyl chloride (44.2 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at room temperature for 1 hr. Water (100 mL) is added and the mixture extracted with ethyl acetate (3×100 mL), the extracts are washed with water (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and evaporated in vacuo. The residue is triturated with dichloromethane to give 4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoic acid ethyl ester (20) as a pale orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:23])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: O=C(CCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 22.8 g of benzyl p-hydroxybenzoate and 8.45 g of glutaric acid dichloride to yield di(p-benzyloxycarbonylphenyl)glutarate, m.p. 93°-94° C., as white crystals.
Reaction SMILES: [CH2:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][C:9]([CH3:15])=[CH:10][C:11]=2Cl)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][C:9]([CH3:15])=[CH:10][C:11]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2nc(C)cc(Cl)c2o1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCc1cc2nc(C)cc(N3CCCCC3)c2o1
Temperature: 100 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a mixture of 2-butyl-7-chloro-5-methylfurano [3,2-b]pyridine (Example 229(c)) (329 mg, 1.45 mmol) and piperidine (3 mL, 30.4 mmol) was added a mixture of K2CO3 (0.85 g, 5.8 mmol) in H2O (1 mL). Mixture stirred at 100° C. under N2 for 16 h. After cooling, the reaction mixture was concentrated. The residue was diluted with H2O (70 mL) and Et2O (50 mL). The mixture was transferred to a separatory funnel and the organic solution was collected. The aqueous solution was washed with Et2O (2×40 mL). The organic solutions were combined, washed with H2O (50 mL), saturated NaCl (70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc:hexanes as elutant to give 310 mg (77%) of 2-butyl-5-methyl-7-piperidylfurano[3,2-b]pyridine as a cream colored solid. This material (310 mg, 1.12 mmol) was dissolved in EtOAc (10 mL) and heated to boiling. To the hot solution was added 1M etheral HCl (1.20 mL, 1.20 mmol). The solution was left to cool to 25° C. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (3×5 mL) and dried under vacuum at 25° C. to give 311 mg (69%) of the title compound as a white colored powder. Mp: 172-173° C. 1H NMR (CDCl3; 400 MHz): δ 0.95 (t, 3, J=7.4), 1.42 (hextet, 2, J=7.3), 1.69 (quintet, 2, J=7.7), 1.79 (br s, 6), 2.71 (s, 3), 2.79 (t, 2, J=7.5), 3.85 (br, 4), 6.29 (s, 1), 7.01 (s, 1), 15.56 (s, 1). MS m/z: 2793 (M+1 for free base). Anal. Calcd for C17H24N2O.HCl.0.5H2O: C, 64.24; H, 8.25; N, 8.82; Cl, 11.15. Found C, 64.42; H, 8.23; N, 8.75; Cl, 11.26.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][C:10]1[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:13]2[O:17][CH:16]=[CH:15][C:14]=2[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:8])[CH3:7].O.CN(C)[CH:30]=[O:31]>>[C:6]([O:9][C:10]1[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:13]2[O:17][C:16]([CH:30]=[O:31])=[CH:15][C:14]=2[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:8])[CH3:7]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2occc2c1C(C)(C)C
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Oc1c(C(C)(C)C)cc2oc(C=O)cc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Phosphorus oxychloride (1.1 g) was added dropwise to N,N-dimethylformamide (0.4 g) under cooling with ice and, subsequently, a solution of 5-acetoxy-4,6-di-tert-butylbenzofuran (1.0 g) in N,N-dimethylformamide (2 ml) was added dropwise. The mixture was stirred first at room temperature for 20 min, then under heating at 80° C. for 75 min. After cooling, the reaction mixture was poured into water and subjected to extraction ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-formylbenzofuran [0.95 g (yield, 86%)] as a colorless, fine-grained crystal.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[CH3:18][I:19]>O1CCCC1>[I-:19].[CH3:1][N+:2]1([CH3:18])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1
Reactant: CI
Reactant: CN1CCCN(c2nc3ccccc3o2)CC1
Solvent: C1CCOC1
Product: C[N+]1(C)CCCN(c2nc3ccccc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
A 200 mg portion of 2-(4-methyl-1-homopiperazinyl)-benzoxazole was dissolved in 5 ml of tetrahydrofuran (THF). Under cooling with ice, 0.064 ml of methyl iodide was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 2 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and 5 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 320 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: CC(C)I
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A DMF (15 mL) solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 21.5 mmol) was cooled to 0° C. and then isopropyl iodide (2.57 mL) and Nail (60%, 775 mg, 32.3 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (5:95) as eluent to obtain 3-isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (189 mg, 32%) as a solid. 1H NMR (CDCl3, 400 MHz): 7.62 (d, 2H), 7.40 (m, 3H), 6.91 (s, 1H), 3.84 (s, 3H), 1.35 (d, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([CH:30]=[CH:31][N+]([O-])=O)[CH:27]=[CH:26][C:25]=1[F:35]>>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:30]([C:28]2[CH:27]=[CH:26][C:25]([F:35])=[C:24]([Cl:23])[CH:29]=2)=[CH:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(F)c(Cl)c1
Reactant: NCc1ccccc1
Product: Fc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1Cl

