Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH3:13][C:14](=[O:17])[C:15]#[CH:16]>C1C=CC=CC=1>[C:14]([C:15]1[CH:16]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1)(=[O:17])[CH3:13]
Reactant: C#CC(C)=O
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: CC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A solution of 19.0 g (0.119 mole) of 3-diazooxindole and 10 g (0.147 mole) of 3-butyn-2-one in 800 ml of benzene is refluxed overnight. The reaction mixture is cooled to room temperature and the product filtered off (23.1 g). Recrystallization from methanol/chloroform gives 18.0 g of product with melting point 296°-229° (d). Further recrystallization from glacial acetic acid gives 14.2 g of pure product melting at 306°-308° (d).
Reaction SMILES: C([C:7]1[O:8][C:9]2[CH:17]=[CH:16][C:15](OCC3C=CC=C(OCC4C=CC5C(=CC=CC=5)N=4)C=3)=[CH:14][C:10]=2[C:11](=[O:13])[CH:12]=1)(OCCC)=O.C(=O)(O)[O-].[Na+]>C(O)C.O>[O:13]=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH:7]=[CH:12]1
Reactant: CCCOC(=O)c1cc(=O)c2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1ccoc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.71 g of 2-carbopropoxy-6-(3-(quinolin-2-yl-methoxy)benzyloxy)-4-oxo-4H-1-benzopyran and 0.45 g of sodium bicarbonate in 20 ml of ethanol in 20 ml of water is refluxed for 1.5 hours, then stirred at room temperature overnight. The mixture was neutralized and the resulting solid is filtered off, washed with water and dried in vacuo to give 0.55 g of 2-carboxy-6-(3-quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a light yellow solid having an m.p. of 253°-54° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.Cl.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>O1CCCC1.C(N(CC)CC)C>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Yield: 21.2 %

Procedure:
A solution of 50 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26, 26 mg of 4-pyridylacetic acid hydrochloride and 0.05 ml of triethylamine in 5 ml tetrahydrofuran was added 37 mg of 1,1′-carbonyldiimidazole as a condensing agent at room temperature. After the completion of the reaction, the reaction mixture was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 11 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([C:37]1([CH3:45])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]2=[O:46].CCOC(C)=O>CN(C)C=O>[CH3:45][C:37]1([N:31]2[C:30](=[O:46])[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=4)[CH:28]=3)[C:32]2=[O:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44]
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
A stirred mixture of 4-(methylthio)benzoic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (CH2Cl2MeOH, gradient, product eluted after 4.7 min). The product fractions were combined and concentrated to give N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methylsulfanyl-benzamide as a white solid (0.24 g, 26% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.74 min (98.27%); mp: 218-220° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 1.99-2.10 (m, 1H), 2.51-2.61 (m, 5H), 2.62-2.78 (m, 1H), 4.61 (d, J=5.9 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.64-7.96 (m, 5H), 9.17 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.12, 21.02, 28.57, 29.09, 42.57, 58.76, 121.60, 123.19, 124.95, 127.74, 129.59, 129.93, 131.38, 133.38, 142.84, 147.52, 165.86, 167.73, 167.88, 172.13, 172.19; LCMS: MH=452; Anal Calcd for C23H21N3O5S: C, 61.18; H, 4.69; N, 9.31. Found: C, 60.82; H, 4.85; N, 8.96.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:39])[C:29]3[N:33]=[C:32]([CH2:34][CH2:35][O:36][CH3:37])[NH:31][C:30]=3[CH:38]=2)[CH:20]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:37][O:36][CH2:35][CH2:34][C:32]1[NH:31][C:30]2[CH:38]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:39])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: COCCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
29 mg (0.11 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 29 mg (0.09 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(2-methoxyethyl)-4-methyl-1H-benzo-[d]imidazole and 50 μL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 50° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C1COCC1.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c(N)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) in acetic acid (10 mL) and THF (10 mL) was added zinc (2.59 g) at 0° C., and the mixture was stirred at 0° C. for 2 h. After stirring at room temperature overnight, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with AcOEt, washed with sat. NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% AcOEt in hexane) to give N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) as a blue solid.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>O1CCCC1.C(N(CC)CC)C>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([C:3]([F:12])([F:13])[F:2])=[CH:5][CH:6]=1)=[O:18]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1c(Cl)cccc1Cl

