Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N+:4]=1[O-:10].Cl.[N-:12]=[N+:13]=[N-].[Na+]>O>[N:2]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N+:4]=1[O-:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)c[n+]1[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)c[n+]1[O-]
Temperature: 25 °C

Procedure:
In this example, 6.70 grams (0.036 mol) of 2-amino-5-chloropyridine N-oxide hydrochloride was added to and dissolved in 100 ml. of water and 10 ml. of concentrated hydrochloric acid under vigorous stirring and was thus cooled to 0° C. to 5° C. in a salt-ice bath. To the above cold solution, a solution of 2.50 grams (0.036 mol) in 30 ml. of water was added dropwise at such a rate that the temperature of the reaction mixture did not rise above 5° C. Immediately after the above addition was complete a solution of 2.30 grams (0.036 mol) of sodium azide in 30 ml. of water was added to the cold vigorously stirred above solution at such a rate that the temperature did not rise above 5° C. When the above addition was complete the cooling bath was removed and the solution slowly warmed to about 25° C. The reaction mixture was continuously extracted with methylene chloride. From the methylene chloride extract, after evaporation in vacuo was obtained 2-azido-5-chloropyridine N-oxide in a yield of 3.75 grams or 62% of theory having a melting point of 80° C. to 82° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:27][C:4]1[O:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 34D (3.37 g, 14.8 mmol) in THF (50 mL) was cooled to −78° C., followed by addition of LiHMDS (1M in THF, 16.3 ml, 16.3 mmol). After 0.5 hr at −78° C., hexachloroethane (3.50 g, 14.8 mmol) was added in one portion. The reaction was allowed to stir overnight with gradual warming to room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic extract was washed with water and brine, and then filtered through celite filter aid. The filtrate was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in minimal toluene and place on silica gel (Analogix® 25×115 column) and eluted with 2 column lengths of hexanes, then 5% to 50% EtOAc/hexanes. The result was 2.20 g (57%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.88 (m, 1H), 8.00-7.93 (m, 1H), 7.72-7.66 (m, 1H), 2.63 (s, 3H). MS (DCI+) m/z 263 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[CH:14](OC)(OC)[O:15][CH3:16].C(OC(=O)C)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:15][CH3:16]
Reactant: COC(OC)OC
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 125 °C
Yield: 76 %

Procedure:
6-Bromo-4H-isoquinoline-1,3-dione (120 mg, 0.500 mmol) and trimethyl orthoformate (106 mg, 1.00 mmol) are suspended in 1.25 ml of a 1:4 ratio mixture of acetic anhydride and dimethylformamide. Mixture is heated at 125° C. for 2 hours causing a yellow solid to form. Mixture is cooled to room temperature and filtered. Residue is washed with 20 ml of ethyl ether to afford the product as a yellow solid (109 mg, 0.380 mmol, 77%); 1H NMR (DMSO-d6) δ 4.25 (s, 3H), 7.60 (dd, J=1.9, 8.4 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 8.07 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 11.38 (s, 1H); mass spectrum [(+) ESI], m/z 282/284 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Nc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 20 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 5-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 47 mg of the target compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]3[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]3=[N:23][CH:22]=2)[CH:2]=1.C=O.[C:35]([BH3-])#N.[Na+]>CS(C)=O.O>[CH3:35][N:19]([C:3]1[CH:2]=[CH:1][C:6]([C:7]([NH:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[C:25]2[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]2=[N:23][CH:22]=1
Reactant: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Yield: 85 %

