Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:11].[N+](=[CH2:27])=[N-].C(O)(=O)C>C(OCC)C>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:14]([O:16][CH3:27])=[O:15])=[O:11]
Reactant: Cc1ccc(CC(CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccc(C)cc1
Temperature: 0 °C

Procedure:
To a suspension of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionic acid (100 mg) in diethyl ether (10 ml) was added a solution of diazomethane in diethyl ether (10 ml) with stirring at 0° C. After the mixture was stirred at room temperature for 1 hour, excess diazomethane was decomposed with acetic acid. The reaction mixture was washed successively with saturated sodium bicarbonate solution and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 60 mg of methyl 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionate as a colorless viscous oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:11]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cccc(Cl)c1
Product: O=C(C=Cc1ccccc1)c1cccc(Cl)c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 3-chloroacetophenone, 1-(3-chlorophenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:5]=NO.Cl.C=[O:18].O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:5]=[O:18]
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Reactant: C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C=O
Temperature: 25 °C

Procedure:
7.1 g of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime (23 mmol) are stirred in a mixture of 17 g of 5% strength hydrochloric acid, 2 g of a 37% strength solution of formaldehyde, 15 ml of water and 30 ml of tetrahydrofuran at 65° C. for 32 hours. During this time, a further 3.5 g of a 37% strength solution of formaldehyde are added in portions of 0.5 g. The mixture is subsequently cooled to room temperature, and the product is filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][N:22]([CH2:21][CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][C:13]3[CH:30]=[C:31]([F:33])[CH:32]=[C:11]([F:10])[CH:12]=3)=[CH:29][CH:28]=2)[C:23](=[O:27])[O:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccc(Cl)cc1

Procedure:
7.6 g of freshly distilled 4-chlorophenylsulfenyl chloride is added dropwise at 0° to +5° C. in the course of 30 minutes to a solution of 12 g of ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 40 ml of pyridine, with stirring. After this, the mixture is stirred for 16 more hours at room temperature. The reaction mixture is poured into 200 ml of 2N hydrochloric acid and ice, and the mixture is extracted twice using diethyl ether. The combined ether extracts are washed to neutrality with water and dried over sodium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography on silica gel (eluent: hexane/diethyl ether, 9:1), which gives pure ethyl N-(4-chlorophenylthio)-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, nD20 1.5763.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[S:12])[C:4]([CH3:7])=[CH:5][CH:6]=1>[OH-].[Na+]>[CH3:7][C:4]1[N:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)=[S:12])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(NC(=S)NCCn2c(C)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C)n1CCNC(=S)Nc1ccc(C(=O)O)cc1

Procedure:
2.8 g (0.008 mol) of N-(2-(2,5-dimethyl-1-pyrolyl)ethyl)-N'-(4-ethoxycarbonylphenyl)thiourea, prepared as in Example 9, are stirred with 10 ml of 1 N sodium hydroxide solution at room temperature for 5 h and under reflux for 15 min. After cooling, the mixture is filtered, and the filtrate is acidified and the product is filtered off with suction. yield: 1.9 g (75% of theory), Melting point: 174°-175° C. Elemental analysis: C16H19N3O2S (317.41) calculated C 60.5 H 6.0 N 13.2 0 10.1 S 10.1 found: C 59.9 H 5.9 N 13.6 0 10.7 S 9.9
Reaction SMILES: [CH3:1][NH2:2].[C:3](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:4][CH2:5][CH2:6][C@@:7]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1>C1COCC1>[CH3:1][NH:2][C:3](=[O:37])[O:4][CH2:5][CH2:6][C@@:7]1([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:20][CH:21]=2)[CH3:15])[CH2:9][CH2:8]1
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccc(F)cc2)OC1=O
Solvent: C1CCOC1
Product: CNC(=O)OCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
Methylamine (15 mg, 0.22 mmol) and TEA (2 mL) was added to a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl 4-nitrophenyl carbonate (70 mg, crude) in 8 mL of THF. The mixture was stirred at rt overnight. The reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc for 3 times, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the residue, which was purified by preparative HPLC to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methylcarbamate (5 mg, 9%). 1H NMR (CDCl3): 1.55 (m, 3H), 2.36 (m, 5H), 2.74 (m, 3H), 2.99 (m, 1H), 4.09 (m, 2H), 5.71 (m, 1H), 6.92 (m, 2H), 7.04 (m, 4H), 7.33 (m, 5H). LC-MS Method 3 tR=1.32 min, m/z=513, 535.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 0 °C
Yield: 90.6 %