Procedure:
The title compound (0.18 g) was prepared from 0.54 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 293 μL of benzylamine, and 0.62 g of 2-chloro-1-fluoro-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H18ClFN2, 340.11; found, m/z 341.1 [M+H]+, 343.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.43 (m, 1H), 7.36-7.16 (m, 8H), 5.15 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3N)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]3[C:11](=[CH:12][CH:13]=2)[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:16](=[O:18])(=[O:17])[NH:15]3)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3N)cccc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 23.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 8-(2-amino-benzenesulfonylamino)-quinoline-4-carboxylic acid methyl ester (Intermediate 288) (270 mg, 0.75 mmol), t-butyl nitrite (0.14 ml, 1.13 mmol), AcOH (2.7 ml) and THF (2.7 ml) gave the title compound (60 mg, 23%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].C(=O)=O.CC(C)=O.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[C:17](=[O:18])[CH2:16][Br:15])[CH:2]=[CH2:3]
Reactant: O=C(Br)CBr
Reactant: C=CCNCC=C
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=CCN(CC=C)C(=O)CBr
Temperature: 25 °C

Procedure:
A 78-g (0.8 mol) sample of diallylamine was added dropwise to a stirred and cooled (dry-ice/acetone bath) solution of 80 g (0.4 mol) bromoacetylbromide in 200 ml methylene dichloride. The reaction mixture was allowed to warm to about 25° C. and stirred overnight. The reaction mixture was then washed with water, aqueous sodium bicarbonate, again with water, dried over magnesium sulfate and evaporated under reduced pressure to give 38 g N,N-diallyl-α-bromoacetamide.
Reaction SMILES: I/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I-].[Li+].C([Li])CCC.Cl[SiH:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19]>>[CH:2]([SiH:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC/C=C\I
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: [I-]
Agent: [Li+]
Agent: [Li]CCCC
Product: CCCCCC=C[SiH](C(C)C)C(C)C
Yield: 95 %

Procedure:
To investigate the influence of the non-transferable groups on the silicon atom (and illustrate an alternative entry to the silanol precurors) di(isopropyl(silanols (E)-52 and (Z)-52 (Scheme 6) were prepared. Catalytic (H2PtCl6) hydrosilylation of 1-heptyne with chlorodi(isopropyl)silane followed by alkaline hydrolysis provided (E)-52 in 78% yield (25). The stereoisomer (Z)-52, was produced by a high yielding four-step synthesis starting from (Z)-1-iodo-1-heptene. Lithium-iodide exchange with n-butyllithium, followed by the addition of chlorodi(isopropyl)silane formed the intermediate (1-heptenyl)di(isopropyl)silane in 95% yield. Oxidation with chlorine (0.9 M solution in CCl4), followed by mild hydrolysis produced (Z)-52 in 90% yield over two steps.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[N:5]([CH2:15][C:16]2[C:17]([O:23][CH3:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:4]=1)[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([C:3]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH2:15][C:16]2[C:17]([O:23][CH3:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(N)c12
Yield: 63.9 %

Procedure:
A mixture of 3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (186 mg, 0.57 mmol), iron powder (318 mg, 5.7 mmol) and NH4Cl (15.2 mg, 0.285 mmol) in EtOH/water (3 mL/0.75 mL) was heated to reflux for 60 minutes. The reaction mixture was filtered through GF/F paper and concentrated to a residue under reduced pressure. Preparative thin layer chromatography eluting with 2% MeOH 0.25% NH4OH in DCM provided the product (108 mg).
Reaction SMILES: [CH:1]1[C:6](C=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[K+]>C(Cl)Cl.CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([OH:17])=[CH:5][C:4]=2[O:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
commercial piperonal (Aldrich) (60 g) was dissolved in CH2Cl2 (500 ml), m--chloroperoxybenzoic acid (MCPBA) (90 g) added in portions and left to stir at room temperature (18 hrs.). The precipitate was filtered off and washed with CH2Cl2. The combined filtrate was then washed with cold saturated Na2CO3 solution, followed by H2O, dried over anhy. MgSO4 and evaporated to dryness. The resulting formate ester, δ (CDCl3, 300 Hz): 5.99 (2H, s, OCH2O), 6.56 (1H, d, J=8 Hz, H-6), 6.65 (1H, d, J=2 Hz, H-2), 6.70 (1H, d, J=8 Hz, H-5), 8.25 (1H, s, formate), was dissolved in MeOH (250 ml) and mixed with a solution of 30 g KOH in 200 ml MeOH. The reaction mixture was left at room temp for 15 hrs., evaporated to dryness, the residue dissolved in water (300 ml), acidified to neutral by dilute HCl (6N) and extracted with ethyl acetate. The organic layer was washed with NaHCO3 followed by water, dried over anhy. MgSO4 and evaporated to dryness. The crude product (57 g) was recrystallized from hexane (48 g), to yield colourless crystals, mp. 54°-55° C.; IR νmaxKBr cm-1 : 3580, 1625; UV νmaxMeOH nm (ε): 300.1 (2436), 234.2 (2269), 215.3 (2697), with KOH in methanol 314.2 (2477), 242.6 (2781), 225.6 (2746); 1H-NMR δ (CDCl3): 5.90 2H, s, OCH2O), 6.15 (1H, dd, J=2.4, 8.0 Hz, H-6), 6.24 (1H, d, J=2.4 Hz, H-2), 6.34 (1H, d, J=8.0, Hz, H-5), 4.68 (1H, bs, exchanged with D2O, phenolic); HRMS m/z: 138.0316 (M+, 100, C7H6O3), 137.0238 (M+ -H, 88.42, C7H5O3).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)([CH3:3])[CH3:2].C1COCC1.[Li][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1.O>CCOCC>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[NH:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([CH3:12])[CH3:11]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C(Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)n1
Temperature: -78 °C

