Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: C[Si](C)(C)C#Cc1cc2c(O)c(C#N)cnc2cn1
Reactant: O=P(Cl)(Cl)Cl
Product: C[Si](C)(C)C#Cc1cc2c(Cl)c(C#N)cnc2cn1

Procedure:
To 500 mg of 4-hydroxy-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 10 mL of phosphorous oxychloride. After two hours at reflux, the excess phosphorous oxychloride was removed in vacuo and ice-water, chloroform, a tract of methanol, and aqueous saturated sodium bicarbonate were added. The chloroform layer was washed with brine, dried with sodium sulfate, and evaporated to give 626 mg of crude 4-chloro-6-trimethylsilanylethynyl-[1.7]naphthyridine-3-carbonitrile as a yellowish solid, which was used in the following step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.CC1C=CC(S(O[CH:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)(=O)=O)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:11]([CH3:12])[C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[CH:16][C:6]=2[C:7]=1[CH3:15])=[O:14]
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(O)cc12
Reactant: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
A solution of 1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.0 g) synthesized above, tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) and tripotassium phosphate (1.26 g) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 3 hr then at 100° C. for 14 hr. Tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) was added to the mixture, and the mixture was stirred at 100° C. for 20 min. Tripotassium phosphate (600 mg) was added to the mixture, and the mixture was stirred at 100° C. for 2 hr then at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (886 mg, 61%) as an orange oil.
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl.O>C(O)C.CN(C=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][S:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: Sc1nc2cnccc2[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Fc1cccc(Cl)c1CSc1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 0.34 g (0.015 g atom) of sodium in 70 mL of ethanol was added 2.0 g (0.013 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine. After stirring at room temperature for 25 minutes, the reaction mixture was evaporated to dryness in a rotary evaporator. To the residue was added 40 mL of DMF. To the resulting solution was added dropwise 2.33 g (0.013 mol) of 2-chloro-6-fluorobenzyl chloride in 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and was then poured into 400 mL of chilled water. The precipitate that formed was collected by filtration and amounted to 3.11 g. An analytical sample (m.p. 224°-226° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[CH3:12][N:13]([CH3:16])[CH:14]=O.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>O>[NH2:7][C:5]1[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=[C:2]([N:1]=[CH:12][N:13]([CH3:16])[CH3:14])[N:6]=1
Reactant: CN(C)C=O
Reactant: CNC(=S)n1nc(N)nc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Product: CNC(=S)n1nc(N=CN(C)C)nc1N
Reaction time: 4.5 h
Yield: 27 %

Procedure:
A solution of the compound (1.00 g) obtained in Example 31, dimethylformamide (25 ml) and triethylamine (1.0 ml, 7.2 mmol) was cooled to 0° C. and benzoyl chloride (0.70 ml) was gradually added dropwise thereto. The mixture was stirred at 0° C.-room temperature for 4.5 hours and the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. After the concentration, silica gel column chromatography (chloroform-methanol) and recrystallization from chloroform-methanol gave 350 mg of pale-yellow crystals (yield 27%).
Reaction SMILES: [N+]([O-])(O)=O.[CH2:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])[CH:6]=[CH2:7].[N:20]#[C:21][NH2:22].N>C(O)C.O>[CH2:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH:19][C:21]([NH2:22])=[NH:20])[CH:6]=[CH2:7]
Reactant: N#CN
Reactant: C=CCOCc1ccc([N+](=O)[O-])cc1N
Agent: N
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CCO
Product: C=CCOCc1ccc([N+](=O)[O-])cc1NC(=N)N
Temperature: 0 °C

Procedure:
Nitric acid (1.04 mL of 65%, 15 mmol) is added to a stirred solution of 2-[(2-propenyloxy)-methyl]-5-nitrobenzenamine (3.15 g, 15 mmol) in ethanol (30 mL) at 200C. A solution of cyanamide (0.95 g, 22.5 mmol) in water (1 mL) is then added dropwise to the stirred mixture at 95° C. over a period of 60 min. The mixture is heated at 95° C. for 14 h, with additional aliquots of cyanamide (total 2.2 g, 58 mmol) being added throughout this period and with the acidity being periodically adjusted to pH 3 by the addition of nitric acid (65%). The resulting mixture is cooled to 0° C., basified with aqueous ammonia (5 mL of 25%), diluted with water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous ammonium chloride (50 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to give the title compound as a brown oil, which is used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](=O)[C:14](=[CH:17][N:18]([CH3:20])C)[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.C(N)=[NH:26]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]3[N:26]=[CH:20][N:18]=[CH:17][C:14]=3[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)C(=CN(C)C)CCC2
Reactant: N=CN
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1-c1ncncc1CCC2
Temperature: 120 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
A mixture of 5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta [b]pyrrole-3-carboxylic acid ethyl ester (840 mg) and formamidine acetate (956 mg, 9.1 mmol) in EtOH (10 mL) is stirred at 120° C. for 4 h. After cooling, the reaction mixture is diluted with CH2Cl2 and washed with half saturated aq NaHCO3 (25 mL), H2O (25 mL), and brine (25 mL) The aqueous washes are reextracted once with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 30:1 CHCl3-MeOH followed by 20:1 CHCl3-MeOH and finally 15:1 CHCl3-MeOH afforded 606 mg (77%) of 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ9.30 (br s, 1H), 9.02 (s, 1H), 8.43 (s, 1H), 7.24 (d, J=2.7 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H) 2.70 (m, 2H), 2.12 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:15]([S:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:14])=[O:13])[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccccc1

