Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.FC(F)(F)C(O)=O.[C@@H:32]12[CH2:38][C@@H:35]([NH:36][CH2:37]1)[CH2:34][O:33]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:36]3[CH2:37][C@H:32]4[CH2:38][C@@H:35]3[CH2:34][O:33]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1O[C@H]2CN[C@@H]1C2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Temperature: 140 °C
Yield: 70.1 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.68 g, 1.9 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane trifluoroacetate (prepared starting from cis-1-Boc-4-hydroxy-D-prolinate, 3.1 mmol) in ethanol (14 mL) was added triethylamine (4 mL, 31 mmol). The mixture was heated in the microwave reactor for 10 minutes at 140° C. The precipitate was collected by Buchner filtration and washed successively with methanol, water, methanol, and diethyl ether. Solid was dried under house vacuum to provide (1R,4R)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane as a pale yellow solid (0.56 g, 70%). MS (ES+): 421.1 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C)C=O>[I:17][C:14]1[CH:15]=[CH:16][C:9]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(I)ccc1F
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(I)cc1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
A solution of 2-methyl-1-propanol (0.56 mL, 6.06 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C. and to this was added sodium hydride (242 mg, a 60% suspension in mineral oil, 6.06 mmol) in small portions. The turbid reaction mixture was stirred at 0° C. for 5 minutes and the temperature was raised to 23° C. Thereafter, the mixture was stirred at room temperature for 10 minutes and cooled again to 0° C. To the reaction mixture was added 2-fluoro-5-iodobenzonitrile (1.0 g, 4.04 mmol) and, after being warmed to room temperature, the reaction mixture was stirred for 1.5 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with a saturated aqueous sodium chloride solution (3×30 mL), and thereafter dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (hexane/ethyl acetate=98/2) to obtain the title compound (950 mg). Yield, 78%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH2:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C@H:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C@H:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C@H:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C@H:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(O[C@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.4 ml of acetyl chloride in 75 ml of chloroform is added dropwise under nitrogen over a 15-minute period to a solution of 5.05 g of the free base of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine of Example 8 in 150 ml of dry chloroform containing 2.74 ml of triethylamine. The pot temperature reaches a maximum of 28° C. The reaction is complete in 30 minutes. The chloroform solution is washed with 10% aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to a foam which solidifies upon trituration with hexane. The hexane mixture is briefly heated to boiling, then cooled to room temperature and allowed to stand for 30 minutes before filtering. A crude solid results, mp s 172°, 173°-175° C. Recrystallization from toluene affords cis-4-(4-acetamidophenoxy)-1-methyl-3-phenylpiperidine, mp 174.5°-176.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C@H:5]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:41])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][C:30]=1[O:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:41])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:6]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[O:37])=[CH:31][C:30]=1[O:39][CH3:40]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-methyl-2-(S)-pirrolidinylmethoxy]benzoate (141 mg, 0.57 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 0.57 mmol) and N,N-dimethylaminopyridine (69.0 mg, 0.57 mmol) in DMF (10 ml) was added EDC.HCl (120 mg, 0.62 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (297 mg, 96%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 1.24–1.34 (m, 3 H), 1.93–2.18 (series of m, 4 H), 2.28 (s, 3 H), 3.65 (s, 3 H), 3.88 (s, 3 H), 3.62–3.87 (m, 3 H), 4.11–4.38 (series of m, 3 H), 6.42–8.06 (series of m, 13 H); MS (ESI) m/z, 546 (M++H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([CH2:37][CH2:38][NH2:39])[N:34]=[CH:33]1.CS(C)=[O:42]>>[CH:18]([OH:22])=[O:42].[CH2:23]([C:20]1[N:19]=[C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([NH:39][CH2:38][CH2:37][C:35]3[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=3)=[N:3][C:4]=4[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[O:12]2)[O:22][N:21]=1)[CH3:24]
Reactant: CS(C)=O
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: Cn1cnc(CCN)c1
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NCCc5cn(C)cn5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 92.5 °C

Procedure:
Intermediate 9 (0.070 g, 0.161 mmol) and 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.101 g, 0.807 mmol) were dissolved in DMSO (0.03 ml) and heated at 85-100° C. under nitrogen for 8 days, a further portion of 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.101 g, 0.807 mmol) was added after the first 5 days. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a cream solid (0.010 g). LC/MS system A Rt=3.36 min, m/z=526 MH+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:9]=1.[C:24]([OH:31])(=O)/C=C/C(O)=O.[CH2:32](O)C>>[OH:1][C@H:2]1[C@@H:6]([OH:5])[C@H:32]([O:31][CH3:24])[CH2:4][C@@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:9]=1
Reactant: CCO
Reactant: O[C@@H]1COC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Reactant: O=C(O)/C=C/C(=O)O
Product: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O

