Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:7].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH3:44])[CH:37]=[C:38]([O:42]C)[C:39]=1[O:40][CH3:41].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[OH:42][C:38]1[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=[C:36]([CH3:44])[C:37]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Aluminum chloride (2.5 g) is added portionwise in a nitrogen atmosphere to a solution of 1 g of methyl 21-chloroformylheneicosanoate and 1.7 g of 3,4,5-trimethoxytoluene in 50 ml of nitrobenzene, and the resulting mixture is stirred at room temperature for 48 hours. To the reaction mixture are added water and diluted hydrochloric acid, and the whole mixture is extracted with ether. After distilling of the solvent, the residue is dissolved in methanol, 4.6 ml of a 30% sodium hydroxide solution is added, and the mixture is stirred at 60° C. for an hour. The reaction mixture is washed with ether, then made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried, the solvent distilled off, and the residue chromatographed on silica gel. The crystals recovered from the chloroform-ethanol (17:1) eluate are recrystallized from ether-hexane to give colorless crystals of 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoic acid. m.p. 103°-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:14](NC(C)C)(C)[CH3:15].C(I)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)[CH3:15]
Reactant: CC(=O)C(C)(C)c1cccc(O)c1
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCI
Product: CCOc1cccc(C(C)(C)C(C)=O)c1

Procedure:
The mixture of 3-(3-hydroxy-phenyl)-3-methyl-butan-2-one (3.4 g, 19.08 mmol), diisopropylamine (16.7 mL, 95.4 mmoL) and ethyl iodide (6.2 mL, 76.32 mmol) in 60 mL of ethanol was heated at refluxed overnight. Thin layer chromatography still showed starting material. Potassium carbonate (9 g) was added, and the mixture was heated at reflux for 12 h. It was concentrated in vacuo, and the residue was taken in ethyl acetate. After being washed with water and brine, the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give 3.727 g of 3-(3-ethoxy-phenyl)-3-methyl-butan-2-one as light brown oil. It was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](F)[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[C:18](=[O:20])[CH3:19])C1C=CC=CC=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:13]2[C:12]([O:16][CH3:17])=[CH:11][C:10]([C:18](=[O:20])[CH3:19])=[C:9]([OH:8])[CH:14]=2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc(C(C)=O)c(OCc2ccccc2)cc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)c(O)cc1N1CCN(Cc2ccccc2)CC1
Temperature: 135 °C
Yield: 85.3 %

