Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31]([C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:37]=2[CH3:38])=[O:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)#[N:17]>O>[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31]([C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37]=2[CH3:38])=[O:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][N:27]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:26][CH2:25]1)#[N:17]
Reactant: Cc1oncc1C(=O)Cl
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1oncc1C(=O)N1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(F)cc4)c3C)cc2C#N)CC1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
5-Methylisoxazole-4-carbonyl chloride (1.4 g) synthesized according to the method described in J. Chem. Soc. Perkin Trans. I, pp. 1875–1879 (1988) was added to a pyridine solution (20 ml) containing N-[3-cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (4 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under pressure. Diisopropyl ether was added to the obtained residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.9 g), melting point: 208° C.
Reaction SMILES: C[CH:2]1[CH2:8][CH2:7][N:6]2[C:9](=[O:21])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4][CH2:3]1.[CH3:22]C1CCC2C3C(=O)N4CCCCCC4=NC=3SC=2C1>>[CH3:22][CH:18]1[CH2:17][CH2:16][C:15]2[C:10]3[C:9](=[O:21])[N:6]4[CH2:7][CH2:8][CH2:2][CH2:3][CH2:4][C:5]4=[N:12][C:11]=3[S:13][C:14]=2[C:19]1=[O:20]
Reactant: CC1CCc2c(sc3nc4n(c(=O)c23)CCCCC4)C1
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Product: CC1CCc2c(sc3nc4n(c(=O)c23)CCCCC4)C1=O

Procedure:
Compound 28 was synthesized by the method described for compound 17 using compound 27 as a starting material.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 28.1 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM, and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a pale yellow solid (0.024 g, 29%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.42 (m, 4H), 2.62-2.71 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.74 (m, 6H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.51 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.12 min—568/570 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 568.1504, calculated for C26H31N7BrOS (M+H)+: 568.1494.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][C:30]([NH:21][S:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=3)[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=2)(=[O:19])=[O:20])=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropionyl chloride, gave N-(3-phenylpropionyl)-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25])[CH3:29]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (2 g) and β-alanine ethyl ester hydrochloride (0.84 g) and 1-hydroxybenzotriazole (0.74 g) in dimethylformamide (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3-MeOH (99:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester as a colorless oil (2.54 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:12][O:13][CH3:14])=[CH:7]2.[OH-:15].[Na+]>O.[Ta]>[OH:15][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:12][O:13][CH3:14])=[CH:7]2
Reactant: COCc1cnc2c(Cl)cccc2c1
Reactant: [OH-]
Agent: [Ta]
Agent: [Na+]
Solvent: O
Product: COCc1cnc2c(O)cccc2c1
Reaction time: 21.5 h
Yield: 63.2 %

Procedure:
Into a tantalum liner in a 600 ml stirred Parr pressure reactor is placed 4.15 g 8-chloro-3-methoxymethylquinoline (20 mmol), 8.0 g 50% aqueous sodium hydroxide (100 mmol) and a solution of 250 mg cupric sulfate pentahydrate (1.0 mmol, 5 mole percent) in 95 ml of water. Sodium hydroxide concentration is 4%. The system is sealed, brought to 160 degrees C and held for 21.5 hours. The cooled solution is filtered through Celite, extracted with two 20 ml portions of toluene, then the aqueous layer is adjusted to pH 3-4 with sulfuric acid and finally to pH 7 with ammonium hydroxide. The mixture is extracted with two 50 ml portions of ethyl acetate. Rotary evaporation of the organic layer gives 2.39 g (63% yield) of crude 8-hydroxy-3-methoxymethylquinoline as a yellow green solid. The crude material is treated with two 500 ml portions of boiling water, leaving behind some insolubles. Long silky yellow needles of pure 8-hydroxy-3-methoxymethylquinoline separate. After filtering and drying, 1.83 g (48% yield) is obtained.
Reaction SMILES: C(N1C2C=C(OC)C([O:14]C)=CC=2C(C2C=CC=CC=2)=NC(CC2C=C(C=CC=2)C#N)C1=O)C.[CH2:34]([O:36][C:37]1[C:64]([O:65][CH3:66])=[CH:63][C:40]2[C:41]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[N:42][CH:43]([CH2:48][C:49]3[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=3)[C:52]#[N:53])[C:44](=[O:47])[N:45]([CH3:46])[C:39]=2[CH:38]=1)[CH3:35]>>[CH2:34]([O:36][C:37]1[C:64]([O:65][CH3:66])=[CH:63][C:40]2[C:41]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[N:42][CH:43]([CH2:48][C:49]3[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=3)[C:52]([NH2:53])=[O:14])[C:44](=[O:47])[N:45]([CH3:46])[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1cccc(C#N)c1)C(=O)N2C
Reactant: CCN1C(=O)C(Cc2cccc(C#N)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1cccc(C(N)=O)c1)C(=O)N2C
Yield: 86 %

