Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)=[O:4].[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11](=[O:13])[N:20]2[CH2:21][CH2:22][N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:34]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:19]2)[CH2:6]1)=[O:4]
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Reactant: COCC1(C(=O)OC)CCN(CC(=O)O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC1(C(=O)OC)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 4 h
Yield: 101.8 %

Procedure:
To a solution of 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 97) (0.21 mmol), 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10, see Example 1 Step 7) (0.21 mmol), O-(7-azabenzotriazol-1-yl-)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU) (78 mg, 0.21 mmol) in dry DMF (2 ml) was added N,N-diisopropylethylamine (108 μl, 0.62 mmol). The reaction mixture was stirred for 4 hours, and evaporated to a residue that was partitioned in ethyl acetate and saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried over magnesium sulfate. Evaporation of solvent provided a crude product which was chromatographed with 5% methanol in dichloromethane to furnish the title compound (97 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[OH-].[K+].[CH2:12]([OH:14])[CH3:13]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:14])[CH:13]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=3)[S:9][C:3]=2[CH:4]=1
Reactant: CCO
Reactant: Nc1ccc(Cl)cc1S
Agent: [K+]
Agent: [OH-]
Product: O=C1Nc2ccc(Cl)cc2SC1c1ccc(Cl)cc1

Procedure:
To a solution of 2-amino-5-chlorothiophenol (4.49 g) in ethanol (30 ml) is added 96% potassium hydroxide (1.63 g), and the mixture is distilled to remove ethanol. The resulting solid material is suspended in toluene (70 ml) and thereto is added methyl α-bromo-4-chlorophenylacetate (7.38 g), and the mixture is refluxed overnight. The reaction mixture is concentrated, and the resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 7-chloro-2-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (6.58 g) as crystals. M.p. 230°-233.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11](I)=[CH:10]2)[CH2:6]1)[CH3:3].[C:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:30]3[CH:29]=[C:28]4[C:33]([CH:34]=[CH:35][C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:27]4)=[CH:32][CH:31]=3)=[CH:10]2)[CH2:6]1)[CH3:3]
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: CN(C)CC1CC(n2cc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C[C@H]1C[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)C1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 7-(3-dimethylaminomethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (891.5 mg, 2.401 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-quinoline (795 mg, 2.40 mmol), Na2CO3 (634 mg, 5.98 mmol), and Pd(PPh3)4 (171 mg, 0.148 mmol; 6 mol %) in DMF (40 mL)/water (8 mL) for 5 min at ambient temperature, then the mixture was heated to 80° C. (bath temp.) for 4.5 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (4×30 mL), and the combined extracts were washed with brine and dried over MgSO4. The crude material (yellow oil) was chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-28)→5% MeOH in CH2Cl2 (29-56)->10% MeOH in CH2Cl2 (57-80)→10% MeOH in CH2Cl2 with 0.07M NH3 (81-130)]. Mixed fractions were chromatographed again [5 g/25 mL cartridge, eluting with CH2Cl2 (1-5)→5% MeOH in CH2Cl2 (6-24)→10% MeOH in CH2Cl2 with 0.07M NH3 (25-40)]. One obtained the target compound as beige solid. 1H NMR (CDCl3, 400 MHz): δ=2.10-2.23 (mc, 2H), 2.27 (s, 6H), 2.35-2.46 (mc, 1H), 2.49 (d, J=6.8 Hz, 2H), 2.77-2.86 (mc, 2H), 5.17 (brs, 2H), 5.20-5.30 (mc, 1H), 7.31 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.6, 8.4 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.30 (brs, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=27.13 (+), 36.50 (2C, −), 45.26 (+), 45.73 (2C, +), 66.10 (−), 101.20 (Cquart), 116.07 (Cquart), 119.00 (+), 120.74 (+), 125.98 (Cquart), 127.38 (+), 127.55 (2C, +), 128.28 (+), 128.47 (+), 128.86 (2C, +), 129.52 (+), 136.45 (Cquart), 136.55 (+), 139.41 (Cquart), 148.51 (Cquart), 150.92 (Cquart), 152.04 (+), 156.99 (Cquart), 158.13 (Cquart). MS (ES+): m/z 449.2 (23) [MH+], 404.1 (4) [MH+—HN(CH3)2], 338.2 (4) [MH+—C4H5CH2N(CH3)2]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:39]1[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=1>O1CCCC1.[Zn]>[CH2:46]([O:45][C:43]([C:42]1[CH:48]=[CH:49][C:39]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:40][CH:41]=1)=[O:44])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
