Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(NN=Cc2cccnc2)cc1

Procedure:
2.2 g of 3-pyridinecarbaldehyde was dissolved in 100 ml of ethanol. The solution was added to a filtered solution of 3.6 g of p-chlorophenylhydrazine hydrochloride and 9.8 g of sodium acetate in 60 ml of 50% by volume aqueous ethanol. The resulting precipitated solid was collected and recrystallized from ethanol to give 1, as a pale yellow prisms, mp 186° C.
Reaction SMILES: O.[P].[Cl:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-])=O>[Pt].O[PH2]=O.C1(C)C=CC=CC=1>[NH2:17][C:5]1[CH:6]=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:8]=[C:9]([NH2:10])[C:4]=1[Cl:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: [Pt]
Agent: O=[PH2]O
Agent: [P]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(C(F)(F)F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
0.48 g of Pt/C catalyst (5%) and 1.5 g of water are placed in a beaker and mixed with 103 mg of aqueous H3PO2 solution (50% by weight, corresponding to 5% by weight phosphorus, based on the catalyst). The mixture is stirred for 10 minutes at room temperature, then 77 mg of vanadylacetyl acetonate VO(acac)2 are added and stirred for a further 5 minutes. 40 g of 4-chloro-3,5-dinitro-benzotrifluoride and 47 g of toluene are placed in an agitator autoclave, and the catalyst suspension is flushed in with 4 g of water. Hydrogenation subsequently takes place at a temperature of 100° C. and at a hydrogen pressure of 5 bar. When the hydrogen uptake is complete, the autoclave is cooled and rendered inert with nitrogen. The catalyst is filtered off and washed with toluene. After working up by distillation, 29.8 g of 3,5-diamino-4-chloro-benzotrifluoride (yield 95.8% of theory) are obtained. Elementary analysis:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26]([S:28]([CH3:30])=[O:29])[C:25]([F:31])=[CH:24][C:23]=1F.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:23]3[CH:24]=[C:25]([F:31])[C:26]([S:28]([CH3:30])=[O:29])=[CH:27][C:22]=3[F:21])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: CS(=O)c1cc(F)c(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(S(C)=O)cc3F)CC2)CC1
Temperature: 120 °C

Procedure:
2d (0.78 g, 1.76 mmol) and 43b (0.66 g, 3.39 mmol) were combined with diisopropylethylamine (0.91 mL, 5.5 mmol) in DMSO (8 mL) and heated to 120° C. overnight. The mixture was cooled to room temperature and poured into 20 mL of ethyl acetate, washed with water (20 mL) and brine (3×20 mL), dried and concentrated. The residue was purified by flash chromatography (eluent: 50 to 90% of EtOAc+0.1% triethylamine in hexane) to afford 4-[1-(2,5-difluoro-4-methanesulfinyl-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 43-1. This material was recrystallized from toluene and hexane to afford 43-1 as a white powder: HPLC, LC-MS 458.1 (MH), tR=6.98 (Method 2). EC50: 58 nM.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][CH:29]([NH2:31])[CH3:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([NH:31][CH:29]([CH3:30])[CH3:28])=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to propan-2-amine via General Procedure B. The product was purified via reverse phase HPLC to give 28.1 mg of 126. MS (Q1) 423.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N=C1SCCN1Cc1ccc(Cl)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and triethylamine (110 mg, 1.1 mmol) were dissolved in 10 ml of acetonitrile, into which, benzoyl chloride (141 mg, 1.0 mmol) dissolved in acetonitrile 5 ml was added under cooling with ice, and stirred at room temperature overnight. After distilling the solvent off under reduced pressure followed by extraction with ethyl acetate, the ethyl acetate layer was washed with 2N-hydrochloric acid, saturated aqueous sodium bicarbonate, and water in this order, and the ethyl acetate layer was dehydrated and dried, and then the ethyl acetate layer was distilled off, and remaining oil was purified by a silica gel column chromatography to obtain the intended substance. The crude crystal of the intended substance was washed with hexane. Yield: 160 mg (65%). Melting point: 133° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3cccc(C(F)(F)F)c3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmole) and 3-(trifluoromethyl)benzylamine (0.63 mL, 4.40 mmole) is stirred under N2 at 140° C. for 1 h. The resulting product is chromatographed on silica gel (3-5t EtOH/EtOAc) to give 7-amino-4-[(3-trifluoromethylphenyl)methylamino]pyrido[4,3-d]pyrimidin (0.24 g, 63%) as a light brown solid. 1H NMR (DMSO) δ 9.10 (1H, s), 8.92 (1H, t, J=5.7 Hz), 8.26 (1H, s), 7.71 (1H, s), 7.66 (1H, d, J=7.4 Hz), 7.62 (1H, d, J=7.8 Hz), 7.57 (1H, t, J=7.6 Hz), 6.49 (2H, brs), 6.38 (1H, s), 4.82 (2H, d, J=5.8 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[N:17]=[C:5]2[N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N+:10]([O-:33])=[CH:9][C:8]=3[N:17]=[C:5]2[N:4]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3cnc4ccccc4c3n21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 18 h
Yield: 100.1 %

