Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[CH2:36]Br>C1COCC1>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[C:30]=1[CH2:36][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: COc1cccc(Cl)c1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(Cl)c1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(0.05 g, 0.224 mmol) in dry THF (1.5 ml) under nitrogen was added a 1 M solution of lithium bis(trimethylsilyl)amide in THF (0.224 ml, 0.224 mmol, Aldrich) dropwise, fairly quickly. The solution was stirred for 30 min then a solution of 2-(bromomethyl)-3-chlorophenyl methyl ether (for a preparation see Intermediate 25)(0.053 g, 0.224 mmol) in dry THF (1.5 ml) was added and stirring continued for 90 min then the solution was left to stand overnight. The solvent was removed in vacuo and the residue was partitioned between chloroform and half saturated sodium bicarbonate and the aqueous phase further extracted with chloroform, the chloroform fractions being filtered through a phase separator. The chloroform was removed in vacuo and the residue purified on MDAP (Method B) to give the title compound as a white solid (0.07 g); LCMS: (System 4) MH+=378, tRET=2.77 min.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C(O)CCC>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CCCCO
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.2 %

Procedure:
cis,trans-Muconic acid (105 mg, 0.739 mmol) is dissolved in n-butanol (10 mL) at room temperature and a crystal of iodine (17 mg, 0.067 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hours. The precipitate is filtered, washed with ice-cold acetonitrile and dried under reduced pressure to yield 80 mg of trans,trans-muconic acid, a 76 percent yield.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[C:16]#[N:17].Cl>C1(C)C=CC=CC=1>[C:1]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[C:16]#[N:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1csc(NC(=O)c2ccccc2)c1C#N
Yield: 81.6 %

Procedure:
After adding 29.4 g (0.21 mole) of benzoyl chloride, a mixture of 36 g (0.2 mole) of 2-amino-3-cyano-4-tert.-butyl-thiophene and 200 ml of toluene was boiled until the evolution of hydrogen chloride had ended (4 hours). Thereafter, the reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue was recrystallized from methanol. 46.4 g of 2-benzoylamino-3-cyano-4-tert.-butyl-thiophene of melting point 130° C. were obtained in this manner.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]2[C:13]([CH3:16])=[N:14][O:15][C:5]=2[C@H:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6]3[C:13]([CH3:16])=[N:14][O:15][C:5]=3[C@H:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)C[C@@H]1N=C(Cl)c2ccccc2-c2c(C)noc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a 100 mL round bottom flask containing methyl 2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.4701 g, 1.543 mmol) was added Pd(PPh3)4 (0.095 g, 0.082 mmol) and 4-chlorophenylboronic acid (0.393 g, 2.51 mmol). The flask was evacuated and purged with N2 (g) (3×), followed by addition of toluene (10 mL) and another cycle of evacuation and purging with N2 (g). To the heterogeneous mixture was added aqueous sodium carbonate (2.4 mL, 4.80 mmol, 2 M) in one portion and the flask was heated to 80° C. After ˜30 min, the reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (3×), dried over Na2SO4, and concentrated to give a dark orange oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 35% EtOAc:65% Hexanes, then isocratic 35% EtOAc:65% Hexanes). The product methyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.444 g, 1.166 mmol, 76% yield) was obtained as yellow foam after drying. LC/MS m/z 381 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C=Nc1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Nc4ccccc4)cc3c2C1
Yield: 6.6 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.4 mg (0.0874 mMol) phenyl isocyanate, 1.0 mg (7%) of the title compound was recovered using the procedure described in detail in Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)O.[CH2:26](N(CC)CC)[CH3:27].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(Br)cc2)N1CC(F)(F)F
Agent: CC[Mg]Br
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCC1(c2ccc(Br)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Reaction time: 0.08 h

Procedure:
To a −18° C. solution of 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (1 g, 2.3 mmol) in anhydrous THF (10 mL) was added triethylamine (1.6 mL, 11 mmol). The reaction was stirred for 5 min and then thionyl chloride (0.18 mL, 2.5 mmol) was added dropwise. After 10 min, 1M ethylmagnesium bromide in THF (9 mL, 9 mmol) was added. The reaction mixture was warmed from −18° C. to 0° C. and allowed to stir for 30 min and then quenched with 15 mL 1N aqueous HCl and extracted with 50 mL ethyl acetate. The organic layer was washed with brine (60 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (90 g silica gel cartridge, linear gradient 10-70% EtOAc/hexanes) gave 6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, NH); 7.53 (br d, 2H, J=8.79 Hz); 7.28 (br d, 2H, J=8.54 Hz); 7.11 (dd, 1H, J=8.54 and 2.19 Hz); 6.69 (d, 1H, J=8.55 Hz); 6.46 (d, 1H, J=2.20 Hz); 3.87 (dq, 1H, J=9.28 and 16 Hz); 3.52 (dq, 1H, J=8.30 and 17 Hz); 2.39 (dq, 1H, J=7.08 and 14 Hz); 2.22 (dq, 1H, J=7.08 and 14 Hz); 0.90 (t, J=7.08 Hz, 3H); MS (Electrospray): m/z 447.1 (M+H, Br=79).
Reaction SMILES: [N:1]1([N:7]=[C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[CH:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[O:19])=[CH:10][CH2:9]2)[CH2:6]CCC[CH2:2]1.CNC.CC(O)=O>>[CH3:6][N:1]([N:7]=[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:35])[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:19])=[CH:12][CH2:13]1)[CH3:2]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCCC2)C=C1)c1ccccc1F
Agent: CNC
Solvent: CC(=O)O
Product: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.205 mmol) from EXAMPLE 42, a pre-mixed dimethylamine and 1.5 eq. HOAc (0.5 M in THF, 2.0 mL, 1.0 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give white powder (43 mg). MS 468.1 and 470.1 (M+H, Cl pattern).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(#N)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: CC#N
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C