Procedure:
To a solution of 1-(2-Benzyloxy-4-fluoro-5-methoxy-phenyl)-ethanone (4.25 g, 15.5 mmol) in 3 mL DMF was added 1-benzyl-piperazine (5.4 mo, 30.9 mmol) and potassium carbonate (4.28 g, 30.9 mmol). The reaction mixture was heated under nitrogen to 130-140° C. for 18 hours. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (hexanes:ethyl acetate 8.5:1.5) to yield 4.5 g (73%) of 1-[4-(4-Benzyl-piperazin-1-yl)-2-hydroxy-5-methoxy-phenyl]ethanone as a solid. MP=90-92° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CNC(=O)C2CC2)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Triethylamine (1.87 g, 18 mmol) was added dropwise to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 7 mmol) in dichloromethane (40 ml). The mixture was cooled in an ice bath to 4° C. Cyclopropylcarbonyl chloride (0.99 g, 9 mmol) was added slowly at 4–8° C. After addition, the mixture was stirred in ice bath for 30 min and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the product was purified by flash chromatography (dichloromethane/ethyl acetate 9 to 1) to give 2.1 g (93%) of the product as a white solid: 1H NMR (CDCl3) (7.87 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.77 Hz, 1H), 6.31 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 1.36–1.29 (m, 1H), 0.99–0.93 (m, 2H), 0.76–0.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[C:34]1([CH:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:42][CH2:41][CH:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:22])(=[O:15])=[O:16])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCC(c1ccccc1)c1ccccc1
Product: O=C(NCC(c1ccccc1)c1ccccc1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Yield: 28.9 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 39 mg of 2,2-diphenylethylamine. 39 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide are thus obtained in the form of a yellow paste [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.95 (s, 3H), 3.77 (mt, 2H), 3.90 (dd, J=8 and 6.5 Hz, 2H), 4.22 (mt, 2H), 4.42 (t, J=8 Hz, 1H), 4.79 (s, 1H), from 7.10 to 7.40 (mt, 10H), 7.38 (d, J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.48 (d, J=8.5 Hz, 4H), 7.70 (mt, 2H), 8.56 (t, J=6.5 Hz, 1H)].
Reaction SMILES: FC1C=NN([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)C=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][C:14]1=[O:19]>>[O:19]=[C:14]1[N:13]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH2:18][CH2:17][O:16][CH2:15]1
Reactant: O=C1COCCN1
Reactant: O=C(O)C1(n2cc(F)cn2)CC1
Product: O=C1COCCN1C1(C(=O)O)CC1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 4, but using morpholin-3-one in Step 1. MS (ES+) (M+H) 186.3; LCMS retention time: 0.59 minutes (Method M).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CS(C)=O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A mixture of fluoride 48 (112 mg, 0.24 mmol) and 1-methylpiperazine (1 mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue was suspended in ice/water (50 mL) for 1 h. The mixture was partitioned between CHCl3 (200 mL) and water (50 mL) and the solvent evaporated. The mixture was dissolved in EtOAc (5 mL) and the precipitated filtered to give benzamide 49 (41 mg, 31%) as a white powder: mp (EtOAc) 210-215° C.; 1H NMR δ 9.23 (s, 1 H, CONH), 8.56 (br s, 1 H, H-2′), 8.46 (dd, J=4.8, 1.6Hz, 1 H, H-6′), 8.00 (d, J=8.6Hz, 2 H, H-2, H-6), 7.91 (d, J=8.6Hz, 2 H, H-3, H-5), 7.73 (dt, J=8.0, 2.0Hz, 1 H, H-4′), 7.50 (d, J=9.1Hz, 2 H, H-3″, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.6Hz, 1 H, H-5′), 7.02 (d, J=9.1Hz, 2 H, H-2″, H-6″), 4.49-4.53 (m, 4 H, CH2SO2, CH2N), 3.30 (br t, J=4.9Hz, 4 H, 2×CH2N), 2.40 (br t, J=4.9Hz, 4 H, 2×CH2N), 2.20 (s, 3 H, CH3), 2.12 (s, 3 H, CH3); 13C NMR δ 165.5, 157.8, 154.0, 149.6, 148.8, 148.1, 135.3, 135.1, 134.9, 129.7 (2), 128.8, 128.0 (2), 126.4, 125.4 (2), 123.4 (2), 113.3 (2), 54.1 (2), 53.2, 46.4 (2), 45.6, 40.4, 9.6; MS m/z 546.8 (MH+, 100%).
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=CC=CC=2N=N1.[CH2:11]([N:18]1[CH2:23]CN(CC(O)=O)C[CH2:19]1)[C:12]1[CH:17]=CC=CC=1.[CH2:28]([N:30](CC)CC)C>>[CH2:6]([N:2]=[C:28]=[N:30][CH2:17][CH2:12][CH2:11][N:18]([CH3:19])[CH3:23])[CH3:7]
Reactant: CCN(CC)CC
Reactant: O=C(O)CN1CCN(Cc2ccccc2)CC1
Reactant: On1nnc2ccccc21
Product: CCN=C=NCCCN(C)C

Procedure:
The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy 1,2,3,4-tetrahydroisoquinolin-2-ylppyrimidine(50 mg, 0.132 mmol ), 1-hydroxybenzotriazole(26.8 mg, 0.1 98 mmol), -ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mol), 4-benzylpiperazinoacetic acid dihydrochyoride (48.7 mg, 0.158mmol), and triethylamine(64 μl, 0.462mmol) to afford the titled compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[CH3:19][NH:20][O:21][CH3:22]>ClCCl>[CH:1]1([CH2:7][CH2:8][C:9]([N:20]([O:21][CH3:22])[CH3:19])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
3-Cyclohexylpropionic chloride (1.00 g, 5.71 mmol) was dissolved in dichloromethane (10 mL). Under ice-cooled condition, pyridine (0.910 mL, 11.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (840 mg, 8.57 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 3-cyclohexyl-N-methoxy-N-methylpropaneamide (1.13 g, yield 99%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[CH3:17]N(C)C=O>O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:17])[N:14]=2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(-c2nnn[nH]2)cc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2nnn(C)n2)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-4-methoxybenzonitrile (9 g, 42 mmol), sodium azide (3.03 g, 46.7 mmol) and ammonium chloride (2.5 g, 46.7 mmol) in N,N-dimethylforlmamide (50 ml) was heated at 90° C. for 18 hours. The reaction was cooled, poured onto ice (200 ml) and acidified with 1N HCl to pH1. The resultant solid was filtered, dried and recrystallized from ethanol/water to give 2-bromo-4-(tetrazol-5-yl)anisole (9.2 g). 1H NMR 360 MHz, DMSO-d6) δ 3.95 (3H, s), 7.35 (1H, d, J=8.6 Hz), 8.05 (1H, d, =8.6 Hz), 8.23 (1H, s). To a suspension of sodium hydride (60% dispersed, 1.5 g, 37 mmol) in N,N-dimethylformamide was added the foregoing anisole (5 g, 32.5 mmol) and the reaction stirred at room temperature for 2 hours. The reaction was diluted with water (70 ml) and the resultant solid filtered, dried and chromatographed on silica eluting with 60% ethyl acetate/hexane to give 2-bromo-4-(2-methyltetrazol-5-yl)anisole (3.2 g), 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 4.39 (3H, s), 7.00 (1H, d, J=12.4 Hz), 8.07 (1H, dd, J=12.4 and 3.0 Hz), 8.34 (1H, d, J=3.0 Hz); and 2-bromo-4-(1-methyltetrazol-5-yl)anisole (0.8 g), 1H NMR (360 MHz, CDCl3) δ 3.94 (3H, s), 4.13 (3H, s), 7.01 (1H, d, J=8.6 Hz), 7.66 (1H, dd, J=8.6 and 2.2 Hz), 7.90 (1H, d, J=2.2 Hz).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:6]([CH3:19])[CH:5]=[CH:4][N:3]=1.CO.C[O-].[Na+].[C:25](=O)(O)[O-:26].[Na+]>>[CH3:25][O:26][C:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:6]([CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(F)c1-c1ccc2cc(N)ncc2c1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(C)c1-c1ccc2cc(N)ncc2c1
Temperature: 50 °C

