Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[F:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].II.[B:19](OC)([O:22]C)[O:20]C>O1CCCC1.BrCCBr.C(OCC)C.C(O)(=O)C.O>[F:15][C:9]1[CH:10]=[CH:11][C:12]([B:19]([OH:22])[OH:20])=[CH:13][C:8]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 81.9 %

Procedure:
A solution of 5-bromo-2-fluorophenyl phenyl ether (8.01 g, 30 mmol) in tetrahydrofuran is added dropwise over 30 minutes to a mixture of magnesium turnings (0.0802 g, 33 mmol), a crystal of iodine and a few drops of 1,2-dibromoethane in tetrahydrofuran at 50°-55° C. under nitrogen. After the addition is complete, the reaction mixture is stirred at 50°-55° C. for 70 minutes and cooled to room temperature. The cooled mixture is added over 25 minutes to a solution of trimethyl borate (4.09 mL, 36 mmol) in diethyl ether at dry ice/acetone bath temperature. After the addition is complete, the mixture is stirred at dry ice/acetone bath temperature for 20 minutes, allowed to warm to -10° C. over 25 minutes, diluted sequentially with acetic acid and water, stirred at room temperature for 30 minutes, and extracted with ether. The organic extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. A mixture of the residue in water is heated over a steam bath for 30 minutes, cooled to room temperature and filtered to obtain a solid which is washed with hexanes and dried to give the title product as a colorless solid (5.7 g, mp 177°-180° C., 82% yield)
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH2:39][CH2:38]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Product: NCCSC(=O)N1CCC(O)CC1
Yield: 146.3 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and 4-hydroxypiperidine (219 mg) were subjected to similar reactions to those described in References 2 and 4 to give 2-(4-hydroxypiperidino)carbonylthioethylamine (crude formate: 185 mg) which was then dissolved in anhydrous methanol (3 ml). To the reaction solution were added triethylamine (515 μl) and mitomycin A (207 mg: 0.8 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 43 (325 mg) in the form of grayish blue powders with a yield of 84%.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(OC(C)(C)C)=O.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Li+].CC([N-]C(C)C)C.Cl>C1(C)C=CC=CC=1.C1COCC1.O>[B:22]([C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=2)([OH:27])[OH:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOC(=O)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc2[nH]c(B(O)O)cc2c1
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
150 g (519 mmol) of N-Boc-5-ethoxycarbonylindole and 192 ml (833 mmol) of triisopropyl borate in 350 ml of toluene were admixed at from 5° C. to 10° C. with 350 ml of a 1.8 molar solution of LDA in THF. The mixture was stirred for a further 5 min and the reaction mixture was added to a solution of 278 g of 30% hydrochloric acid and 940 ml of water. Subsequently, the mixture was stirred at from 5° C. to 10° C. for 30 min. Thereafter, the mixture was filtered and the filtercake was suspended in 530 ml of ethanol. This suspension was added at 40° C. to a solution of 500 ml of 30% hydrochloric acid and 224 ml of ethanol. Subsequently, the mixture was stirred at from 40° C. to 45° C. for 2.5 h and admixed at 30° C. with 380 ml of water. The mixture was then cooled to from 10° C. to 15° C., stirred at this temperature for 30 min and filtered. Drying under reduced pressure afforded 79.5 g (61% of theory) of 2-borono-5-ethoxycarbonylindole (HPLC: 92.7 area %).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:25]4[S:26][C:22]([C:21]([F:30])([F:29])[F:20])=[CH:23][CH:24]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1ccc(C(F)(F)F)s1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (100 mg), [5-(trifluoromethyl)thiophen-2-yl]methanol (143 mg) and triphenylphosphine (308 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (275 mg) at 60° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (71 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2]>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=3[N:18]=2)[CH:6]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Reaction time: 4 h
Yield: 95 %

