Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[S:11].CS(O[CH2:17][CH2:18][CH2:19][C:20]([Br:23])([F:22])[F:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.CCCCCC>[Br:23][C:20]([F:22])([F:21])[CH2:19][CH2:18][CH2:17][S:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CS(=O)(=O)OCCCC(F)(F)Br
Reactant: S=c1cnc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: FC(F)(Br)CCCSc1cnc2ccccc2n1
Yield: 66.9 %

Procedure:
A mixture of the product from Step 1 (1 g), 4-bromo-4,4-difluorobutyl methanesulfonate (1.65 g) and potassium carbonate (0.852 g) were stirred together in acetone (30 cm3) at ambient temperature for 7 hours. Inorganic solids were removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil. Chromatography on silica gel using 1:4 ethyl acetate:hexane as eluant gave 2-(4-bromo-4,4-difluorobutylthio)-quinoxaline (1.375 g). M+ =332; 1H NMR: δ 2.19(2H,m); 2.50-2.70(2H,m); 3.43(2H,t); 7.60-7.73(2H,m); 7.93(1H,dd); 8.03(1H,dd); 8.60(1H,s); (oil).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][C:14]1[C:15](=O)[C:16](=[O:21])[C:17]=1[O:18]CC)[CH3:12]>C(#N)C.C(OCC)(=O)C>[O:18]=[C:17]1[C:16](=[O:21])[C:15]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])=[C:14]1[O:13][CH2:11][CH3:12]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Cc1cc(C#N)ccc1N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1c(Nc2ccc(C#N)cc2C)c(=O)c1=O
Reaction time: 48 h
Yield: 23.9 %

Procedure:
4-Amino-3-methylbenzonitrile (1.94 g, 14.7 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.53 g, 14.9 mmol) in acetonitrile (5 mL). After refluxing the mixture for 24 h a second portion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) was added and heating was continued for an additional 48 h. The reaction mixture was diluted with ethyl acetate (50 mL), stirred vigorously and filtered free of undissolved solid. The filtrate was chromatographed (CH3OH/CH2Cl2) to afford 0.90 g (24%) of product as a yellow solid: 1H NMR (DMSO-d6): δ 10.50 (s, 1H), 7.76-7.63 (m, 2H), 7.31 (d, 1H), 4.71 (q, 2H), 2.33 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][O:15][N:14]=[C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCON=C(c1ccccc1)c1ccccc1
Yield: 73.5 %

Procedure:
Benzophenone oxime (3.94 g, 20 mmol), 1-bromo-2-chloroethane (28.7 g. 200 mmol) and dried, powdered potassium carbonate (5.53 g, 80 mmol) in acetone (60 ml) were heated at reflux for 72 h. The reaction mixture was cooled and filtered and the filtrate was evaporated to an oily residue which was purified by "flash" chromatography (eluting with heptane/ethyl acetate 19/1) to provide diphenylmethanone O-(2-chloroethyl)oxime (3.82 g, 73%) as an oil, tlc rf 0.36 (SiO2, heptane/ethyl acetate 9/1).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCc1cccc(F)c1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2cccc(F)c2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 3-fluoro-benzylamine and DIEA to give 2-(3-fluoro-benzylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 379 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:10][C@H:9]1[C:31](=[O:47])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]2=[O:45])=[CH:35][C:34]=1[F:46])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:31](=[O:47])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]2=[O:45])=[CH:35][C:34]=1[F:46])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
(2S,4S)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg) was dissolved in CH2Cl2 (2 ml) and piperidine (43 μl) was added. The mixture was stirred for 17 h at 25° C. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->methanol 2N NH3) to yield (2S,4S)-4-amino-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless amorphous solid (96 mg). MH+=417.5
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41]1[CH:66]=[CH:65][C:44]([CH2:45][N:46]2[C:50]3=[N:51][CH:52]=[CH:53][C:54]([O:55][C:56]4[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][C:57]=4[F:63])=[C:49]3[C:48]([CH3:64])=[N:47]2)=[CH:43][CH:42]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:63][C:57]1[CH:58]=[C:59]([NH:62][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:60]=[CH:61][C:56]=1[O:55][C:54]1[CH:53]=[CH:52][N:51]=[C:50]2[N:46]([CH2:45][C:44]3[CH:65]=[CH:66][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[N:47]=[C:48]([CH3:64])[C:49]=12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (37 mg, 0.16 mmol), EDCI (91 mg, 0.48 mmol), and HOBt (64 mg, 0.48 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. 3-Fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (30 mg, 0.079 mmol; prepared as in Example 5, Step D) was added, followed by Et3N (0.066 mL, 0.48 mmol). After stirring for 15 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 45 mg (96%) of the desired product. LRMS (ESI pos) m/e 594.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.72 (dd, 1H), 8.28 (d, 1H), 7.99 (dd, 1H), 7.92 (dd, 1H), 7.51 (m, 2H), 7.41 (m, 1H), 7.32 (m, 3H), 7.24 (d, 2H), 6.84 (d, 2H), 6.75 (t, 1H), 6.28 (d, 1H), 5.54 (s, 2H), 3.76 (s, 3H), 2.71 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −113.2, −128.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[NH:14][C@H:13]([CH3:18])[CH2:12]1.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([S:28]([N:14]2[C@@H:13]([CH3:18])[CH2:12][N:11]([CH2:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:19])[CH2:16][C@H:15]2[CH3:17])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1

