Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:18]Br>O>[Br:18][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2oc3ccccc3c2c1
Reaction time: 20 h
Yield: 30.3 %

Procedure:
150 grams (892 mmol) of dibenzofuran and 1 L of acetic acid were loaded into a flask. The air in the flask was replaced with nitrogen, and then the contents were dissolved under heat. 188 grams (1.18 mol) of bromine were dropped to the solution while the flask was sometimes cooled with water. After that, the mixture was stirred for 20 hours under air cooling. The precipitated crystal was separated by filtration, and was then sequentially washed with acetic acid and water. The washed crystal was dried under reduced pressure. The resultant crystal was purified by distillation under reduced pressure, and was then repeatedly recrystallized with methanol several times. Thus, 66.8 g of 2-bromodibenzofuran were obtained (in 31% yield). The resultant was identified as Intermediate 2-3 by FD-MS analysis.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCCCCC>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:4])[NH:6][CH:7]=1
Reactant: Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1c[nH]c(C(=O)Nc2ccccc2C)c1
Temperature: 80 °C
Reaction time: 75 h
Yield: 45 %

Procedure:
A solution of 2,2,2-trichloro-1-(4-methyl-1H-pyrrol-2-yl)ethanone (2 g, 8.8 mmol) in a mixture of o-toluidine (1.76 mL, 16.5 mmol) and triethylamine (2.1 mL, 15.07 mmol) under argon was heated to 80° C. with stirring during 75 h. Afterwards, the reaction mixture was concentrated to dryness giving a residue that was treated with hexane and the resulting solid filtered to afford 848 mg of the title compound (45% yield).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[CH:25]=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-2:27].[O-2:28].[O-2].[Cr+6:30].[S:31](=[O:35])(=[O:34])([OH:33])[OH:32]>CC(C)=O.O>[O-2:14].[O-2:32].[O-2:27].[Cr+6:30].[S:31](=[O:33])(=[O:32])([OH:35])[OH:34].[C:19]1([C:18]#[C:17][C:15]2[CH:16]=[C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:10]([C:25]([OH:27])=[O:26])=[CH:11][C:12]=2[C:13]([OH:28])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(C=O)c(C#Cc2ccccc2)cc1C#Cc1ccccc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(=O)O)c(C#Cc2ccccc2)cc1C#Cc1ccccc1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
4,6-Bis(phenylethynyl)isophthalaldehyde (7.8 g, 0.023 mole) was dissolved in acetone (distilled from solid potassium permanganate) and the solution was chilled to 0° C. A chromium trioxide-sulfuric acid solution was prepared by slurrying 26.7 g of chromium trioxide in 23 ml of concentrated sulfuric acid and 40 ml of distilled water. This solution was diluted in the cold with distilled water to 110 ml. A portion of this solution (16.9 ml) was added dropwise over 1.5 hours to the stirred yellow acetone solution. During this period the color of the reaction mixture changed from yellow to brown and finally to green. After an additional 20 hours of reaction, the mixture was warmed to room temperature and poured into a vessel containing ice and water. The yellow precipitate was collected by filtration and washed thoroughly with water. Suction drying on the frit yielded 7.3 g (85.5% yield) of the light yellow 4,6-bis(phenylethynyl)isophthalic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13](Br)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:1]=[N+:2]=[N-:3])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(Br)c2cccc([N+](=O)[O-])c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(N=[N+]=[N-])c2cccc([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Sodium azide (26.1 g) was added to a solution of α-(4-methoxyphenyl)-3-nitrobenzyl bromide (25.8 g) in dimethylformamide (200 ml) in an ice bath. The mixture was stirred on the ice bath for 1 hour and then at ambient temperature for 1 hour. The dimethylformamidle was then removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and water two times. The ethyl acetate layers were combined and washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 6:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford the title compound (18.6 g) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]#[CH:13].C([O-])(O)=O.[Na+].[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]#[CH:13])=[O:22]
Reactant: C#CCOCCOCCOCCN
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCOCCOCCNC(=O)CBr
Yield: 78.1 %