Procedure:
N-[5-(3,5-Difluorobenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 28 from 0.15 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide, 13.5 ml of pyridine and 0.06 ml of benzoyl chloride. 30 mg of N-[5-(3,5-difluorobenzenesulfonylamino)-1H-indazol-3-yl)benzamide are thus obtained in the form of a cream solid melting at 246° C. (analysis C20H14F2N4O3S.1.33H2O % calculated C, 56.08; H, 3.29; F, 8.87; N, 13.08; O, 11.20; S, 7.48. % found C, 56.49; H, 3.38; N, 11.90; S, 6.95).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8](=[CH:14]N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.Cl.[C:24]([NH2:27])(=[NH:26])[CH3:25].C(N(CC)CC)C>C(O)C>[CH3:25][C:24]1[N:27]=[C:6]([C:5]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:26]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(OC)c(OC)c1
Reactant: CC(=N)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C)nc1-c1ccc(OC)c(OC)c1
Yield: 45.9 %

Procedure:
A solution of ethyl 2-(3,4-dimethoxybenzoyl)-2-(dimethylaminomethylene)acetate (31 g), acetoamidine hydrochloride (13.3 g) and triethylamine (16.2 g) in ethanol (200 ml) was refluxed for 10 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The separatedorganic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl ether to give ethyl 2-methyl-4-(3,4-dimethoxyphenyl)-5-pyrimidinecarboxylate (14 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:20])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Temperature: 90 °C
Yield: 97.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(pyridin-2-ylamino)phenyl]propionamide (190 mg, 0.69 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (186 mg, 0.78 mmol) and DIPEA (380 μL, 2.22 mmol) in n-butanol (1.5 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded into an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo to afford the title compound as an orange/brown oil (263 mg, 97%). LCMS (Method C): RT 1.67 min [M+H]+ 393.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[C:21]([C:23]2[N:27]([CH2:28]C)[CH:26]=[C:25]([C:30]([OH:32])=O)[CH:24]=2)[CH:20]=[CH:19][N:18]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([C:66]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[C:67]=1[NH2:68])[CH3:65]>CN(C)C=O.C(OCC)(=O)C>[CH2:64]([C:66]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[C:67]=1[NH:68][C:30]([C:25]1[CH:24]=[C:23]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)=[CH:8][C:3]=3[O:2][CH3:1])[N:22]=2)[N:27]([CH3:28])[CH:26]=1)=[O:32])[CH3:65]
Reactant: CCn1cc(C(=O)O)cc1-c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2OC)n1
Reactant: CCc1cccc(CC)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
A suspension of 5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-ethyl-1H-pyrrole-3-carboxylic acid (75 mg, 0.178 mmol) in anhydrous dimethylformamide (5 mL) was treated with N-ethyl-N,N-diisopropylamine (0.3 mL, 1.775 mmol) and TBTU (91 mg, 0.284 mmol). The mixture was then treated with 2,6-diethylaniline (0.3 mL, 1.775 mmol). The resulting mixture was stirred at 80° C. for 4 hours under argon. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL), washed with a saturated aqueous solution of sodium hydrogen carbonate (20 mL), brine, dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) afforded 23 mg (23%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1.[N-:17]=[N+:18]=[N-:19].[Na+].[C:21](O)(=O)C>>[N:1]1([CH:2]2[CH2:16][CH:5]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:8][CH:4]3[CH2:3]2)[CH:21]=[N:19][N:18]=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC2CC(n3cnnn3)CC2C1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0 g, 4.4 mmol) and triethylorothoformate (4.4 mL, 26.4 mmol) in acetic acid (20 mL) was added sodium azide (1.7 g, 26.4 mmol) and the resulting mixture was set under inert atmosphere. The mixture was heated at 100° C. for 4 h and then cooled to RT at which time the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with aqueous sodium bicarbonate solution, followed by brine. The organics were dried over sodium sulfate, filtered, and concentrate to dryness under vacuum. The residue was placed in the refrigerator overnight and the next day a solid white precipitate was observed. The precipitate was triturated with hexane and the solvent was carefully decanted to give the pure product (675 mg, 55%) as a white solid. EST-MS calculated for C13H21N5O2: Exact Mass: 279.28. Found 280.28 (MH) and 302.27 (MNa)+.
Reaction SMILES: C([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C(O)=O)#N.O.[CH3:17][N:18](C=O)C>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([CH3:3])[C:17]#[N:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(C#N)C(=O)O)cc1
Reactant: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C#N)cc1