Procedure:
4-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (58 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), piperazine-1-carboxylic acid tert-butyl ester (34 mg), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 635.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH:10]1([NH:18][C:2]2[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCCCC1
Reactant: Cc1c(I)ccnc1F
Solvent: ClCCl
Product: Cc1c(I)ccnc1NC1CCCCCCC1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in cyclooctanamine (3.8 g) was heated at 130° C. overnight, cooled and diluted with dichloromethane. The resulting mixture was loaded onto a silica gel cartridge, eluting with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH:16]=[C:11]2[CH:10]=[C:9]1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:31])([F:30])[CH2:28][CH2:29]3)=[O:23])[NH:8][C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCCCCl)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Temperature: 0 °C

Procedure:
The solution of 1.3 g (2.8 mmol) 5-(3-chloro-propoxy)-2-(4,4-difluoro-piperidine-1-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 15 ml dichloromethane was cooled down to 0° C., then 4.2 ml (6.3 g, 55.5 mmol) trifluoroacetic acid was added and the cooling bath was removed. After 1.5 hours the solution was cooled again down to 0° C. and 60 ml of an aqueous 1M sodium hydroxide solution was added slowly. The solution was extracted three times with dichloromethane, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and 50 ml n-heptane) was added. The dichloromethane was evaporated at a rotary evaporator and the resulting suspension was filtered and washed with n-heptane and the colorless solid (0.92 g, 93%) was dried under high vacuum.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCOc1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1
Yield: 86 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(octyloxy)benzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.57 (d, 2H, J=7.9 Hz), 7.45 (d, 2H, J=7.9 Hz), 7.22 (m, 2H), 6.85 (m, 2H), 3.93 (t, 2H, J=6.5 Hz), 3.84 (s, 2H), 3.72 (s, 2H), 1.82-1.70 (m, 2H), 1.50-1.23 (m, 10H), 0.89 (m, 3H). M−(LC/MS(ESI)): 406.3 HPLC (Condition A), Rt: 4.42 min (HPLC purity: 98.7%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([CH:15](C1N=C(C(O)=O)C=C(OC)C=1)[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([CH:15]([C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCC(CC)c1cc(OC)cc(C(=O)O)n1
Reactant: COC(=O)c1cc(C)cc(Cl)n1
Product: CCC(CC)c1cc(C)cc(C(=O)O)n1

Procedure:
Methyl 6-chloro-4-methyl-pyridine-2-carboxylate (500 mg, 2.69 mmol) is treated with 1-ethyl-propyl zinkbromide and saponified as described for 6-(1-ethyl-propyl)-4-methoxy-pyridine-2-carboxylic acid to give the title compound (220 mg) as a pale yellow oil; LC-MS**: tR=0.37 min, [M+1]+=208.29; 1H NMR (CDCl3): δ 0.80 (t, J=7.3 Hz, 6H), 1.69-1.81 (m, 4H), 2.48 (s, 3H), 2.58-2.67 (m, 1H), 7.21 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: CS(Cl)(=O)=O.CC1SC([C:12]([C:20]([C:22]([OH:35])([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)C2C=CC=CC=2)=O)(O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15]C=2)=CC=1.[NH:36]1[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]1=[S:43]>CC(C)=O.O.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:34][C:31]1[S:30][C:29]([C:22]2([OH:35])[N:38]3[CH2:39][CH2:40][CH2:41][CH2:42][N:36]=[C:37]3[S:43][CH:20]2[C:12]2[CH:13]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(C(O)(C(=O)C(O)(c2ccccc2)c2ccc(C)s2)c2ccccc2)s1
Reactant: S=C1NCCCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(O)C(c3ccccc3)SC3=NCCCCN32)s1
Reaction time: 20 h