Procedure:
To a solution of 4 (50 mg, 0.27 mmol) in CH2Cl2 (3 mL) was added sat. NaHCO3 (3 mL). Under stirring, bromoacetyl bromide (80 mg, 040 mmol) was added. The pH was controlled in the range 8-9 by adding solid NaHCO3. The reaction was stirred at rt for 15 min. CH2Cl2 (5 mL) was added and the reaction mixture was extracted 5×3 mL CH2Cl2. The organic layers were combined, washed with brine, dried with Na2SO4. The solvent was evaporated and the residue was purified by FCC to afford 5 as clear oil (65 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 2.42 (t, J=2.4 Hz, 1H), 3.48 (dd, J=5.2, 5.2 Hz, 2H) 3.57 (t, J=5.2 Hz, 2H), 3.62 (m, 4H), 3.66-3.70 (m, 4H), 3.85 (s, 2H), 4.18 (d, J=2.4 Hz, 2H). 6.91 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 29.35, 40.11, 58.65, 69.32, 69.56, 70.53, 70.61, 70.76, 74.90, 79.73, 165.86. ESIMS calcd for C11H18BrNNaO4 [M+Na]+ 330.03, 332.03, found: 330.33, 332.46.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[F:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[NH:8][C:7]([S:9][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(F)c(F)cc3[nH]2)o1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
5,6-Difluoro-1,3-dihydro-benzimidazole-2-thione (1.0 g, 5.37 mmol) is suspended into 50 mL of tetrahydrofuran under argon. Then, 0.39 g (8.06 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.76 g, 5.37 mmol) is then added and the reaction mixture is stirred at room temperature for 16 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 200 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol 95/5 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is recrystallized from ethyl acetate/n-heptane, filtered, washed with n-heptane and dried under reduced pressure. 1.16 g of 5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a crystalline brown powder. mp: 133° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=O)[CH2:6][NH2:7].CN(C)[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19].CC[O-].[Na+]>C(O)C>[C:18]([C:17]1[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:3]=2[Cl:2])=[CH:6][NH:7][CH:16]=1)([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C=CN(C)C
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl

Procedure:
10.7 g of 2,3-dichlorophenacylamine hydrochloride and 6 g of methyl 3-dimethylaminoacrylate are heated for 2 hours under reflux in 120 ml of ethanol. Then a solution of 4 g of sodium ethylate in 40 ml of ethanol is added dropwise and the reaction mixture is heated for another hour under reflux. The reaction mixture is then concentrated by evaporation and the oily residue is purified by column chromatography (silica gel; elution with a 3:1 mixture of toluene/ethyl acetate. Melting point: 205°-206° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C:26]([OH:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C:26]([OH:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CCOC(=O)C(C)(O)C(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-hydroxy-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil. (66%). MS: m/e=426(M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]1[CH2:15][CH2:14][NH:13]CC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:23]1COC[CH2:24]1>>[NH2:13][CH2:14][CH:15]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1
Reactant: C1CCOC1
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of N-benzylisonipecotamide (7.34 g, 34 mmol) in 60 mL of anhydrous THF, was added, LiAlH4 (1.9 g, 51 mmol) and the mixture was stirred at room temperature for 10 minutes followed by heating to reflux for 3 h. The reaction was quenched by addition of 100 mL sat'd. sodium potassium tartrate, and was extracted with EtOAc (3×50 mL). The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4, filtered and concentrated to give the desired product. 1H-NMR (400 MHz, CDCl3) δ 7-13 (m, 5H), 3.42 (s, 2H), 2.91 (m, 2H), 2.59 (m, 2H), 1.97 (m, 2H), 1.62 (m, 2H), 2.21 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][Cl:18])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCCl

Procedure:
A mixture of 20 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 34 parts of sulfinyl chloride and 300 parts of trichloromethane is stirred and refluxed for 4 hours. The trichloromethane is evaporated and the residue is crystallized from 4-methyl-2-pentanone (activated charcoal). The product is filtered off (the filtrate is set aside), yielding a first fraction of 8.2 parts of 5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one. The filtrate, which was set aside, is concentrated and the concentrate is stirred with 2,2'-oxybispropane. The precipitated product is filtered off and dried, yielding a second fraction of 8 parts of 5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:4]([CH3:30])=[C:5]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[CH:18]=3)(O)[CH2:12][S:11]2)[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.C(O)(=O)CC>[BrH:1].[Cl:2][C:3]1[C:4]([CH3:30])=[C:5]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[CH:18]=3)=[CH:12][S:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(Cl)cccc1N=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)N1C
Agent: Br
Solvent: CCC(=O)O
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(3-chloro-2-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide, by heating under reflux for 20 minutes in glacial acetic acid or by heating at 110° C. in propionic acid for 45 minutes. Colorless crystals; melting point 226°-228° C. (with decomposition).
Reaction SMILES: [I-].[K+].[N+](C1C=C[C:9]2[N:15]3C(CCl)=NN=C3CN=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C:10]=2C=1)([O-])=O.C[NH:30]C1CC1>O1CCCC1>[NH:30]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:11]=[CH:10][CH:9]=[N:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CNC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner given in Example 2, potassium iodide and 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran are treated with methylcyclopropylamine to give 8-nitro-1-[(cyclopropylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-]1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.Br[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:20][C:21]#[N:22])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: N#CCBr
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.4 g, 1.311 mmol), 2-bromoacetonitrile (0.472 g, 3.93 mmol) and potassium carbonate (0.544 g, 3.93 mmol) in DMF (4 ml) was stirred at 50° C. for 2 h. The reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (3×20 ml). The combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give crude product which was purified by column chromatography (biotage 25 g) eluted with 0-50% ethyl acetate/cyclohexane to afford product (0.19 g) 1H NMR (500 MHz, CDCl3) 7.45-7.50 (m, 3H), 7.4-7.43 (m, 2H), 7.31 (s, 1H), 4.93 (s, 2H), 4.83 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-])=O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[NH2:24][C:3]1[CH:4]=[C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(N)c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III)triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10(m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20(s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>C1COCC1>[Br:1][C:2]1[C:3]([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: Cn1cc(Br)c(C2(O)CCC3(CC2)OCCO3)n1