Procedure:
reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of acetonitrile to form a reaction mixture comprising 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)=[N:6][CH:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl>CO>[CH:1]1([C:4]2[C:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)=[N:6][CH:7]=[CH:8][N:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cc1ccc(-c2nccnc2C2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(-c2nccnc2C2CC2)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 0.10 g (0.37 mmol) of methyl [4-(3-cyclopropylpyrazin-2-yl)phenyl]acetate in 0.75 ml of MeOH was added 0.75 mL (0.75 mmol) of 1N LiOH. After 1 h at room temperature, the reaction mixture was acidified with 1 N HCl, extracted twice with ethyl acetate. The combined organic layers were washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afforded 0.080 g (84%) of [4-(3-cyclopropylpyrazin-2-yl)phenyl]acetic acid. ES-MS M+1=255.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:19]=4[O:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30].[NH2:31][OH:32].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([NH:31][OH:32])=[NH:26])=[CH:24][C:19]=4[O:18][C:17]3=[O:27])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: NO
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C#N)ccc43)CC2)ccc1Cl
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C(=N)NO)ccc43)CC2)ccc1Cl

Procedure:
A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49) (150 mg, 0.35 mmol, 1 eq), NH2OH.HCl (73 mg, 1.05 mmol, 3 eq), TEA (270 ml), in ethanol (2 ml) was stirred at 60° C. overnight. The resultant mixture was cooled and precipitated material was removed by filtration. The reaction solution was washed with ethyl acetate to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxamidine (50).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[O:39][CH3:40]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (50 mg, 0.3593 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 74% yield (0.115 g, 0.1965 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Morpholine (0.235 mL, 2.7 mmol) was added to a solution of Example 133 (0.6 g, 1.3 mmol) in DMF (8 mL). The reaction mixture was stirred at 120° C. for 4 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 1% methanol/chloroform) to obtain the title compound. Yield: 0.57 g, (85%); 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3), 3.2 (s, 2H, CH2), 3.7 (t, 4H, 2CH2), 3.9 (s, 2H, CH2), 4.28 (s, 2H, CH2), 5.35 (s, 2H, CH2), 7.82 (d, 1H, Ar), 8.0 (s, 1H, Ar), 8.12 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (CI+) 495 (M+1).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl([O-])(=O)(=O)=O.[Li+]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=C(OCc1ccccc1)N1CCC(O)(CNc2ccc(F)cc2)CC1

Procedure:
The object product (2.8 g, 98%) was obtained in the same manner as in Example 24(1) and using benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g), 4-fluoroaniline (889 mg) and lithium perchlorate (960 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:8]=1)([O-])=O.CO>[Pd]>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnn(Cc2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(Cc2ccc(C(F)(F)F)cc2)c1
Reaction time: 48 h
Yield: 99.5 %

Procedure:
4-Nitro-1-(4-trifluoromethyl-benzyl)-1H-pyrazole (2.40 g, 0.00867 mol) was dissolved in Methanol (3.0E1 mL, 0.74 mol) and 10% Palladium on carbon (0.180 g) was added. The reaction was hydrogenated under balloon pressure for 2 days. The reaction was filtered through celite and concentrated in vacuo to give 2.08 g of product as a red oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][OH:19]>>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([C:14](=[N:18][OH:19])[NH2:15])=[CH:16][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)cn1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)cn1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 6-({[t-butyl(dimethyl)silyl]oxy}methyl)nicotinonitrile (2.0 g, 8.1 mmol) that was obtained in Example 23 (23b) and a 40% aqueous solution of hydroxylamine (1 ml). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane (1:9) to afford the title compound (2.1 g) in a yield of 94% as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:23]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccc(C#N)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with 4-aminobenzonitrile (0.47 g, 4.0 mmol). Purification on silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/ethanol to give 123 as a white solid (m.p. 250-251° C.).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:6][CH:5]=1.[Cl:23]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O.O>[Cl:23]/[C:3](/[C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:8][CH:9]=1)=[N:2]\[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=NO)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(/C(Cl)=N/O)cc1
Temperature: 55 °C
Yield: 93.3 %