Procedure:
Reductive alkylation of diethyl p-aminobenzoyl-L-glutamate) (VI; R=H; R1 =C2H5) with III (Y=CHO) and hydrogen in 70% acetic acid containing Raney nickel gave a 32% yield of 5-deazaaminopterin diethyl ester. Saponification of the ester groups in a mixture of dimethyl sulfoxide-water at ambient temperature gave an 87% yield of 5-deazaaminopterin (II, R=H). Methylation of the latter compound was accomplished by treatment of II (R=H) with formaldehyde and sodium cyanoborohydride in aqueous solution at pH 6.4 to give an 85% yield of 5-deazamethotrexate, (II, R=CH3). The structure of II (R=CH3) was established as described hereinafter in Example 8C by oxidation with alkaline potassium permanganate to give the previously prepared 2-amino-4(3H)oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (VIII), which indicated that methylation had occurred either on the 4- or 10-amino group. Methylation of the 4-amino group was eliminated from consideration by alkaline hydrolysis of the 4-amino group to give 5-deaza-10-methylfolic acid (I, R=CH3).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.I.[NH2:32][C:33]1[C:34]([C:41]([NH:43][C:44](=[NH:47])SC)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1>C(O)C>[NH2:32][C:33]1[C:34]([C:41]([N:43]=[C:44]([NH2:47])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=2)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCCNCC(N)=O)cc1
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution composed of compound 4 (0.065 g, 0.194 mmol), Hunig's base (0.17 mL, 0.97 mmol) and ethanol (6 mL) was heated at 65° C. for 30 min, then 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (5, 0.072 g, 0.213 mmol) was added. The resulting solution was continuously stirred at 65° C. temperature for an additional three hours, then cooled to room temperature. The solvent was then removed by evaporation, and the resulting residue was column chromatographed on silica gel eluting with a mixture of methanol (0-22%), ammonium hydroxide (0-2.2%) and dichloromethane (100-75.8%). This afforded compound 6 (0.078 g, 84%) as a yellow solid. m.p. 92-94° C. (decomposed). 1H NMR (500 MHz, DMSO-d6) δ 1.54 (m, 4H), 2.51 (m, 2H), 2.89 (m, 2H), 3.20 (s, 2H), 3.31 (m, 2H), 4.00 (m, 2H), 6.89 (d, 2H), 7.08 (br, 2H), 7.12 (d, 2H), 7.57 (br, 2H), 9.08 (br, 1H). m/z (ESI) 478.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:46])[C@@H:6]([NH:38][C:39](OC(C)(C)C)=[O:40])[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>O1CCCC1.CO>[CH2:31]([C:23]1[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][S:8][CH2:7][C@:6]([N:38]=[C:39]=[O:40])([O:1][C:10]([CH3:15])([CH3:11])[CH3:9])[C:5]([OH:4])=[O:46])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: [OH-]
Reactant: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)O[C@](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)(N=C=O)C(=O)O
Reaction time: 1 h
Yield: 84 %

Procedure:
1N Sodium hydroxide (2 mL) was added to a stirred solution of (2R)-methyl-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionate (100 mg) in a mixture of tetrahydrofuran (6 mL) and methanol (2 mL). The solution was stirred for 1 hour and then acidified to pH 3 with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (82 mg, 84%): mp. 89-90° C. Rf=0.50 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.8 (2H, d, J=9 Hz, Ar—H), 7.6 (6H, m, Ar—H), 7.4 (2H, d, J=9 Hz, Ar—H), 7.28 (5H, m, Ar—H), 7.21 (2H, d, J=8 Hz, Ar—H), 6.42 (1H, d, J=8 Hz, NH), 4.26 (2H, s, PhCH2), 3.95 (1H, m, CHN), 3.75 (2H, s, PhCH2S), 2.9 (1H, dd, J=15, 5 Hz, CHHCHN), 2.74 (1H, dd, J=15, 8 Hz, CHHCHN), 1.39 (9H, s, tBu); ESI-LCMS e/z calcd for C36H35NO5S 593.74, found 617 (M+Na)+.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[Cl:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][C:50]2[O:51][CH:52]=[CH:53][CH:54]=2)[C:45]([C:55]([O:57][CH2:58][C:59]([Cl:62])([Cl:61])[Cl:60])=[O:56])=[CH:44][C:43]=1[S:63]([NH:66][CH2:67][O:68][C:69](=[O:79])[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77]Cl)=[O:75])(=[O:65])=[O:64]>C(#N)C>[Cl:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][C:50]2[O:51][CH:52]=[CH:53][CH:54]=2)[C:45]([C:55]([O:57][CH2:58][C:59]([Cl:60])([Cl:62])[Cl:61])=[O:56])=[CH:44][C:43]=1[S:63]([NH:66][CH2:67][O:68][C:69](=[O:79])[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:75])(=[O:65])=[O:64]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride, (700) (U.S. Pat. No. 3,819,706; U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) are stirred with cooling on an ice bath. A solution of chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles are removed by spin evaporation, and the residue is partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that is recrystallized to give 2-[(6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone. See U.S. Pat. No. 5,104,870; Sandler et al., Organic Functional Group Preparations, (1968) p. 324.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2C#N)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(Cl)(=O)C([Cl:28])=O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=2)=[CH:9][C:5]([C:6]([Cl:28])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2ccc(C(F)(F)F)nc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring dichloromethane solution (5 mL) containing 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid (Step 38C or 38C.1, 436 mg, 1.2 mmol), was added 2 drops of DMF and then oxalyl chloride (128 μL, 1.5 mmol) under N2. The mixture was stirred at rt for 2 hrs and concentrated to yield 4-chloro-2-methoxy-5-(6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride as a solid, which was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([F:1])[CH:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2[N+](=O)[O-])CCC1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1F
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][CH2:10][CH2:9][C:7](=O)[C:5]=2[CH:6]=1.O1C2C(=CC=CC=2)CCC1O>>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:9][CH2:10]1
Reactant: O=C1CCOc2ccccc21
Agent: OC1CCc2ccccc2O1
Product: C1=Cc2ccccc2OC1