Procedure:
The title compound was prepared from the product of Example 15 step (ii) (0.2 g) and 3-cyanobenzenesulphonyl chloride (0.28 g) by the method of Example 74 as a white solid. Yield 8 mg.
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.O>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[N:25]=2)[CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (10.5 g, 30.8 mmol) in N,N-dimethylacetamide (40 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (8.39 mL, 92.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, trifluoroacetic acid (50 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in water. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (7.44 g, 78%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][C:17](=O)[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:8][C:7]=1[CH3:27].O=P(Cl)(Cl)Cl.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:8][C:7]=1[CH3:27]
Reactant: COC(=O)COc1cc(OC)c(SCCC(=O)N(C)c2ccccn2)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)COc1cc(OC)c(SCCCN(C)c2ccccn2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 63A was dissolved POCl3 (250 mg, 1.6 mmol) and stirred for 15 minutes. The reaction was concentrated by blowing with nitrogen followed by concentration under vacuum. The intermediate was dissolved in 5 ml dimethoxyethane and cooled to ca. 5 C. Sodium borohydride (20 mg, 0.53 mmol) was added followed by warming to room temp. After 3 h 25 ml 2N HCl was added and heated to boiling for 1 minute. Saturated sodium bicarbonate was added to pH ca. 7–8. The crude product was extracted with 2×20 ml ethyl acetate, dried over anhydrous sodium sulfate, decanted and concentrated. Liquid chromatography gave the title product as a clear colorless oil. MS m/z 391 (M+1).
Reaction SMILES: [Na]N([Si](C)(C)C)[Si](C)(C)C.[I:11][C:12]1[C:13]2[C:14](=[CH:18][NH:19][N:20]=2)[N:15]=[CH:16][CH:17]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(O[Cu]OC(=O)C)(=O)C>[CH:21]1([N:19]2[CH:18]=[C:14]3[N:15]=[CH:16][CH:17]=[C:12]([I:11])[C:13]3=[N:20]2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: Ic1ccnc2c[nH]nc12
Agent: CC(=O)O[Cu]OC(C)=O
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)N([Na])[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Ic1ccnc2cn(C3CC3)nc12
Temperature: 95 °C

Procedure:
N-Sodiohexamethyldisilazane (3.40 mL, 2.041 mmol), N,N-dimethylpyridin-4-amine (748 mg, 6.12 mmol), 7-iodo-2H-pyrazolo[4,3-b]pyridine (500 mg, 2.041 mmol), diacetoxycopper (371 mg, 2.041 mmol) and cyclopropylboronic acid (351 mg, 4.08 mmol) were combined in toluene (15 mL) and sparged with air. The mixture was heated at 95° C. overnight. The mixture was then cooled and poured into saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated to give a residue which was purified on silica column chromatography eluted with EtOAc/Hexanes (0-97%) using a step gradient and then to 98% EtOAc to give 2-cyclopropyl-7-iodo-2H-pyrazolo[4,3-b]pyridine. The other fractions were further purified on a second silica column chromatography eluted with EtOAc/Hexanes (0-50%) using a step gradient and then to 90% EtOAc to give the title compounds. MS [M+H] found 286.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:16][CH3:17].NC1C=CN=CC=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:2]=2)=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: Brc1ccncc1
Agent: Nc1ccncc1
Product: COc1cc(Cl)ccc1Nc1cccnc1

Procedure:
The title compound was prepared by substituting 4-bromopyridine and 2-amino-5-chloroanisole for Example 189A and 4-aminopyridine, respectively, in Example 191. MS (ESI) m/e 235 (M+H)+.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:21][C:22]1([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>>[F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:21][C:22]3([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]3)=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 2-(3-amino-1,1-dioxo-thietan-3-yl)-N-methyl-acetamide (example 282a) as starting materials and isolated (15 mg, 19%); MS (ESI, m/z): 468.3 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])(=[O:4])=[O:3].[OH-].[Na+].O.Cl>CO>[CH3:1][S:2]([C:5]1[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([F:27])([F:28])([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Nc2ccc(S(F)(F)(F)(F)F)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
70 mg of methyl 5-methanesulfonyl-2-methyl-4-(4-pentafluorosulfanyl-phenylamino)benzoate were dissolved in 2 ml of MeOH, and 0.12 ml of a 2N aqueous NaOH solution was added. The mixture was stirred at RT for 2 h and then left to stand at RT for 16 h. The reaction mixture was then poured into 50 ml of water, adjusted to pH=2 with aqueous HCl solution and stirred at RT for 30 minutes, and finally the product was filtered off with suction. 66 mg of colorless crystals were obtained, mp 106-109° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[Cs+].[Cs+].O>FC1C=CC(O)=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([O:15][C:12]2[CH:6]=[CH:5][C:4]([F:11])=[CH:3][CH:2]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: O=C([O-])[O-]
Agent: Oc1ccc(F)cc1
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)cc(Oc2ccc(F)cc2)c1
Temperature: 50 °C
Yield: 296.7 %