Procedure:
To a solution of tert-butyl (3R)-3-[4-[hydroxyiminomethyl]phenyl]morpholine-4-carboxylate 12 (5.57 g, 18.18 mmol) in DMF (33.06 mL) at 55° C. was added 1-chloropyrrolidine-2,5-dione (2.549 g, 19.09 mmol) and the resulting mixture heated at 55° C. for 20 mins. The reaction mixture was then cooled to rt and diluted with EtOAc (50 mL) and water (50 mL) and the organic layer separated. The aqueous later was extracted further with extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with water (3×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo to leave the product as a white foam (5.78 g, 89% yield); 1H NMR (400.0 MHz, DMSO) d 1.23 (9H, s), 3.37 (1H, m), 3.48 (1H, m), 3.75 (3H, m), 4.26 (1H, m), 5.01 (1H, s), 7.43 (2H, m), 7.78 (2H, m) and 12.40 (1H, s) ppm
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][OH:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.[CH2:26]([O:28][C:29](=[O:39])[C:30]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)=[O:31])[CH3:27].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:26]([O:28][C:29](=[O:39])[C:30](=[O:31])[C:32]1[CH:37]=[CH:36][C:35]([O:21][CH2:20][C:19]#[C:18][C:16]2[S:17][C:13]3[N:12]4[C:22]([CH3:25])=[N:23][N:24]=[C:11]4[CH2:10][N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:14]=3[CH:15]=2)=[CH:34][CH:33]=1)[CH3:27]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: Cc1nnc2n1-c1sc(C#CCO)cc1C(c1ccccc1Cl)=NC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OCC#Cc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)cc1
Yield: 73 %

Procedure:
As in Example 15, 4-(-2-chlorophenyl)-2-(3-hydroxy-1-propynyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.369 g) was reacted with 4-hydroxyphenylglyoxylic acid ethyl ester (0.195 g) in the presence of diethyl azodicarboxylate (0.175 g) and triphenylphosphine (0.263 g) in dichloromethane (30 mL). The crude reaction product, isolated in the usual manner, was purified by flash chromatography over silica gel (120 g; ethanol-dichloromethane; 3.5:96.5) to furnish 0.398 g of 4-[3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl]-2-propynyloxy]-alpha-oxobenzeneacetic acid ethyl ester (4:1 ) hydrate as a white foam.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[C:7](=[O:20])[N:8]([CH3:19])[C:9]2[C:14]([CH:15]=1)=[CH:13][N:12]=[C:11]([NH:16][CH2:17][CH3:18])[CH:10]=2)CCC.[C:29]([N:36]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:37]1[C:42]([F:43])=[C:41](I)[C:40]([F:45])=[CH:39][N:38]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:32]([O:31][C:29]([N:36]([C:37]1[C:42]([F:43])=[C:41]([C:6]2[C:7](=[O:20])[N:8]([CH3:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][N:12]=[C:11]([NH:16][CH2:17][CH3:18])[CH:10]=3)[C:40]([F:45])=[CH:39][N:38]=1)[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cnc(NCC)cc2n(C)c1=O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(F)c(I)c1F
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F)c(=O)n2C
Temperature: 60 °C

Procedure:
A tube was charged 3-(tributylstannyl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (48 mg, 0.1 mmol), N,N-bis-BOC-3,5-difluoro-4-iodopyridin-2-amine (54 mg, 0.12 mmol), Ph3As (25 mg, 0.08 mmol), CuI (7.5 mg, 0.04 mmol) and Pd2(dba)3 (9 mg, 0.01 mmol). The tube was degassed and refilled with nitrogen gas. DMF (10 mL) was added, and then the tube was sealed and heated at 60° C. for 48 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (70% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 533.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1COCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:21]=1>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:29]1[CH2:30][CH2:31][N:26]([C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][N:23]=2)[CH2:27][CH2:28]1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1ccnc(N2CCNCC2)n1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccnc(N2CCN(C(=O)c3cc4ccccc4[nH]3)CC2)n1
Reaction time: 8 h

Procedure:
To a solution of 0.83 g (5.15 mmol) of indol-2-carboxylic acid in 15 mL of dry THF 0.83 g (5.15 mmol) of N,N′-carbonyldiimidazol is added. After 30 minutes 1.0 g (5.15 mmol) of 4 methoxy-2-(1-piperazinyl) pyrimidine is added to the solution and it is left overnight with continuous stirring. The solvent is eliminated under reduced pressure and H2O added. This produces a precipitate which is filtered and dried, to give 1.7 g (5.04 mmol) of 2-[4-(2-indolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine. m.p.=202-203° C.