Procedure:
Then, the so-obtained chromanone compound was converted to a chromanol compound in the same manner as described in Example 2, and the dehydration reaction was carried out. Then, the separation and purification were carried out to obtain a 5.84 g of a chromene compound represented by the following formula: ##STR73##
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[O:1]1[C:2]([C:10]([Cl:16])=[O:12])=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2o1
Reaction time: 15 h

Procedure:
A suspension of 2-benzofurancarboxylic acid (0.746 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethylformamide. The reaction mixture was shaken for 15 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of benzo[b]furan-2-carbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][O:16][C:13](=[O:15])[CH3:14])=[N:7][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)Nc1ccc(Cl)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
2-Cloro-N-(5-chloropyridin-2-yl)acetamide (30.68 g) obtained in Reference Example 20(1) is dissolved in N,N-dimethylformamide (500 ml), thereto is added sodium acetate (24.55 g) and the mixture is stirred at 60° C. for 5 hours. The reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine. The solution is dried over magnesium sulfate, treated with activated charcoal, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and the resulting crystals are collected by filtration, washed with n-hexane, and dried to give N-(5-chloropyridin-2-yl)-2-acetoxyacetamide (30.58 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH:16]([CH3:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:16]([CH3:25])[CH:15]=3)[CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccccn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccccn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-2-methyl-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (180 mg) in acetic acid (5 mL) was added ammonium acetate (472 mg), and the mixture was stirred at 110° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (140 mg, yield 81%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 451 (MH+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29].O>CN(C=O)C>[F:29][C:28]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: OCC1CCCNCC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of azepan-4-ylmethanol (1.40 g) and potassium carbonate (3.00 g) in DMF (54.2 mL) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (2.03 mL). The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.901 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:8]=[CH:7][C:6]([C:18]#[N:19])=[C:5]2[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:23]([Cl:35])[CH:22]=1.N1C=CC=CC=1.[CH2:42]1C[O:45][CH2:44][CH2:43]1.C(Cl)(=O)C=C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)=[C:2]([NH:1][C:44](=[O:45])[CH:43]=[CH2:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:18]#[N:19])[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(N)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1OC1CCOC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a reaction flask were added 6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (100 mg, 0.205 mmol), pyridine (0.3 ml), DMAP (20 mg) and THF (10 ml). The mixture was cooled to the temperature of 0° C. To the mixture was added acryloyl chloride (20 mg, 0.22 mmol). The resultant mixture was stirred for 30 min at the temperature of 0° C. Then the mixture was warmed to the room temperature and stirred for 5 hr. After the reaction finished, the resultant mixture was filtered and the filtrate was rotary-evaporated to dryness to give a solid. The solid was dissolved in ethyl acetate. The solution was washed with saturated sodium carbonate once, acetic acid solutioni (10%) once and saturated saline once, successively. The resulting solution was dried over anhydrous magnesium sulfate, filtered and rotary-evaporated to dryness to give a crude prodcut. The product was purified with thin layer chromatography.
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:9]1[C:22]2[C:21]3([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([N:31]=[C:32]=[O:33])[CH2:27][CH2:26]4)[CH2:23][CH:14]([C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:19]1[C:20]2[C:21]3([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH:7][CH2:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:33])[CH2:27][CH2:26]4)[CH2:23][CH:14]([C:13]4[C:22]3=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C=NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: NCC1CCCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a cold (ice bath) stirred solution of cyclopentylmethyamine (664 mg, 6.70 mmol) in methylene chloride (5 mL) was added [(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidyl]isocyanate hydrochloride (221 mg, 0.67 mmol). After stirring the resulting mixture for 0.5 h, at 0° C., the cooling bath was removed and the reaction was allowed to reach ambient temperature. After stirring for 18 h, the reaction mixture was treated with 1N sodium hydroxide and extracted with methylene chloride (2×50 mL). The combined extracts was washed with 1N sodium hydroxide (2×50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated to give a tan syrup. Chromatography of this material over silica gel (eluant: 98:2 methylene chloride:methanol) affords a white foam. This was triturated with hot ether to provide the title compound as a white solid (101 mg, 35%), mp 197.0°-8.0° C.; MS(CI): 430 (M+H); NMR (300 MHz,DMSO-d6): 1.05-1.35 (m, 4H), 1.38-1.78(m, 8H), 1.89(quintet, 1H, J=7.3 Hz), 2.20-2.36(m, 2H), 2.45(s, 2H), 2.78-2.95(m, 4H), 3.26-3.42(m, submerged, 3H), 4.30(s, 1H), 5.66(d, 1H, J=7.5 Hz), 5.73(t, 1H, J=5.5 Hz), 6.84-6.99(m, 4H), 7.18(d, 2H, J=6.4 Hz), 7.26(d, 2H, J=6.9 Hz).