Procedure:
A stirred solution of α-cyano-β(4-methoxyphenyl)propionic acid (127.3 g) in DMF (280 ml) is heated to 150° C. for 5 hours. The reaction mixture is cooled, poured into a liter of water and extracted with ether. The ether extract is washed, dried over Na2SO4, filtered and the filtrate evaporated in vacuo yielding a liquid which upon distillation yields the decarboxylated product as a clear liquid, B.P. 115° C. (1 mm).
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=O.FC1C=CC=CC=1.[Cl:17]Cl.[N+](C1C=CC=CC=1F)([O-])=O.[Cl:29][C:30]1[C:31]([F:39])=[C:32]([N+]([O-])=O)[CH:33]=[CH:34][CH:35]=1>>[CH:33]1[C:34]([Cl:17])=[CH:35][C:30]([Cl:29])=[C:31]([F:39])[CH:32]=1
Reactant: ClCl
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1ccccc1F
Solvent: O=[N+]([O-])O
Solvent: Fc1ccccc1
Product: Fc1ccc(Cl)cc1Cl

Procedure:
Process for the preparation of 2,4-dichlorofluorobenzene in high yield and purity without intermediate separation of the isomers formed,(1) by nitrating 1 mol of fluorobenzene to give nitrofluorobenzene using a mixture comprising 35 to 65 parts by weight of 50 to 90% strength sulfuric acid and 35 to 65 parts by weight of a nitrating acid comprising 35 to 55 parts by weight of 95 to 98% strength sulfuric acid and 45 to 65 parts by weight of 96 to 98% strength nitric acid, with the proviso that 0.8 to 2.0 equivalents of the nitrating agent NO2+ are used per mol of fluorobenzene, at 20° to 90° C., (2) allowing 25 g to 150 g of chlorine, in the presence of a ring chlorinating catalyst, to act on each 100 g of the crude nitrofluorobenzene mixture obtained, at 20° to 100° C., and (3) allowing about 18 g to about 203 g of chlorine or equivalent amounts of a chlorine releasing agent to act on each 100 g of the crude chlorofluoronitrobenzene mixture obtained, after removal of the ring chlorinating catalyst, at 110° to 220° C., and isolating the 2,4-dichlorofluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[CH:70](C1C=CC=CC=1)[C:71](O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH:46]7[CH2:45][CH:44]([CH2:70][CH2:71]7)[N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 46.6 %

Procedure:
This compound was synthesized using the procedure used to synthesize [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-phenyl-acetic acid (0.079 g, 0.380 mmol) giving the title compound (0.100 g, 46.6% yield) as a white solid. LCMS-ESI+: calc'd for C49H52N8O6: 848.40 (M+); Found: 849.50 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][O:28][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=1[C:25](=[O:27])[CH3:26]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), morpholine (49 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (60 mg, 68%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=S)[C:13]2[CH:23]=[CH:24][CH:25]=[N:26][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:27](OCC)(=[O:30])[NH:28][NH2:29]>>[CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:27](=[O:30])[NH:28][N:29]=[C:14]2[C:13]2[CH:23]=[CH:24][CH:25]=[N:26][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCOC(=O)NN
Reactant: CCCN(CCC)CC(=O)N1c2ccccc2NC(=S)c2cccnc21
Product: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-[(dipropylamino)acetyl]5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido-[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-3-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=1.5 Hz, 1H), 7.95 (dd, J=7.8, 1.5 Hz, 1H), 7.67-7.62 (m, 3H), 7.51-7.44 (m, 3H), 7.37 (t, J=6.8 Hz, 1H), 6.72-6.69 (m, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t, J=6.6 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.51-1.43 (m, 2H), 1.33-1.23 (m, 5H), 0.85 (t, J=7 Hz, 3H); Rf=0.24 (2% ethyl acetate/dichloromethane).