Procedure:
By replacing 3-[(1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIcp) in example IIcs by 3-[(8-ethoxy-7-methoxy-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIdf) and proceeding in the same manner, the abovenamed product is obtained. Yield: 86%. M: 199–201° C. 1H-NMR (CDCl3, 300 MHz): d 1.52 (s, 3H, CH3), 3.39 (s, 3H, NCH3), 3.66–3.79 (m, 3H, —CH2Ph+CH+OCH3), 4.17 (q, 2H, CH2), 5.84 (m, 1H exchangeable —NH2), 6.24 (m, 1H exchangeable —NH2), 6.64 (s, 1H Ar), 6.74 (s, 1H Ar), 7.26–7.83 (m, 9H Ar).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2([CH3:28])[CH:19]3[CH:15]2[CH2:16][N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]3=O)[CH:11]=[CH:12][CH:13]=1.Cl.[OH-].[Na+]>O1CCCC1.O>[CH2:21]([N:17]1[CH2:16][CH:15]2[CH:19]([C:14]2([C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=2)[CH3:28])[CH2:18]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(c2cccc(N)c2)C2CN(Cc3ccccc3)C(=O)C21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cccc(N)c2)C2CN(Cc3ccccc3)CC21
Temperature: 50 °C
Yield: 96.2 %

Procedure:
Lithium aluminium hydride (1M in tetrahydrofuran, 11.84 ml, 11.84 mmol) was added dropwise to dry tetrahydrofuran (60 ml) under nitrogen. 6-(3-Aninophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 29, 1.73 g, 5.90 mmol) was suspended in dry tetrahydrofuran (100 ml) and added slowly to the lithium aluminium hydride solution by cannula. The reaction was then heated at 50° C. for 2 hours. After cooling, water (20 ml) was cautiously added to the solution, the pH of the aqueous layer was adjusted to 4 by the addition of 2N hydrochloric acid and then adjusted to 10 using dilute sodium hydroxide solution. The mixture was extracted with ethyl acetate (3×200 ml), and the combined extracts were washed with water (100 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow oil (1.58 g, 96%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccccc1N
Reactant: CS(=O)(=O)c1ccc(NCc2ccc(C(=O)O)cc2)cc1
Product: CS(=O)(=O)c1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1

Procedure:
The compound was obtained by reacting the acid 211a with 1,2-phenylenediamine following the procedure described in the scheme 1, step 5 (example 1). 1H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.35 (t, J=6.0 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.93 (dt, J=1.6, 8.0 Hz, 1H), 6.73 (dd, J=1.6, 8.0 Hz, 1H), 6.66 (d, J=8.8 Hz, 2H), 6.55 (dt, J=1.2, 7.6 Hz, 1H), 4.88 (bs, 2H), 4.43 (d, J=6.0 Hz, 2H). LRMS: (calc.) 395.5; (obt.) 396.4 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.CC1(C)COB([C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[C:40]#[N:41])OC1>>[C:40]([C:39]1[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=1[C:7]1[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH2:1][CH3:2])#[N:41]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: CC1(C)COB(c2ccccc2C#N)OC1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2C#N)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H19N2O3 (M+H): 359.1390. Found 359.1386
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:17])([CH2:14][CH:15]=C)[CH:12]=[O:13].[BH4-].[Na+].ClCCl.C[OH:24]>[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:17])([CH2:14][CH2:15][OH:24])[CH2:12][OH:13]
Reactant: C=CCC(C)(C=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(CO)(CCO)c1cc([N+](=O)[O-])ccc1F
Temperature: -78 °C