1,2-Dibromoethane (0.286 mL, 3.32 mmol) was added to a suspension of zinc powder (2.12 g, 32.4 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred at 65° C. for 10 minutes. The reaction liquid was allowed to stand to cool to room temperature, then chlorotrimethylsilane (0.400 mL, 3.13 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate described in Production Example 26-3 (5.91 g, 20.9 mmol) in tetrahydrofuran (10 mL) was added to the reaction liquid over 5 minutes, and the mixture was stirred at room temperature for 40 minutes (a solution A). A solution of iris(dibenzylideneacetone)dipalladium(0) (382 mg, 0.418 mmol) and tri-2-furylphosphine (402 mg, 1.73 mmol) in tetrahydrofuran (10 mL) was stirred under nitrogen atmosphere at room temperature for 15 minutes, and then the previously prepared solution A was added at room temperature. Subsequently, a solution of ethyl 4-iodobenzoate (6.92 g, 25.1 mmol) in tetrahydrofuran (18.5 mL) was added under nitrogen atmosphere at room temperature. The reaction liquid was stirred at 65° C. overnight. The reaction liquid was allowed to stand to cool to room temperature, then was filtered with celite, and the resultant was washed with ethyl acetate. The filtrate was washed serially with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, then the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1) to obtain the title compound (4.35 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a stirring solution of Example 158 (0.400 g, 0.914 mmol) and pyridine (0.591 mL, 7.312 mmol) in dichloromethane was added methanesulfonyl chloride (0.141 mL, 1.829 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.365 g, 77% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm -0.22 (m, 2H) 0.24 (m, 2H) 0.85 (m, 2H) 1.57 (s, 3H) 2.14 (m, 1H) 2.32 (m, 1H) 3.08 (s, 3H) 7.56 (m, 4H) 7.73 (m, 4H) 8.14 (d, J=8.09 Hz, 1H) 10.23 (m, 1H) 13.79 (m, 1H). MS (ESI+) m/z=416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[C:3]=1[CH2:9][O:10][CH3:11].[H-].[Na+].[CH3:14]I.Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:14])[C:4](=[O:8])[C:3]=1[CH2:9][O:10][CH3:11]
Reactant: COCc1c(Cl)cn[nH]c1=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1c(Cl)cnn(C)c1=O
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Into 22 ml of an N,N-dimethylformamide solution of 2.17 g of 5-chloro-4-methoxymethylpyridazin-3-(2H)-one prepared in the above step (3), 0.55 g of sodium hydride (containing 40% of mineral oil) was added at room temperature. After the addition, the mixture was stirred for 30 minutes. Then, 2.12 g of methyl iodide was dropwise added thereto at a temperature of not higher than 20° C. After completion of the dropwise addition, the mixture was stirred at room temperature for one hour. After completion of the reaction, 70 ml of water and 4 ml of 10% hydrochloric acid were added to the reaction mixture, and the mixture was extracted with 70 ml of benzene. The benzene layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and from a fraction of n-hexane:ethyl acetate=3:1, 1.53 g of 5-chloro-2-methyl-4-methoxymethylpyridazin-3-(2H)-one having a melting point of from 47 to 49° C., was obtained.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[O:14]=[CH:15][CH2:16][C@H:17]1[O:22][CH2:21][O:20][C@@H:19]([CH2:23][C:24]#[N:25])[CH2:18]1.C(OCC)C>CC(C)=O>[C:24]([CH2:23][C@H:19]1[O:20][CH2:21][O:22][C@@H:17]([CH2:16][C:15]([OH:3])=[O:14])[CH2:18]1)#[N:25]
Reactant: N#CC[C@H]1C[C@@H](CC=O)OCO1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: N#CC[C@@H]1C[C@H](CC(=O)O)OCO1
Reaction time: 0.25 h