Procedure:
To 21.1 g (0.1 mole) of 4-trifluoromethylbenzylamine hydrochloride was added 20.9 g (0.10 mole) of 2,6-dichlorobenzoyl chloride in 200 ml of tetrahydrofuran. Then was added in 1 portion 30 ml triethylamine.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH2:13][CH2:14][S:15][C:16](=[O:34])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:18])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][C@@H:17]([C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])=[O:34])[NH2:18])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCSC(=O)[C@@H](N)Cc1ccccc1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](Cc1ccccc1C(=O)c1ccccc1)C(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
The product of Example 17, N-(2-benzoylphenylalanylthiopropanoy L-proline-t-butyl ester, 1.25 g, was suspended in 4 ml anisole and with 8 ml trifluoroacetic acid for 1 hour at room temperature with stirring. In view of the fact that some starting material was later recovered, the reaction time should be increased. Trifluoroacetic acid was removed with a rotary evaporator under high vacuum. The residue was dissolved in 1 ml THF and chromatographed on a 2.2 cm×99 cm column of Sephadex LH-20 eluted with THF. Fractions of about 5.3 ml were collected. The product was eluted in fractions 41-43. The combined fractions 41-43 were evaporated to dryness, dissolved in a small amount of isopropanol and rechromatographed on a 1.2 cm×95 cm LH-20 column, eluted with isopropanol. Fractions of about 2.05 ml were collected. Fractions 48-50 contained 78 mg of the desired compound as an oil. Side fractions 46-47 and 51-53 were saved for rechromatography. The oil was dissolved in a small volume of THF in a vial, then the THF was evaporated under a stream of N2 . The vial was then placed in a round bottom flask connected to a rotary evaporator. After 3 hr under high vacuum, a stable, dry foam was obtained.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1[C:27]2[CH2:26]C3C(=CC=CC=3)[C:19]=2[CH:18]=[N:17][CH:16]=1>>[N:12]1[CH:11]=[CH:10][C:9]([CH2:1][C:2]2([CH2:26][C:27]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)Cc1ccncc1-2
Reactant: C(=Cc1ccncc1)c1ccccc1
Product: c1ccc2c(c1)-c1cnccc1C2(Cc1ccncc1)Cc1ccncc1

Procedure:
Following the photocyclization conditions described above, 4-styrylpyridine (169) may be converted to 3-azafluorene (170) and alkylated to yield the target 9,9-bis(4-pyridinylmethyl)-3-azafluorene (171) (Scheme 70). ##STR90##
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][CH2:19][CH2:18][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][CH:26]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCSc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCCSc2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (10 mL) at 0° C. The mixture was stirred for 30 min at 50° C., cooled to room temperature and 1-bromo-3-(4-benzyloxy-phenylsulfanyl)-propane (CAB02037, 1.686 g, 5.0 mmol) was added. The reaction mixture was stirred for 15 h and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography (eluent: ethyl acetate, Rf: 0.41). Yield: 1.724 g (78%) colourless oil. The oil was crystallised from a small amount of methanol. Yield: 1.517 g (68%). 1H-NMR (400 MHz, CDCl3) δ=1.84 (tt, J=6.4, 6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 5.06 (s, 2H, —OCH2Ph), 6.52 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.33-7.44 (m, 5H), 7.52 (d, J=9.0 Hz, 2H), 8.26 (s, 2H). LRMS (FAB+): 442.2 (100, [M+H]+)
Reaction SMILES: Br[CH:2]([CH2:5][CH2:6]Br)[C:3]#[N:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:8]([N:21]1[CH2:6][CH2:5][CH:2]1[C:3]#[N:4])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: N#CC(Br)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CC1CCN1C(c1ccccc1)c1ccccc1