Procedure:
tert-Butyl (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate (1.16 g, 3.58 mmol) was dissolved in 50 mL of CHCl3 and treated with MCPBA (1.05 g, 77% max). After 18 hours, the reaction was treated with 20 mL of 1% Na2CO3 solution and the layers were separated. The aqueous layer was extracted with CHCl3 (6×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate 5-oxide (1.22 g) as a brown foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:16][CH2:15][C:14](=O)/[C:13](=[CH:18]/[N:19](C)C)/[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:31]N>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:16][CH2:15][C:14]3[C:13](=[CH:18][NH:19][N:31]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Reaction time: 3 h
Yield: 67 %

Procedure:
To a stirred solution of (E)-tert-butyl 1-(3-tert-butylphenyl)-3-((dimethylamino) methylene)-4-oxocyclohexylcarbamate (801 mg, 2.0 mmol) in 6 mL of ethanol was added hydrazine monohydrate (150 μL, 3.0 mmol). The reaction was allowed to stir for 3 h. The reaction was concentrated and purified using a biotage 40S column eluting with DCM/MeOH (95:5) to afford 500 mg (67% yield) of an off white foam. LCMS corresponded to the desired material: retention time (min)=2.45 (method [8]); MS (ESI) 370.0.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Br:13])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][C@H:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[Br:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:27]([CH2:28][C@H:29]([OH:31])[CH3:30])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(Br)cc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(Br)ccc1C2
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-6-bromo-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.37 g of (R)-1-amino-2-propanol in 10 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 4:1). 1.19 g (52%) of (R)-1-(7-bromo-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH2:9][CH2:10]C.[CH3:14]C(C)/C=C/C(=O)C>>[NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH:9]([CH3:10])[CH3:14]
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(=O)/C=C/C(C)C
Product: Cc1cc(C(C)C)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 5) using (3E)-5-methyl-3-hexen-2-one (20 g, 137 mmol). LCMS E-S (M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.9 (br s, 1H), 7.86-7.96 (br s, 3H), 6, 0.10 (s, 1H), 3.82-3.86 (m, 2H), 3.02-3.09 (m, 1H), 2.17 (s, 3H), 1.08 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9])([O-:3])=[O:2].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.C(=O)([O-])[O-].[K+:23].[K+]>CO>[K+:23].[C:8]([C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[CH:15][C:14]([O-:18])=[O:17])#[N:9]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC(=CC(=O)[O-])c1cccc([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
A suspension of 3-nitrobenzyl cyanide (1.62 g), glyoxylic acid monohydrate (1.38 g) and potassium carbonate (3.59 g) in methanol (20 ml) was stirred for 5 hours. The precipitate was collected by filtration, washed with dichloromethane and dried. The precipitate was suspended in water and stirred for an hour. The insoluble material was collected by filtration and dried to give 3-cyano-3-(3-nitro-phenyl)-acrylic acid potassium salt (2.18 g, 85.2%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C@H:7]1[N:12]([C:13](=O)[CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2].CO.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:6][C@H:7]1[N:12]([CH2:13][CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[S:35]([C:38]([F:40])([F:39])[F:41])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A mixture of 4-((R)-4-((R)-3-((diethylamino)methyl)morpholino)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 91, 200 mg, 0.31 mmol) and 1 M borane-tetrahydrofuran complex (662 μl, 0.66 mmol) was stirred at room temperature for 16 hours. The reaction mixture was treated carefully with MeOH (5 ml) and concentrated HCl (1 ml). The mixture was heated at 80° C. for 3 hours, cooled to r.t, and the pH was adjusted to pH 10 with 4 N aqueous sodium carbonate. The mixture was diluted with ethyl acetate (300 ml), washed successively with water (150 ml) and brine (150 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM over 15 minutes) to give the title product (109 mg, yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:25](=[O:24])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][CH2:14]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of Example 213a (7.00 g, 19.91 mmol) and triethylamine (3.61 mL, 25.9 mmol) in tetrahydrofuran (150 mL) was added BOC2O (5.08 mL, 21.90 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc and washed with brine and saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 150 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 5.42 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH2:31][N:32]4C(=O)C5=CC=CC=C5C4=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.NN.O.CCOC(C)=O>CCO>[NH2:32][CH2:31][CH2:30][N:28]1[CH:29]=[C:9]2[C:10]([N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:27]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 66.7 %