Procedure:
A mixture of 1.71 ml. of methanesulfonyl chloride in 40 ml. of toluene is added dropwise to a stirred slurry of 4.65 g. of 5-methyl-2-thienyl-α-hydroxybenzyl ketone and 5.6 ml. of triethylamine in 40 ml. of toluene. The mixture is stirred 20 hours, water is added and the organic layer is separated, washed with water and concentrated to dryness. A 20 ml. portion of ether is added to the residue giving a solid which is collected, washed with ether and dried, giving 4.8 g. of 5-methyl-2-thienyl-α-hydroxybenzyl ketone methanesulfonate ester. A mixture of 2.01 g. of this ester and 0.84 g. of hexahydro-2H-1,3-diazepine-2-thione in 40 ml. of acetone is allowed to stand 48 hours. The solvent is removed, 50 ml. of water and one ml. of concentrated ammonium hydroxide are added and the resulting solid is collected and washed with water. This solid is dissolved in 7 ml. of ethanol and then cooled. The resulting solid is collected, washed with ethanol, then ether and dried in vacuo, giving 1.2 g. of the desired product as a yellow solid, m.p. 70°-90° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:9][NH:8][C:7]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:6]2[O:5]1.Cl.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][C:4]1([CH3:17])[CH2:9][N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-:26])[C:7]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:6]2[O:5]1
Reactant: [O-][n+]1ccccc1Cl
Reactant: CC1(C)CNc2cc3nonc3cc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc3nonc3cc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
To a suspension of 215 mg sodium hydride (60%) in 5 ml hexamethylphosphoramide, were added 500 mg 7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine and 486 mg 2-chloropyridine N-oxide hydrochloride in that order, and the mixture was stirred at room temperature for six hours. The reaction mixture was poured into ice water, the resulting mixture was extracted with ethyl acetate, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvents were distilled off from the dried solution. The residue was subjected to column chromatography on silica gel, and the crystals obtained by elution with a 2:1 mixture of chloroform and acetone were recrystallized from 6 ml ethanol, giving 409 mg of 2-(7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazin-8-yl)pyridine 1-oxide.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][CH:34]([F:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:35][CH:34]([F:42])[F:33])[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: FC(F)CN1CCNCC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(CC(F)F)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2,2-difluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=4.72 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=513 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.57 (br. s, 4H) 2.73 (td, J=15.64, 3.91 Hz, 2H) 3.09-3.22 (m, 4H) 6.13 (s, 1H) 6.67 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.33 (br. s, 1H) 8.73 (s, 1H) 10.40 (br. s, 1H) 12.98-13.22 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[C:21]([CH:22]=O)=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CO>[Cl:12][C:13]1[C:21]([CH:22]=[N:5][O:4][CH2:2][CH3:3])=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCON
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
1.63 g (0.017 mol) of ethoxyamine hydrochloride and 1.15 g (0.0085 mol) of finely pulverulent potassium carbonate were stirred for 1 hour in 60 ml of dry methanol. 4.00 g (0.015 mol) of 2-chloro-3-formyl-4-methylsulfonylbenzoic acid in 40 ml of methanol were subsequently added. After the mixture was stirred for 12 hours at room temperature, the solvent was removed, the residue was taken up in ethyl acetate, and the organic phase was washed four times with water. After the mixture had been dried and the solvent distilled off, 3.60 g of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoic acid were obtained (78% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[NH2:14].C(N(CC)CC)C.[CH2:23]([O:25][CH2:26][C:27](Cl)=O)[CH3:24].CO.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[N:3]1[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]=[C:24]1[CH2:23][O:25][CH2:26][CH3:27]
Reactant: CN(C)Nc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1N(C)C
Reaction time: 1.5 h
Yield: 14.3 %

Procedure:
A solution of 4-(2,2-dimethylhydrazino)quinolin-3-amine (4.64 g, 23.0 mmol) in 75 mL of CH2Cl2 was cooled to 0° C. under an atmosphere of nitrogen. The reaction mixture was treated with triethylamine (6.72 mL, 48.2 mmol) followed by dropwise addition of ethoxyacetyl chloride (2.95 g, 24.1 mmol). After 1.5 h, the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in 75 mL of ethanol, treated with triethylamine (9.60 mL, 68.9 mmol) and heated to reflux. After 5 d, the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in CH2Cl2, washed with 2% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown oil. Chromatography (SiO2, 5–10% MeOH/CHCl3) gave N,N-dimethyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine (0.89 g) as a brown oil.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=3)[N:14]([CH2:26][CH3:27])[C:13]2=[O:28])[CH2:8][CH2:7]1)=O)C.Br.C(N1C2C(=CC([N+]([O-])=O)=CC=2)C(=O)N(C2CCNCC2)C1=O)C.[Cl:53][C:54]1[N:63]=[C:62](Cl)[C:61]2[C:56](=[CH:57][C:58]([O:67][CH3:68])=[C:59]([O:65][CH3:66])[CH:60]=2)[N:55]=1>>[Cl:53][C:54]1[N:63]=[C:62]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=4)[N:14]([CH2:26][CH3:27])[C:13]3=[O:28])[CH2:8][CH2:7]2)[C:61]2[C:56](=[CH:57][C:58]([O:67][CH3:68])=[C:59]([O:65][CH3:66])[CH:60]=2)[N:55]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)c3cc([N+](=O)[O-])ccc3n(CC)c2=O)CC1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: Br
Agent: CCn1c(=O)n(C2CCNCC2)c(=O)c2cc([N+](=O)[O-])ccc21
Product: CCn1c(=O)n(C2CCN(c3nc(Cl)nc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 78 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 3.62 g (9.4 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound ii) was used in place of Compound a, whereby 3.20 g of crude 1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound jj) was obtained. The product (198.0 mg) was treated in the similar manner as in Example 40, except for the use of 2,4-dichloro-6,7-dimethoxyquinazoline in place of 4-chloro-6,7-dimethoxy-quinazoline, to give 220.7 mg (yield: 78%) of Compound 79 as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CCOCC>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)=[S:30]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc([N+](=O)[O-])cc1
Yield: 81.8 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.976 g, 4.02 mmol) and 4-nitrophenyl isothiocyanate (0.723 g, 4.02 mmol) to afford the product (1.39 g) after trituration in ether; m.p. 183-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([F:23])[CH:18]=2)=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 96%).