Procedure:
Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (97.6 mmol), is added dropwise to a 0° C. solution of (±)-cis-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile, 1.29 g of (7.6 mmol), dissolved in 50 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.2 g of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCC1CCOCC1
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Yield: 94.3 %

Procedure:
The method described in Part E of Examples 431–436 was used to treat 7-bromo-4-chloro-3-nitroquinoline (12.43 g, 43.45 mmol) with C-(tetrahydropyran-4-yl)methylamine (10 g, 87 mmol) to provide 15.0 g of (7-bromo-3-nitroquinolin-4-yl)(tetrahydropyran-4-ylmethyl)amine as a bright yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CO>[CH:7]([N:10]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]
Reactant: CC(C)NC(C)C
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(C(C)C)C(C)C
Reaction time: 24 h
Yield: 99780.8 %

Procedure:
A! Methyl acrilate (89 ml, 0.988 mmole) was slowly dropped into a solution of diisopropylamine (27.7 ml, 0.198 mmole) in methanol (300 ml) at -10° C. The reaction mixture was brought to room temperature and stirred for 24 hours, then the solvent and the methyl acrilate in excess were evaporated off thus obtaining 37 g of crude methyl 3-(N,N-diisopropylamino)propionate (quantitative yield) which was directly employed in the next step.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)(=O)=O.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27](O)[C:28]3[N:29]=[CH:30][CH:31]=[N:32][C:33]=3[CH:34]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:27]2[CH:26]=[C:25]([N:22]3[CH2:21][CH2:20][O:19][CH2:24][CH2:23]3)[CH:34]=[C:33]3[C:28]=2[N:29]=[CH:30][CH:31]=[N:32]3)[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)OC1CCC(Oc2ncccn2)CC1
Reactant: Oc1cc(N2CCOCC2)cc2nccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cnc(O[C@H]2CC[C@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Temperature: 110 °C