Procedure:
2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal (1 eq) was dissolved in dichloromethane:methanol (3:1) and cooled to −78° C. Ozone was then bubbled through the solution until a blue color was noticed. Air was then passed through the solution followed by the addition of sodium borohydride (5 eq). Resulting solution was allowed to warm to room temperature and diluted with brine, extracted with dichloromethane. Organics were dried with sodium sulfate and concentrated to afford 2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol. The product was used in the next step with no further characterization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[OH-].[Li+]>C1COCC1.O>[OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a stirred solution of methyl 2-hydroxy-2′-methyl-1,1′-biphenyl-4-carboxylate (12 g, 0.05 mol) in a mixture of THF/water (150 mL:15 mL) was added lithium hydroxide (6.23 g, 0.1485 mol) in portions. After being stirred at RT for 24 h, the reaction mass was evaporated to dryness and the residue diluted with little amount of water. The aqueous phase was acidified with conc.hydrochloric acid and extracted with EtOAc. Organic layer was washed with brine solution and was dried over Na2SO4. Evaporation of the solvents afforded the title compound as a white solid (10 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 12.72 (1H, bs), 9.78 (1H, bs), 7.50 (1H, s), 7.41-7.43 (1H, m), 7.08-7.24 (5H, m), 2.09 (3H, s). LC/MS (Method A): 227 (M−H)−. HPLC (Method B), Rt 4.09 min (purity: 99.69%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O1C2C=CC=CC=2C=CN1>O>[Cl:1][C:2]1[C:3]([F:13])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17](=[O:16])[C:11]([CH:12]=1)=[C:5]23
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1COc2c(ccc(Cl)c2F)N1
Agent: C1=Cc2ccccc2ON1
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)OCC2C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 1.11 g (5.5 mmols) of 7-chloro-8-fluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine and 1.4 g (6.2 mmols) of diethyl ethoxymethylenemalonate was stirred for 2 hours while heating at 130°-140° C. (bath temperature). After confirming disappearance of the starting benzoxazine compound by thin-layer chromatography, 5 g of ethyl polyphosphate was added to the reaction mixture and the mixture was again allowed to react for 1 hour at 140° C. (bath temperature). After cooling, 20 ml of water was added to the mixture and the precipitate formed was extracted with 150 ml of chloroform. The chloroform extract was dried with sodium sulfate and chloroform was then distilled off. The resulting residue was purified by silica gel (20 g) column chromatography using methanol-chloroform (5:95 by volume) as an eluant to provide 1.2 g (67.0% yield) of ethyl 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate with m.p. 263°-264° C.
Reaction SMILES: C1(C(C)C=O)CCCCC1.[C:11]([C:13](=[CH:19][CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21])C(OCC)=O)#[N:12]>>[CH:22]1([CH:20]([CH3:21])[CH2:19][CH2:13][C:11]#[N:12])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(C#N)=CC(C)C1CCCCC1
Agent: CC(C=O)C1CCCCC1
Product: CC(CCC#N)C1CCCCC1