Procedure:
Under an argon atmosphere and at room temperature, in a 500-mL pear-shaped evaporating flask, 4-fluorophenol (18.5 g) and 1,3-difluoro-5-nitrobenzene (25.0 g) were dissolved in DMA (300 mL). The reaction system was added with cesium carbonate (15.3 g) and stirred. The reaction system was then heated to 50° C., stirred for 3 hours, then heated to 65° C., stirred for 1 hour and further heated to 85° C. and stirred for 1 hour. The reaction solution was allowed to cool to room temperature, diluted with ethyl acetate and added with water to extract an organic layer. The aqueous layer was added with ethyl acetate to extract an organic layer. The organic layer was combined and washed with water and a saturated sodium chloride solution and the solvent was then distilled off under reduced pressure to give the titled compound (35.0 g) having the following physical properties.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CNCCCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzylamine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 5 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[4-(naphthalen-2-yloxy)-butyl]amine, solid, m.p. 105° C., (yield 0.62 gm, 95.3%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[OH:24].C(N(CC)CC)C.Cl>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]
Reactant: OC1CCCCC1CC1CCCCO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCCC1CC1CCCCO1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Neat, dry DMSO (4 equivalents) is added slowly to a CH2Cl2 solution of the oxalyl chloride (1.25 equivalents) cooled to -70° C. under N2. After stirring for about 15 min., the product of Example 193 (1 equivalent) in CH2Cl2 is added slowly. Neat triethylamine (4 equivalents) is then added and the mixture is warmed to 0° C. After 30 min., the mixture is poured into stirred ice-water and neutralized with dilute HCl. The mixture is then separated and the aqueous layer extracted with CH2Cl2. The organic extracts are then combined, washed with dilute brine, dried (MgSO4) and stripped of all solvent under reduced pressure. The crude title compound is purified by column chromatography.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[CH:54][C:55]4[N:60]5[C:61](=[O:65])[N:62]([CH3:64])[N:63]=[C:59]5[CH2:58][O:57][C:56]=4[N:66]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[CH:54][C:55]4[N:60]5[C:61](=[O:65])[N:62]([CH3:64])[N:63]=[C:59]5[CH2:58][O:57][C:56]=4[N:66]=3)=[CH:48][CH:47]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: Cn1nc2n(c1=O)-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: Cn1nc2n(c1=O)-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Yield: 84.6 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-methyl-1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (26 mg, 0.05 mmol) was reacted to afford the title compound (18 mg, 56%). LCMS (method D): RT=0.764 min, M-NH2=409. 1H NMR (500 MHz, MeOD): 8.56 (1H, s), 7.45 (2H, d), 7.41 (2H, d), 7.33-7.31 (3H, m), 7.24-7.23 (2H, m), 5.43 (2H, s), 3.53 (3H, s), 2.78-2.72 (2H, m), 2.59-2.53 (2H, m), 2.25-2.18 (1H, m), 1.99-1.91 (1H, m).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15]2)=[CH:10][CH:9]=1>>[C:19]([NH:18][CH:14]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])[C:8]([O:7][CH3:6])=[CH:17][C:16]=2[CH2:15]1)(=[O:21])[CH3:20]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)CC(NC(C)=O)CC2
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC(NC(C)=O)C2
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To chlorosulfonic acid (15 mL), cooled to −10° C. was added N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (1.44 g; 6.6 mmol). The reaction mixture was stirred at −10° C. for 15 min and quenched carefully by pouring over ice-water. The aqueous phase was extracted with CH2Cl2 (3×), the organic extracts combined, dried over Na2SO4, filtered and evaporated under reduced pressure to yield 6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([F:13])([F:12])[F:1]
Reactant: Oc1ccc(C(O)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C(Cl)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (ice bath) mixture of 4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (4.3 g, 22 mmol) and anhydrous pyridine (1.8 ml, 22 mmol) in toluene was added thionyl chloride (SOCl2) (2.3 ml, 31 mmol) drop wise via a syringe. After stirred for 1 h at 0° C., the reaction was heated at 70° C. for 2 h. At this point, reaction did not go completion, indicated by LCMS. Heating was continued for 16 h. Reaction was quenched with ice water. The resulted mixture was diluted with EtOAc. The organic layer was washed with saturated Na2CO3, water and brine. After dried over Na2 SO4, the solution was filtered and concentrated. The residue was purified on a silica gel column (5-10% EtOAc/hexane) giving the title compound as a light yellow oil. MS m/z: 211 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution of 1.0 g (5.4 mmol) of 4'-methyl-2-hydroxy-1,1'-biphenyl in 2.0 mL of pyridine was treated with 2 mL of acetic anhydride. The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under vacuum to yield 1.11 g (4.9 mmol,90%) of the product as an oil. 1H NMR (200 MHz,CDCl3): 2.07 (s,3H), 2.36 (s,3H), 7.07 (dd;3,8 Hz;1H), 7.15 (d,8 Hz,2H), 7.2-7.4 (m,5H).