Procedure:
To a solution of 7-(2-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (94.8 mg; 0.374 mmol) in methanol (2.0 mL; 50 mmol) was added a solution of sodium methoxide (25 mass %) in methanol (1.0 mL; 4.5 mmol). The reaction mixture was heated at 50° C. for 5 days. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×50 mL). The combined dichloromethane extracts were dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound in quantitative yield, which was carried forward without purification. LCMS (ESI): M+H=266.2; 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.04 (d, J=5.1 Hz, 1H), 7.64 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.98 (d, J=5.1 Hz, 1H), 6.65 (s, 1H), 5.92 (s, 2H), 3.76 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=C[C:24]([O:25]C2C=CC(N)=C([N+]([O-])=O)C=2)=[CH:23]C=1)([O-])=O.[NH2:38]C1C=CC(O)=CC=1.C([S-])#N.[K+].BrBr>>[C:24]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:17]([CH:16]=2)[NH2:38])=[CH:10][CH:11]=1)(=[O:25])[CH3:23]
Reactant: Nc1ccc(O)cc1
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: BrBr
Agent: N#C[S-]
Agent: [K+]
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is S, and q is 0, can be prepared according to the synthetic sequence shown in Scheme 7 and further detailed in the Examples section following. 4-(4-Nitrophenoxy)aniline (2), derived from (1) and 4-aminophenol, was cyclized with KSCN and Br2 in the presence of acid to provide thiazole (3). Subsequent reaction with ClCO2Me or butylisocyante (BuNCO) to give (4), followed by reduction with SnCl2 to give (5) and finally coupling with isocyanate afforded (6).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][N:8]=2)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1)=[CH:5]2
Reactant: Clc1ccc2ncc(I)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of 2-chloro-7-iodo-1,5-naphthyridine (D-17) (586 mg, 2.02 mmol, 1.0 eq) in 1,4-dioxane (20 mL), tert-butyl piperazine-1-carboxylate (372 mg, 2.00 mmol, 1.0 eq), cesium carbonate (922 mg, 2.83 mmol, 1.4 eq), tris(benzylideneacetone)dipalladium (37 mg, 0.04 mmol, 0.02 eq) and Xantphos (35 mg, 0.06 mmol, 0.03 eq) were added. The mixture was stirred at reflux for 16 h under an argon atmosphere. After the reaction mixture was cooled to RT, it was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (15% ethyl acetate/petroether) to afford the desired product, tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate (D-18) (207 mg, 29.4% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3-d6) δ: 8.79 (d, J=2.7 Hz, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 3.64 (m, 4H), 3.34 (m, 4H), 1.49 (s, 9H); ESI-MS m/z: 349.13[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+:14]([O-])=O)[CH:6]=1.[N-:25]=[N+:26]=[N-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N:14]=[N+:25]=[N-:26])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.0 g, 5.5 mmol) and sodium azide (1.1 g, 16.6 mmol) in acetone (25 ml) is heated under reflux for 3.5 hours. The reaction is then cooled and filtered, and the filtrate is stripped. The residue is taken up in chloroform, washed with water (2X) and with brine, dried, stripped and purified by preparative thin layer chromatography (prep. TLC) (silica gel, eluting with 15% ethyl acetate/hexane) to give 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenyl azide.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].S(Cl)(Cl)=O.[CH2:38](Cl)Cl>>[CH3:38][CH:1]1[CH2:2][CH2:3][CH2:4][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([NH:33][CH2:32][CH2:31][O:30][CH3:29])([CH3:25])[CH3:26])[N:9]=2)=[C:6]1[CH3:7]
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: ClCCl
Reactant: COCCN
Solvent: O=S(Cl)Cl
Product: COCCNC(C)(C)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=C(C)C(C)CCC2)n1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in Example 59, step (e)), methoxyethylamine and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[C:3]1=[O:15].[CH:16]([C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1)=[O:17]>>[OH:17][CH:16]([C:10]1[S:11][C:5]2[N:4]([CH:12]([CH3:13])[CH3:14])[C:3](=[O:15])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1)[C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1
Reactant: CC(C)n1c(=O)n(C)c(=O)c2ccsc21
Reactant: Cn1c(C=O)nc2ccccc21
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(C(O)c3nc4ccccc4n3C)sc21