Procedure:
To a solution of 1.30 g (2.54 mmol) of (2,6-diisopropylphenyl){[6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridin-2-yl]methylene}amine in 20 ml of THF 8.60 ml (6.35 mmol) of 0.74 M PhLi in ether was added by vigorous stirring at −78° C. The reaction mixture was stirred for 10 minutes at room temperature, then 2 ml of water was added, and, finally, this mixture was poured into 50 ml of water. The product was extracted with 3×20 ml of ether. The organic extract was washed by 2×30 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 1.30 g (86%) of yellow oil which crystallized at room temperature. Anal. calc. for C42H43N3: C, 85.53; H, 7.35; N, 7.12. Found: C, 85.72; H, 7.39; N, 6.95. For 1H NMR (in CDCl3) see FIG. 3—Top spectrum.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[NH:10][C:9]1=[O:16])=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]1=[O:16])=[O:6])[CH3:17]
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H]1C
Reaction time: 0.5 h

Procedure:
A solution of (3S-cis)-hexahydro-3-[[(1,1-dimethylethoxy)carbonyl]amino]-7-methyl-2H-azepin-2-one [prepared as described in Example 64 (f), 500 mg., 2.06 mmol.] in tetrahydrofuran (13 ml.) at room temperature under argon was treated dropwise with 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 ml., 2.7 mmol.) immediately followed by the dropwise addition of ethyl bromoacetate (0.47 ml., 4.21 mmol.). The resulting mixture was stirred for 30 minutes, quenched with aqueous ammonium chloride, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated to a yellow oil. Following flash chromatography (E Merck silica gel) eluting with 2:1 hexane/ethyl acetate, 750 mg. of title product was obtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) Rf =0.52.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[C:7]2([CH2:12][CH2:11][N:10](CCCCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:9][CH2:8]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[C:54](=[O:55])[C:53]2[CH:56]=[CH:57][CH:58]=[C:51]3[C:52]=2[C:47](=[CH:48][CH:49]=[CH:50]3)[C:46]1=[O:59].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:2]=[C:3]1[C:7]2([CH2:8][CH2:9][N:10]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][CH:58]=[C:51]5[C:52]=4[C:47](=[CH:48][CH:49]=[CH:50]5)[C:46]3=[O:59])[CH2:11][CH2:12]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
Following the procedure of part (b) of example 26 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains the titled compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]OS(C)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:41].C(OCC)(=O)C>C(#N)C>[F:41][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]([O:22][CH3:23])[O:2][CH3:1]
Reactant: [F-]
Reactant: COC(COCCOCCOCCOCCOS(C)(=O)=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(COCCOCCOCCOCCF)OC
Temperature: 90 °C
Yield: 93 %

Procedure:
A mixture of the sulfonate (Compound 6) (75 mg, 0.21 mmol) and TBAF (1.1 M in THF, 573 μl, 0.63 mmol) in acetonitrile (8 ml) was heated at 90° C. for 30 minutes. TLC (ethyl acetate) monitoring showed the reaction was completed. After cooling to ambient and evaporation of the solvent the residue was flashed (Ethyl acetate) to afford the product (56 mg, 93%) as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)N.N([O-])=[O:12].[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([OH:12])[CH:8]=1
Reactant: Cc1cc(Br)cc(N)c1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
10.00 g of 5-bromo-2,3-dimethylaniline (3-11) was dissolved in a mixed solution of 50 ml of 25% sulfuric acid and 50 ml of toluene, and under cooling with ice, 20 ml of aqueous solution of 3.80 g of sodium nitrite was dropped thereto. The resulting mixture was stirred at the same temperature for 1 hour, and then stirred at 100° C. for 1 hour, and thereafter, the reaction solution was poured into ice water and extracted with ethyl acetate and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=9:1) to obtain 5.49 g of 5-bromo-2,3-dimethylphenol (3-17).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][N:15]1[C:19](B(O)O)=[CH:18][C:17]([CH3:23])=[N:16]1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:14][N:15]1[C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:18][C:17]([CH3:23])=[N:16]1
Reactant: Cc1cc(B(O)O)n(C)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cc(C)nn3C)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=351.3 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 1,3-dimethyl-1H-pyrazole-5-boronic acid (Example J) and 2-amino-4-methylthiazole.