Procedure:
5-(2-Ethoxy-5-nitrophenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.64 g, 0.0018 mol) was dissolved in ethanol (50 ml) and the solution stirred with 5% palladium on charcoal catalyst (0.050 g) under hydrogen at room temperature and 50 p.s.i. pressure for 4 hours. The mixture was filtered to remove the catalyst, the filtrate evaporated under vacuum, and the residue triturated with ether to give the title compound as an off-white solid (0.56 g, 95%), m.p. 147-148° C. Found: C,62.63; H,6.60; N,21.57. C17H21N5O2 requires C,62.36; H,6.47; N, 21.39%.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]1[I:18])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:21])=O.C(N)C1C=CC2OCOC=2C=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C.C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH2:10][Cl:21])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]1[I:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(I)nc(-c2ccccc2)c1CO
Reactant: O=S(Cl)Cl
Agent: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCn1c(I)nc(-c2ccccc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole (1.96 g, 6.1 mmol) is dissolved in 20 ml dichloromethane and cooled to 0° C. To the solution is added 5 equivalents of thionyl chloride and the resulting solution is stirred at room temperature for 2 h. The reaction mixture is evaporated at reduced pressure and 20 ml of toluene is added to the residue and evaporated to remove any residual thionyl chloride. The crude product is dissolved in 20 ml of anhydrous acetonitrile and added to an ice-cooled solution of piperonyl amine (2.0 eq.) in acetonitrile (10 mL) containing potassium carbonate (2 eq.). The resulting mixture is stirred at room temperature for 4 h, diluted with 100 ml of ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated at reduced pressure. The residue is purified by silica gel chromatography (hexanes/ethyl acetate, from 2:1 to 1:1) to give 2.28 g of 1-butyl-5-chloromethyl-2-iodo-4-phenylimidazole. MS (+VE) m/z 490 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:35])[C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41]>C(O)(C)C>[F:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[C:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]4[CH:42]=[CH:43][CH:44]=[C:38]([C:37]([F:36])([F:45])[F:46])[CH:39]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[N:11]3[N:10]=2)[CH:20]=1)=[O:35]
Reactant: COc1cccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: COc1cccc2c(-c3ccnc(Nc4cccc(C(F)(F)F)c4)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12

Procedure:
The title compound was prepared through standard displacement conditions by microwaving N-{3-[3-(2-chloropyrimidin-4-yl)-7-methoxypyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-trifluoromethylaniline in isopropanol at 150° C. for 15 min. 1H (400 MHz, DMSO d-6) 4.15 (s, 3H), 6.59 (d, J=5.2 Hz, 1H), 6.62 (d, J=7.6 Hz, 1H), 7.24 (m, 3H), 7.33 (d, J=8.0 Hz, 1H), 7.46 (m, 2H), 7.58 (m, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 8.00 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.27 (s, 1H), 8.31 (d, J=5.2 Hz, 1H), 9.91 (s, 1H), 10.9 (s, 1H); LCMS (APCI): [M+H]+=617.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[N:9]=[CH:8][CH:7]=1>O1CCOCC1.N1C=CC=CC=1>[C:1]([NH:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[N:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cn1nccc(N)c1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccnn(C)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution of 2.7 ml of acetyl chloride in 20 ml of dioxane was added dropwise to a solution of 4.0 g (0.032 mol) of 5-amino-1-methyl-6-pyridazone in 100 ml of pyridine. After stirring for 12 hours at 25° C., the solvent was distilled off under reduced pressure, and the residue was taken up with methylene chloride, washed with sodium bicarbonate solution and dried. After the solvent had been stripped off under reduced pressure and the residue stirred with a small amount of diisopropyl ether, there was obtained 3.1 g (58.0%) of 5-acetylamino-1-methyl-6-pyridazone (active ingredient 1.001) of melting point 152°-153° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH2:7].C([O-])([O-])=O.[K+].[K+].O.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH:7][C:19](=[O:20])[CH2:18][O:17][CH3:16]
Reactant: COCC(=O)Cl
Reactant: Cc1csc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COCC(=O)Nc1c(C)csc1C