Procedure:
As shown in step 7-iv of Scheme 7, a mixture of (4-pyrimidin-2-yloxycyclohexyl) methanesulfonate (105 mg, 0.386 mmol), 7-morpholinoquinoxalin-5-ol (178.3 mg, 0.7712 mmol), and Cs2CO3 (125.6 mg, 0.3856 mmol) in dioxane (1.5 mL) was sealed in a 5 mL microwave tube and heated to 110° C. for 14 hours using an oil bath. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth which was subsequently washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified via preparative reversed-phase HPLC (10-90% CH3CN/water gradient containing 0.1% TFA). Fractions containing a mixture of cis and trans isomers were further purified via SFC using a chiral OJ column and eluting with 40% MeOH in CO2 to provide 21 mg of 4-(8-(((trans)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)quinoxalin-6-yl)morpholine (compound 34): 1H NMR (300 MHz, Chloroform-d) δ 8.69 (dd, J=3.4, 1.9 Hz, 1H), 8.62 (dd, J=3.6, 1.9 Hz, 1H), 8.51 (dd, J=4.8, 2.2 Hz, 2H), 7.01-6.83 (m, 3H), 5.18 (tt, J=7.0, 3.4 Hz, 1H), 4.79 (tt, J=6.9, 3.1 Hz, 1H), 4.00-3.85 (m, 4H), 3.34 (dq, J=4.8, 2.6 Hz, 4H), 2.44-2.16 (m, 4H), 1.92 (tdd, J=16.4, 7.7, 2.8 Hz, 4H); ESMS (M+H+)=408.56, and 22 mg of 4-(8-(((cis)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)-quinoxalin-6-yl)morpholine (compound 42): 1H NMR (300 MHz, Chloroform-d) δ 8.70 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.52 (d, J=4.8 Hz, 2H), 7.01-6.87 (m, 3H), 5.17 (ddt, J=8.7, 6.7, 3.4 Hz, 1H), 4.76-4.58 (m, 1H), 4.00-3.87 (m, 4H), 3.40-3.27 (m, 4H), 2.43-2.22 (m, 4H), 2.05-1.87 (m, 2H), 1.86-1.71 (m, 2H); ESMS (M+H+)=408.56.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[CH:16]1([C:21](=[O:34])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[CH:16]1([C:21]2([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[O:34][C:3](=[O:2])[CH2:4][C:5](=[O:6])[CH2:7]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(CCC(=O)C2CCCC2)c(OC)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) were carefully added and the reaction mixture was stirred for 20 min. A solution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was added dropwise and the resulting mixture was stirred an additional 20 min. A solution of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one (2.33 g, 7.55 mmol) from Step 4 above in THF (37 mL) was added dropwise. After stirring 1 h, the reaction mixture was quenched with saturated aq NH4Cl (100 mL) and extracted with Et2O (600 mL). The organic phase was dried over MgSO4 and evaporated. The residue was then stirred overnight in a mixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of solution of 10% aqueous KHSO4 (50 mL), the resulting mixture was stirred 30 min and then extracted with Et2O (600 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (50% EtOAc in hexanes) to give the product (1.54 g, 52%) as a white foam. 1H NMR (CDCl3) δ 1.43 (m, 2 H), 1.78 (m, 8 H), 2.33 (m, 1H), 2.58 (m, 2H), 2.78 (s, 2H), 3.43 (s, 2H), 3.78 (s, 6H), 6.37 (s, 1H), 6.47 (s, 1H), 6.93 (d, J=7.93 Hz, 1H). MS (APCI) calcd for C20H26O5: 346.2; found (M+1): 347.0.
Reaction SMILES: Cl.[CH:2]([O:5][NH2:6])([CH3:4])[CH3:3].Cl.CON.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:22][C:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:23]1[N:6]([O:5][CH:2]([CH3:4])[CH3:3])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)ON
Reactant: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Agent: CON
Agent: Cl
Product: CCCCc1nc2cnc3ccccc3c2n1OC(C)C
Yield: 72.7 %

Procedure:
The method of Part B of Example 25 was followed using O-isopropylhydroxylamine hydrochloride (2.4 g, 21 mmol) in lieu of O-methylhydroxylamine hydrochloride to treat N-(4-chloroquinolin-3-yl)pentanamide (4.5 g, 17 mmol) with the modification that the reaction was heated at reflux overnight. 2-Butyl-1-isopropoxy-1H-imidazo[4,5-c]quinoline (3.5 g) was obtained as a dark oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[F:38][C:37]([F:39])([F:40])[O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:29]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:27]=1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccccc1-c1noc(-c2ccc(N3CCCCC3)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 42 (137 mg; 0.5 mmol; 1 eq.), Intermediate 2 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from MeOH/water afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C[O-].[Na+].[Cl-].[NH4+:24].[C:25]([OH:28])(=[O:27])[CH3:26]>CO>[C:25]([OH:28])(=[O:27])[CH3:26].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](=[NH:24])[NH2:15])[N:6]=1
Reactant: N#Cc1nc(Cc2ccccc2F)n2ncccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nc(Cc2ccccc2F)n2ncccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
584 mg (2.315 mmol) of the compound prepared in Example 6A were added to 125 mg (2.315 mmol) of sodium methoxide in methanol (10 ml), and the mixture was stirred at 20° C. for 16 hours. 148 mg (2.778 mmol) of ammonium chloride and acetic acid (0.517 ml) were then added, and the mixture was heated at reflux for 8 h. The mixture was then concentrated to dryness, the residue was taken up in water and ethyl acetate and 1 N aqueous sodium hydroxide solution was added. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, concentrated and then dried under high vacuum. This gave 543 mg of the target compound (71% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: COc1ccc(F)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(OC)cc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2-fluoro-5-methoxynitrobenzene and dimethyl sulfoxide, ethyl 2-(4-methoxy-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.