Procedure:
The title compound was prepared as a white solid from 4-bromo-1-methyl-1H-pyrazole, as prepared in the previous step, and 1,4-dioxa-spiro[4.5]decan-8-one in THF using the procedure described in Step A of Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CC(C)CN
Product: Cc1ccc(NC(=O)c2ccnc(NCC(C)C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(isobutylamino)isonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and isobutylamine using method C. NMR; δH [2H6]-DMSO 10.27,(1H, s), 8.62,(1H, t), 8.07,(1H, d), 7.93,(2H, d), 7.70-7.66,(2H, m), 7.43,(2H, d), 7.28,(1H, d), 6.88-6.84,(3H, m), 3.16,(2H, t), 3.09,(2H, t), 2.20,(3H, s), 1.83,(1H, m), 1.04,(1H, m), 0.90,(6H, d), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.02 min, MH+457.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=2)[C:30](=[O:38])[NH:29]1)=O)(C)(C)C.O>CN1C(=O)CCC1>[CH:18]([C:16]1[CH:17]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:37][C:34]3[CH:35]=[C:36]4[C:31]([C:30](=[O:38])[NH:29][NH:28]4)=[CH:32][CH:33]=3)[N:11]=2)[NH:14][N:15]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cc(Nc2nc(Nc3ccc4c(=O)[nH][nH]c4c3)nc3ccccc23)[nH]n1
Temperature: 130 °C

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(5-isopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.17 mmol) in NMP (1 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (65 mg, 0.26 mmol). The mixture was heated at 130° C. for 3 hrs, cooled to room temperature, and then poured into water. The crude material was collected by filtration and treated with TFA in CH2Cl2 for 30 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of COMPOUND 117 (51 mg, 0.10 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 137 as a white solid (48 mg, 85%) following work-up and purification. 1H NMR (CDCl3) δ 0.97-1.18 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.24 (s, 3H), 2.31 (s, 6H), 2.55 (t, 1H, J=10.5 Hz), 2.74-2.87 (m, 3H), 3.24-3.31 (m, 1H), 3.57-3.63 (m, 1H), 3.77 (s, 2H), 3.85-3.91 (m, 1H), 6.51 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.1 Hz), 6.93-7.05 (m, 3H), 7.43-7.52 (m, 4H), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 14.53, 20.27, 22.20, 30.06, 31.46, 32.06, 40.96, 44.70, 49.60, 53.28, 57.84, 61.68, 113.66, 115.15, 120.06, 123.21, 128.42, 129.52, 130.36, 131.08, 131.64, 132.01, 135.21, 139.77, 143.16, 143.23, 147.35, 170.96, 171.27. ES-MS m/z 533 (M+H). Anal. Calcd. for C34H40N4O3.0.6H2O: C, 72.47; H, 7.37; N, 9.94. Found. C, 72.38; H, 7.25; N, 9.83.
Reaction SMILES: [CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:12])[C:6]([O:8][CH3:9])=O)([CH3:4])[CH3:3].[NH2:14][OH:15].Cl>N1C=CC=CC=1>[CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:12])[C:6](=[N:14][OH:15])[O:8][CH3:9])([CH3:4])[CH3:3]
Reactant: NO
Reactant: COC(=O)C(C)(CC=O)C(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=NO)C(C)(CC=O)C(C)(C)C
Temperature: 0 °C
Yield: 103.9 %

Procedure:
A solution of the aldehyde, methyl 2-(1,1-dimethylethyl)-2-methyl-4-oxobutanoate (2.05 g, 11 mmol) and H2NOH.HCl (1.15 g, 16.5 mmol) in dry pyridine (10 mL) was stirred at 60° C. for 4 h in a nitrogen atmosphere. After cooling the reaction mixture was poured into ice cold HCl (3N, 50 mL), and extracted with ether (3×40 mL). The combined ether extract was washed sequentially with 40 mL portions of saturated NaHCO3, water, and brine, and dried over MgSO4. The solvent was removed in vacuo to give 2.30 g of pale brown colored viscous liquid. Flash chromatography over silica gel (hexanes-EtOAc, 4:1) followed by bulb-to-bulb distillation (pot temp. 100°-105° C. (0.4 mmHg)) afforded the anti- and syn- oxime mixture (2.03 g, 92%) in the ratio of 58/42 as a colorless viscous liquid.