Procedure:
To 12.7 g (0.1 mol) of 2,4-dimethyl-3-aminothiophene, 13.84 g (0.1 mol) of K2CO3, 50 ml of water and 160 ml of methylene chloride are added without cooling 10.8 g (0.1 mol) of methoxyacetyl chloride.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CC#N>[CH2:21]([NH:25][CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14])[CH:22]([CH3:24])[CH3:23]
Reactant: CCCc1c(CBr)ncn2ncnc12
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1c(CNCC(C)C)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromomethyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine (16.58 mmol) in CH3CN (30 ml) is added K2CO3 (9.15 g, 66.3 mmol), isobutylamine (6.6 ml, 66.3 mmol) and the mixture is stirred at room temperature overnight. The solvent is removed in vacuo and to the residue is added water (60 ml) and EtOAc (60 ml). The layers are separated and the organic layer is washed with brine (20 ml) and dried (Na2SO4). Evaporation of the solvent provides a light yellow oil, which is used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13].C1C(=O)N([Br:30])C(=O)C1>C1(C)C=CC=CC=1.CN(C)C=O.[Cl-].[Na+].O>[Br:30][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][CH:21]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Yield: 75.9 %

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (3.30 g, 10 mmol, Example 1) and NBS (1.869 g, 10.50 mmol) were heated at 110° C. for 2 hr in Toluene (50 ml) and N,N-dimethylformamide (DMF) (10 ml). The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). Very bad emulsions were obtained that did not clear using brine, filteration or saturation with salt. Repeated extractions with ethyl acetate (×10) and treatment of the organic extracts with anhydrous sodium sulfate removed the water. The solvents were concentrated in vacuo, and the residue dissolved in chloroform (500 mL), dried over anhydrous sodium sulfate and concentrated to an oil. The crude oil was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% gradient of [10% 2M NH3/MeOH in DCM]/DCM) to afford product 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (3.1 g, 7.59 mmol, 76% yield), as a beige foam. A 0.180 g sample of this material was further purified by mass-directed automated preparative HPLC and then dissolved in dichloromethane (5 ml) and treated with 4N HCl in dioxane (0.5 ml). The solvents were removed in vacuo and the resulting solid tritruated in diethyl ether to afford 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (0.095 g, 0.213 mmol, 2.135% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (0.05 g, 0.176 mmol), morpholine-4-carbonyl chloride (26.3 mg, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr and monitored by LC/MS. The crude product was purified using preparative reverse-phase HPLC, giving the desired product morpholine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide. MS calcd. for C21H21ClN3O3 [(M+H)+] 398.1, obsd. 398.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13].[C:36]1([N:42]2[C:46]([S:47]Cl)=[N:45][N:44]=[N:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:47][C:46]2[N:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:43]=[N:44][N:45]=2)=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13]
Reactant: ClSc1nnnn1-c1ccccc1
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(Sc3nnnn3-c3ccccc3)c3ccccc3c2O)c(C(C)(C)CC)c1
Yield: 77.7 %

Procedure:
To a solution of 47.6 g of 1-hydroxy-N-[4-(2,4-di-t-amylphenoxy)-butyl]-2-naphthamide in 500 ml of carbon tetrachloride, was added a solution of 21 g of 1-phenyl-5-tetrazolylsulfur chloride (prepared according to Org. Synth. Coll., vol. II, page 445) in 200 ml of carbon tetrachloride. The mixture was refluxed overnight and concentrated in vacuo. The solid was recrystallized from 500 ml of acetonitrile, yielding 50 g of 1-hydroxy-4-(1-phenyl-5-tetrazolylthio)-N-[4-(2,4-di-t-amylphenoxy)-butyl]-2-naphthamide of formula ##STR10## which melted at 147°-148° C. (Synthesis as described in U.S. Pat. No. 3,701,783).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[F:24][CH:25]([F:42])[C:26]1[N:34]=[CH:33][C:32]([CH2:35][NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:31][C:27]=1[C:28](O)=[O:29].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:42][CH:25]([F:24])[C:26]1[N:34]=[CH:33][C:32]([CH2:35][NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:31][C:27]=1[C:28]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=1)=[O:29]
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)ccnc23)c1
Yield: 7.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-44, 50 mg, 0.16 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 52 mg, 0.19 mmol), oxalyl chloride (37 mg, 0.29 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57 mmol) in CH2Cl2 (2 mL) to afford 7 mg of the title product. 1H NMR (300 MHz, CDCl3): δ 10.39 (s, 1H), 8.93 (d, 1H), 8.75 (s, 1H), 8.60 (d, 1H), 8.07 (m, 2H), 7.66 (t, 1H), 7.47 (m, 1H), 7.37-7.15 (m, 2H), 6.60 (d, J=5.4 Hz, 1H), 4.63-4.60 (d, J=6.9 Hz, 2H), 2.45 (m, 1H), 1.21 (d, J=6.9 Hz, 6H); MS (m/z): 577.97 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24](C3C(C)=CC=C4C=3C=CC=N4)[C:25]3[O:29][C:28](=[O:30])[NH:27][C:26]=3[CH:31]=2)=[C:20]([CH3:43])[O:19][N:18]=1>>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:12]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:25]3[O:29][C:28](=[O:30])[NH:27][C:26]=3[CH:31]=2)=[C:20]([CH3:43])[O:19][N:18]=1
Reactant: OB(O)c1cccnc1-c1ccccc1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)oc12
Product: Cc1noc(C)c1-c1cc(-c2cccnc2-c2ccccc2)c2oc(=O)[nH]c2c1