Procedure:
In a 2 L flask with a distillation tube attached thereto, 475 g of ethyl cyanoacetate (VI-1) (4.20 moles, 1.05 times by mole with respect to the 2-cyclohexylpropanal (II)), 6.0 g of acetic acid (0.10 millimole, 0.025 times by mole with respect to the 2-cyclohexylpropanal (II)), and 3.4 g of piperidine (40 millimoles, 0.01 times by mole with respect to the 2-cyclohexylpropanal (II)) were placed, which then was stirred at room temperature. Then, 561 g (4.00 moles) of 2-cyclohexylpropanal (II) (“Pollenal II” (Trade Name), manufactured by Kao Corporation) was dropped thereinto over 40 minutes. Thereafter, this was heated to 50° C., the pressure was reduced gradually to 4.0 kPa over two hours, and the reaction was continued while by-product water was removed. Furthermore, excessive ethyl cyanoacetate was distilled under 130 Pa at 110° C. Then, 921 g of the concentrated liquid thus obtained was subjected to gas chromatography quantitative analysis. As a result, the conversion ratio of the 2-cyclohexylpropanal (II) was 100% and the ethyl 2-cyano-4-cyclohexylpenta-2-enoate (VII-1) had a purity of 98.0% and a reaction yield of 95.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:13]=O)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.C[C:16]1[NH:17]C2C(C=1C=O)=CC=CC=2>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:13][NH:17][CH3:16])=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: COc1ccc2c(C=O)cn(C)c2c1
Product: CNCc1cn(C)c2cc(OC)ccc12
Yield: 87 %

Procedure:
According to the procedure of Preparation 12, except substituting 6-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the 2-methylindole-3-carboxaldehyde, the title compound (2.1 g, 87%) was obtained as an oil: MS (ES) m/e 205.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[CH2:10][CH:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[C:8]=1[CH3:27])(=[O:5])=[O:4].B(Br)(Br)Br>ClCCl>[F:28][C:2]([F:1])([F:29])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH:9]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[C:8]=1[CH3:27])(=[O:4])=[O:5]
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C(OS(=O)(=O)C(F)(F)F)=C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=C(OS(=O)(=O)C(F)(F)F)c2cc(O)ccc2CC1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Compound 5a (0.315 g, 0.735 mmol) was dissolved in dichloromethane (5 ml) to obtain a clear colorless solution. This solution was cooled to 0° C. and then boron tribromide (0.283 ml, 2.94 mmol) was added carefully to give a brown solution. The mixture was stirred at room temperature for 2 h and then poured into ice water (25 ml) and extracted with dichloromethane (2×10 ml). The organic phases were combined, washed with a saturated sodium bicarbonate solution (50 ml) and water (50 ml), dried with sodium sulfate and concentrated. The crude product was purified by column chromatography (toluene/ethyl acetate 90:10) to give compound 20 as a yellow oil (0.206 g, 70% yield). 1H NMR (CDCl3): δ 1.86 (s, 3H), 2.80 (dd, J1=5 Hz, J2=16 Hz, 1H), 3.26 (dd, J1=7 Hz, J2=16 Hz, 1H), 3.57 (dd, J1=5 Hz, J2=7 Hz, 1H), 6.66 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.79 (AB, J1=10 Hz, J2=90 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH3:19][O:20][CH2:21]CCl>>[CH3:19][O:20][CH2:21][CH2:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)C
Reactant: COCCCl
Product: COCCc1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 45, 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2 g 8.4 mmol,) was reacted with 2-chloroethyl methyl ether (0.76 mL, 10 mmol) to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][CH:20]([OH:42])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[CH2:11]([O:18][CH2:19][C:20](=[O:42])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCCCCCCCCCCCOCCC(O)COCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOCCC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a complex prepared at -60° C. from the addition of 10.4 ml of dry dimethyl sulfoxide to 8.9 g (70 mmol) of oxalyl chloride in 150 ml of methylene chloride, was added, dropwise, 27.7 g (62.2 mmol) of the compound prepared in (a) above. After stirring the mixture under a nitrogen atmosphere for 1 hour, 50 ml of triethylamine in 50 ml of methylene chloride was added and the resultant mixture was allowed to warm to 0° C. over a period of 30 minutes, after which time it was quenched with 75 ml of water. After the mixture was allowed to warm to room temperature, the organic layer was separated, washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford an oil which solidified on standing. Flash chromatography on silica gel employing a mixture of petroleum ether and diethyl ether in a ratio of 7:3 as the eluent yielded a solid, m.p. 33°-34° C.