Procedure:
To a solution of 4,6-bis(4-fluorophenyl)-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.09 g, 0.2 mmol, obtained in example 89) in EtOH (2 mL), hydrazine monohydrate (0.02 g, 0.3 mmol) was added and the mixture was heated to reflux for 3 h. A mixture of water and EtOAc was added. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3-MeOH mixtures of increasing polarity as eluent, to afford 57 mg of the title compound (yield: 83%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:22])=[CH:15][CH:16]=1
Reactant: CCNCC
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of diethylamine (89.1 mL), triethylamine (120.2 mL) and CH2Cl2 (500 mL) cooled in an ice-bath was added dropwise p-anisoyl chloride (133.8 g) over 40 minutes. The reaction mixture was stirred at room temperature for 40 minutes, the mixture was filtered, washed with ether and the solvent was removed in vacuo. Ether was added, then water to the residue, then the organic layer was separate and washed with 5% NaOH, then in HCl, then brine and then was dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by kugelrohr distillation at 140°-180° C. under high vacuum to afford 163.8 g of 4-methoxy-N,N-diethylbenzamide, m.p. 40°-42° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:30][CH2:31][CH:32]1[O:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:33]1>ClCCl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH:32]2[O:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:33]2)=[O:8])=[C:4]([O:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-2-ethoxybenzoic acid (2.9 g) in dichloromethane (50 ml), triethylamine (1.6 g) is added at 25° C. The resulting mixture is cooled to -10° C., and isobutyl chloroformate (2.0 g) is added slowly. After the mixture is stirred at the same temperature for 1 hour, a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (3.0 g) in dichloromethane (10 ml) is added. The reaction mixture is stirred for 1 hour at a temperature of between -10° C. and -5° C. and then at 25° C. overnight. The mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recyrstallized from ethanol to give the title compound (4.1 g), mp 151°-153° C.
Reaction SMILES: CS(O[C:6]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:33][C:32]([C:38]4[CH:43]=[C:42]([Cl:44])[C:41]([Cl:45])=[C:40]([Cl:46])[CH:39]=4)([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N-:47]=[N+:48]=[N-:49].[Na+].CS(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:47]([C:6]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:33][C:32]([C:38]4[CH:43]=[C:42]([Cl:44])[C:41]([Cl:45])=[C:40]([Cl:46])[CH:39]=4)([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[N+:48]=[N-:49]
Reactant: CS(=O)(=O)OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 1.19 grams (1.88 mmole, 1.0 eq) of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol in 17 mL of CH2Cl2 was added 500 μL (2.8 mmole, 1.5 eq) of diisopropyl-ethylamine, neat via syringe, followed by 438 mg (2.5 mmole, 1.3 eq) of methylsulfonic anhydride solid. After stirring 3.5 hours at room temperature an aliquot of the reaction mixture was placed in 1.0 mL of methanol and analyzed via LC/MS. The chromatograph indicated the starting material was consumed. The reaction with diluted with 20 mL of CH2Cl2 and 20 mL of saturated NaHCO3 solution. After stirring for 2 hours the layers were separated via a Biotage Phase Separator cartridge. The organic layer was concentrated under reduced pressure to give 1.29 grams (96% yield) of intermediate 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-yl methanesulfonate as light yellow solid. A 227 mg sample of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-yl methanesulfonate (0.35 mmole, 1.0 eq) and 72.1 mg of sodium azide (1.1 mmole, 3.1 eq) were weighed into a 100 mL flask, to this was added 3 mL of anhydrous DMSO. After stirring for 1.5 hours at room temperature the reaction was diluted with 30 mL of CH2Cl2 and 15 mL of saturated NaHCO3 solution. After stirring this mixture for 1 hour the layers were separated via a Biotage Phase Separator cartridge. The water layer was rinsed with additional CH2Cl2 and the combined organic layers were concentrated by evaporation utilizing a stream of N2 gas. The resulting crude oil was purified via silica gel column chromatography eluting with 100% CH2Cl2. Evaporation of the appropriate fractions gave 144.5 mg of product, 3-(4-(3-azido-1-benzhydrylazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole, (63% yield) as a glassy yellow solid. ms 656 [M+H], HPLC retention time: 3.600 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1.C[CH2:19][OH:20]>[Ni]>[Cl:1][C:2]1[C:7]([NH:8][CH:19]=[O:20])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCO
Agent: [Ni]
Product: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
The title compound of Example 24 (6.77 g, 24.26 mmol) was placed in a Parr bottle containing 220 ml absolute EtOH and 10.0 g (wet) Raney nickel catalyst that had been previously shaken under hydrogen (40 psi) for 10 minutes. The mixture was shaken under hydrogen (40 psi) for an hour, filtered over celite, and the filtrate was concentrated to a yellow-white solid that was dried under vacuum overnight. This solid was stirred in 1,2-dichloroethane (250 ml) at 0° C. Acetic anhydride (30 ml) was added, followed by formic acid (30 ml), dropwise under nitrogen. The resulting mixture was stirred at room temperature for 2 hours, concentrated to half the original volume; and azeotroped with toluene to remove residual formic/acetic acid. The crude solid was triturated with methanol to give the title compound (4.92 g, 73%) as an off-white solid; m.p. 206°-209° C. (dec); 'H-NMR (DMSO-d6) δ 1.08 (d, J=6.8 Hz, 6.0 (CH3)2CH), 2.74 (m, J=6.8 Hz, 1.0 (CH3)2CH), 8.18 (d, J=10.3 Hz) and 10.26 (br s) [total 1.0, NHCHO from two conformers], 11.17 (br s, 1.0).