Procedure:
Reflux for 18 hours, a stirred mixture of 10 g of 2,4-dibromobutyronitrile, 7.35 g of benzhydrylamine, and 7.41 g of sodium bicarbonate in 100 ml of acetonitrile. Filter off the solids and remove the acetonitrile in vacuo. Treat the residue with ether and filter out insoluble solids. Wash the ether solution first with water, then with a solution of 5.40 g of oxalic acid in 200 ml of water, and finally with brine (saturated aqueous NaCl solution). Dry the solution over anhydrous magnesium sulfate and remove solvent in vacuo. Crystallize the solid residue from methylene chloride-hexane to obtain the analytically pure title compound, m.p. 103.5°-105.0° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)=[N:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:16][CH2:17][N:18]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]([F:21])([F:32])[F:33])[CH2:19][CH:20]=3)=[N:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(C2=CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(C2=CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a stirred solution of 1′,2′,3′,6′-tetrahydro[2,4′]bipyridinyl-5-carboxylic acid (2-cyclopropylethyl)amide (0.050 g, 0.184 mmol) in dichloromethane (5.0 mL) was added 2-(trifluoromethyl)benzoyl chloride (32 μL, 0.203 mmol), and triethylamine (31 μL, 0.203 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The organic phase was washed with water (5 mL), saturated NaCl (5 mL), dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography to afford the pure title compound in 42% yield (0.453 g). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.73-7.67 (m, 1H), 7.63-7.51 (m, 3H), 7.46-7.41 (m, 1H), 7.38-7.32 (m, 1H), 6.77 (s, 1H), 6.49-6.43 (m, 1H), 4.70-4.43 (m, 1H), 4.33-4.26 (m, 1H), 4.15-4.06 (m, 1H), 3.96-3.88 (m, 1H), 3.56-3.49 (dd, J=6.7 and 6.3 Hz, 2H), 3.47-3.30 (m, 2H), 2.76-2.60 (m, 2H), 1.54-1.47 (dd, J=6.8 and 7.0 Hz, 2H), 0.74-0.66 (m, 1H), 0.49-0.44 (m, 2H), 0.10-0.045 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.7, 165.3, 158.8, 147.2, 135.6, 134.7, 132.3, 129.3, 128.6, 127.2, 127.1, 125.4, 124.3, 118.6, 60.4, 47.1, 43.9, 42.3, 40.4, 34.3, 25.9, 8.6, 4.2. MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]=[CH:7][CH2:8]2.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]1[O:21][CH:7]1[CH2:8]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc2c1CC=CC2
Solvent: ClCCl
Product: COc1cccc2c1CC1OC1C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.00 g (0.019M) of 1,4-dihydro-5-methoxynaphthalene are dissolved in 52 ml of methylene chloride, and cooled with an ice bath to 0°. 3.07 g (0.018M) of m-chloro-perbenzoic acid are subsequently added to this solution over the course of one minute. The ice bath is removed, and the reaction mixture is stirred for 15 hours at room temperature. The suspension is then added to a mixture of 20 ml of 10% sodium hydroxide and 40 g of ice. The organic phase is separated, and the aqueous phase is extracted twice, each time with 20 ml of methylene chloride. The combined organic phases are washed with water and sodium chloride solution, dried and concentrated by evaporation. 1a,2,7,7a-tetrahydro-3-methoxynaphth[2,3-b]oxirane is obtained (melting point 49.5°-50.5°, after purification by column chromatography, silica gel 0.063-0.200 mm, methylene chloride and recrystallisation from hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:11]2=3)=[CH:4][CH:3]=1.C[CH2:28][N:29]=C=NCCCN(C)C.Cl.CN.C1COCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([NH:29][CH3:28])=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:11]2=3)=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN1CCc2c(c3cc(C(=O)O)ccc3n2C#Cc2ccc(F)cc2)C1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Fluoro-phenylethynyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (20 mg, 0.0044 mmol) was dissolved in DMF and EDCI.HCl (42.17 mg, 0.22 mmol) was added. Methyl amine (2.0 M) in THF (0.0446 mL, 0.0089 mmol) was added. The reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC and LCMS. The DMF was evaporated under vacuum and the product purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.05 (s, 1H), 7.82 (d, 1H), 7.62 (m, 3H), 7.20 (t, 2H), 4.40 (m, 1H), 3.70 (m, 1H), 3.38 (m, 4H), 3.20 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].O=C1C[CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:2]1[CH2:4][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:3]1
Reactant: CCOC(=O)CC1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC(CC(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a cooled (0° C.) suspension of methyl triphenylphosphonium bromide (8.58 g, 23.5 mmol) in THF (60 mL) was added KOtBu (3.17 g, 28.3 mmol) in portions under N2. The reaction was slowly warmed to rt and stirred for 1 h. The resulting mixture was cooled to 0° C. and added a solution of ethyl 2-(4-oxocyclohexyl)acetate (2.9 g, 15.7 mmol) in THF (15 mL). The resulting mixture was stirred at RT for 2 h and at 50° C. overnight. After cooling to RT, the reaction was quenched by addition of saturated NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes) gave the product as colorless oil (2.11 g, 73.7%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=394.1, tR (minutes, Method F)=1.88
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.[CH3:12][O-:13].[Na+].[Na]>CO>[CH3:12][O:13][C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1

Procedure:
To a suspension of 4-nitro-2-picoline-1-oxide (0.952 g) in dry methanol (20 ml) was added dropwise a solution of sodium methox-ide prepared from sodium (0.60 g) and methanol (10 ml) under stirring at cooling in an ice-bath. The mixture was stirred for 3 hours under the same condition. The resultant mixture was concentrated in vacuo. The residue was treated with chloroform and water. The organic layer was washed with water and a brine, and dried over sodium sulfate. Removal of the solvent gave 4-methoxy-2-picoline-1-oxide (0.958 g).
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C(C)C)ncc1Cl
Yield: 42 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine to yield 7-{5-Chloro-4-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-2-ylamino}-1-isopropyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (39.63 mg, 42% yield) as a beige oil. 1H-NMR (CDCl3) δ 8.12 (d, J=8.9 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (s, 1H), 6.56 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.83 (m, 1H), 3.90 (s, 3H), 3.19 (m, 4H), 2.76 (m, 1H), 2.59 (m, 3H), 2.50 (m, 1H), 2.37 (m, 3H), 2.23 (m, 2H), 1.87 (m, 1H), 1.42 (d, J=6.8 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H). LC/MS (ESI+)=550 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
A suspension of 0.7 g (1.6 mmole) of ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-3-carboxylate, 6 ml of 10% aqueous sodium hydroxide and 2 ml of ethanol was refluxed for three hours. The reaction was filtered through a fiber glass pad to clarify and acidified to pH 1.5 with 6.0M hydrochloric acid and lyophilized. The residue was dissolved in 10 ml of ammonium hydroxide and the solution concentrated in vacuo. The precipitate which formed was removed by filtration, washed with aqueous ethanol, ether and dried in vacuo to give 0.04 g, mp 274°-276° C.