Procedure:
The title compound was synthesized using 2-phenylpyridin-3-ylboronic acid in a similar fashion with 5-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)benzo[d]oxazol-2(3H)-one (Example 11).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:19])(=O)[NH2:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1>CN(C)C=O.CC(CC(C)C)=O>[C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:19])#[N:2]
Reactant: NC(=O)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1
Product: N#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Reaction time: 6 h
Yield: 49 %

Procedure:
Two drops of N,N-dimethylformamide were added to a mixture of 4-carbamoylmethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (1.4 g), thionylchloride (1.2 g) and toluene (20 ml), and the mixture was stirred at a temperature of 100° C. to 110° C. for 6 hours. After the liquor was allowed to cool, methylisobutyl ketone (300 ml) was added thereto, and the liquor was washed with water, a saturated aqueous solution of sodium bicarbonate, water and a saturated table salt solution, in that order, subsequently dried with anhydrous sodium sulfate. After the solvent was distilled off, toluene (300 ml) and activated carbon (0.5 g) were added to the residue, the mixture was heated for a minute, and filtered while it was still hot. The resulting product was allowed to stand overnight, resulting crystals were recovered by filtration, and dried to give the desired 4-cyanomethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (0.64 g). When the residue obtained by distilling the mother liquor was recrystallized from a minimum amount of toluene, an additional amount (0.3 g) of the desired compound was produced. mp. 196°-200° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:53][C:54]1[CH:62]=[C:61]([CH3:63])[C:57]([C:58](O)=[O:59])=[C:56]([CH3:64])[N:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:53][C:54]1[CH:62]=[C:61]([CH3:63])[C:57]([C:58]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])[C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:59])=[C:56]([CH3:64])[N:55]=1
Reactant: Cc1ccncc1CN(c1ccc(C(F)(F)F)nc1)C1CCN([C@H](C)CCN)CC1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1CN(c1ccc(C(F)(F)F)nc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(Cl)nc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(6-trifluoromethyl-pyridin-3-yl)-amine (72.9 mg, 0.17 mmol), EDCI (36.4 mg, 0.19 mmol) and HOBT (25.7 mg, 0.19 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 6-chloro-2,4-dimethyl-nicotinic acid hydrochloride salt (42.2 mg, 0.19 mmol) followed by DIPEA (66.3 μL, 0.38 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded 6-chloro-2,4-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(6-trifluoromethyl-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-nicotinamide as a white foam (61.1 mg, 60%). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=5 Hz), 1.23 (m, 1H), 1.40 (m, 1H), 1.65 (m, 3H), 1.76 (m, 1H), 1.91 (d, 2H, J=11 Hz), 2.24 (m, 1H), 2.30 (s, 3H), 2.41 (s, 3H), 2.51 (s, 3H), 2.61 (m, 1H), 2.85 (m, 3H), 3.40 (m 1H), 3.48 (s, 1H), 3.74 (m, 2H), 4.25 (s, 2H), 6.84 (dd, 1H, J=3 Hz, 9 Hz), 6.99 (s, 1H), 7.13 (d, 1H, J=5 Hz), 7.41 (m, 2H), 8.05 (d, 1H, J=3 Hz), 8.17 (s, 1H), 8.38 (d, 1H, J=5 Hz). ES-MS m/z 589 (M+H), 612 (M+Na). Anal. Calcd. For C30H36ClF3N6O: C, 61.17; H, 6.16; Cl, 6.02; F, 9.67; N, 14.27.