Procedure:
Prepared from 3-Methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione and 2-formyl-1-methylbenzimidazole following the method of Example 1 step d.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][N:10]=[CH:11][C:5]=2[NH:4][CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Br:25])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>>[Br:13][C:14]1[CH:15]=[C:16]([C:17]([N:4]2[CH2:3][C:2]([CH3:12])([CH3:1])[O:7][C:6]3[CH:8]=[CH:9][N:10]=[CH:11][C:5]2=3)=[O:18])[CH:20]=[C:21]([Br:25])[C:22]=1[O:23][CH3:24]
Reactant: CC1(C)CNc2cnccc2O1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Product: COc1c(Br)cc(C(=O)N2CC(C)(C)Oc3ccncc32)cc1Br
Yield: 44.5 %

Procedure:
By the same method as in the step d) of Example 2, 2,2-dimethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (60 mg, 0.36 mmol) was reacted with 3,5-dibromo-4-methoxy-benzoyl chloride (120 mg, 0.36 mmol) to obtain the target compound, (3,5-dibromo-4-methoxy-phenyl)-(2,2-dimethyl-2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (73 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[ClH:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:16]1[N:17]=[N:18][C:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: Cl
Reactant: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Temperature: 100 °C
Yield: 98.8 %

Procedure:
18.0 g 6-(3-methoxy-4-n-propoxyphenyl)-3[2H]pyridazinone are suspended in 63.6 g phosphorus oxytrichloride. The mixture is stirred at 100° C. until a clear solution has formed and the evolution of HCl stops. The solution is cooled to about 50° C. and poured onto 1 kg of ice, while stirring constantly, whereupon a crystalline precipitate forms immediately, this being filtered off with suction and washed free from acid with water, dilute sodium bicarbonate solution and again with water. Drying in vacuo gives 19.1 g (98.8%) of the title compound of m.p. 129° C., and of m.p. 132° C. after crystallization from cyclohexane.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:6]=2[S:5][CH:4]=1>ClCCl.O=[Mn]=O>[N:8]1[C:7]2[C:3]([CH:2]=[O:1])=[CH:4][S:5][C:6]=2[CH:11]=[N:10][CH:9]=1
Reactant: OCc1csc2cncnc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1csc2cncnc12
Reaction time: 2 h
Yield: 31.2 %

Procedure:
7-hydroxymethyl-thieno[3,2-d]pyrimidine (250 mg, 1.56 mmol) was dissolved in dichloromethane (10 mL), added with MnO2 (1.36 g, 15.60 mmol), followed by stirring for 2 hours. The reaction mixture was filtered through a Celite pad under reduced pressure, and concentrated to obtain the title compound (80 mg, 30%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6]O.S(Cl)([Cl:11])=O>C(O)C>[ClH:11].[Cl:11][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCCCO
Solvent: CCO
Product: CN(C)CCCCCl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 170.2 %

Procedure:
4-(Dimethylamino)butanol (88.5g) was added dropwise at 0° C. over 2 hours to stirred thionyl chloride (93.4 g) then the mixture was stirred at ambient temperature for 1 hour and poured into ethanol (500 ml). The stirred solution was heated under reflux for 10 minutes, then the solvent was removed in vacuo. The solid residue crystallised from ethanol as a white solid which was collected by filtration, washed with ethanol, and dried in vacuo at ambient temperature for 24 hours to give 1-chloro-4-(dimethylamino)butane hydrochloride as a white solid (115 g), m.p. 100°-105° C.