Procedure:
4-[(3R,4R)-(4-Hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 19) (499 mg) and fumaric acid (192 mg) are dissolved in ethanol (20ml), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration, and recrystallized from water-acetone to give 4-[(3R,4R)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl) quinazoline 1/2 fumarate (462 mg) as crystals.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:34][C:2]([F:1])([F:33])[CH:3]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 85 °C
Yield: 65.2 %

Procedure:
To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino)isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:10][CH:9]=1)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[C:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[N:17][C:16]([CH2:15][CH2:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:31]=[N+:32]=[N-:33])=[CH:13][CH:12]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOS(C)(=O)=O)cc3)nc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCN=[N+]=[N-])cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of 2-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)ethyl methanesulfonate (608.9 mg, 1.411 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium azide (918.0 mg, 14.12 mmol), and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with tert-butyl methyl ether (10 ml) and dried under reduced pressure to give 1-acetyl-4-(6-{2-[4-(2-azidoethyl)phenyl]ethyl}pyridin-3-yl)piperazine (405.9 mg, yield 76.0%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4F)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]([O:54][CH3:55])=[O:53].C(O)(C(F)(F)[F:59])=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18](=[O:19])[NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:59])[CH:22]=4)=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:40][CH2:39]1
Reactant: COC(=O)CBr
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 45 °C

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (50.0 mg, 0.092 mmol) and DIEA (0.064 mL, 0.367 mmol) in CH2Cl2 (1 mL) was added methyl 2-bromoacetate (21.07 mg, 0.138 mmol), and the reaction mixture was heated 45° C. in a seal-tube apparatus for 14 hrs. The reaction mixture was concentrated, treated with TFA (0.424 mL, 5.51 mmol) and heated at 65° C. for 1 hr. The reaction mixture was concentrated and diluted with methanol and purified using preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, methyl N-(trans-4-((8-(cyclopropylamino)-3-((2-fluoro-4-pyridinyl)carbamoyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)glycinate, as an off-white solid ((23 mg, 0.046 mmol, 50.5% yield). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.32 (M+H=497.3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Product: O=C/C=C/c1ccc(-c2cnccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-pyrazinylbenzaldehyde (prepared as described in Reference Example 17) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Reactant: OCc1ccccc1
Product: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2O)cc1
Yield: 94.7 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (8.0 g, 31.0 mmol) and benzyl alcohol (3.37 mL, 32.55 mmol), 10.23 g (95%) of the title compound was obtained as a white solid: mp 97-98° C. (lit. 93-95° C.); IR (KBr) 1635, 1611, 1512, 1496, 1387, 1351, 1289, 1227, 1173, 1131, 1029, 994, 948, 842, 830, 791, 745, 725, 695, 535 cm−1; 1H NMR (250 MHz, CDCl3) δ 12.73 (s, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.33-733-7.40 (m, 5H), 7.18 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.53-6.49 (m, 2H), 5.07 (s, 2H), 4.14 (s, 2H), 3.78 (s, 3H); 13C NMR (69.3 MHz, CDCl3) δ 202.77, 166.19, 165.63, 159.10, 136.26, 132.51, 130.82, 129.15, 128.77, 127.97, 126.71, 114.63, 113.73, 108.71, 102.48, 70.6.5, 55.69, 44.38; HRMS calculated for C22H20NaO4 (M+Na)+ 371.1259, found 371.1265.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:9]1([O:15][C:16]2[N:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH:9]1([O:15][C:16]2[N:21]=[CH:20][C:19]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1nccnc1Cl
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nccnc1-c1ccc(OC2CCCCC2)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (53.5 mg) was added to a suspension of 3-chloropyrazin-2-amine (200 mg), 6-(cyclohexyloxy)pyridin-3-ylboronic acid (375 mg) and sodium carbonate (327 mg) in DME (5 mL) and water (1 mL) and the mixture was stirred at 90° C. under nitrogen for 3 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (332 mg) as brown gum.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[C:26]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[Cl:35])=[CH:18][C:17]([C:37](O)=[O:38])=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[CH:40]1([NH2:43])[CH2:42][CH2:41]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.B(Cl)(Cl)Cl>CN(C=O)C.O>[Cl:35][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:27][C:22]=1[C:21]([NH:20][C:19]1[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[N:16]=[C:17]([C:37]([NH:43][CH:40]2[CH2:42][CH2:41]2)=[O:38])[CH:18]=1)=[O:36]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: ClB(Cl)Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of 1-(3-(benzyloxy)phenyl)-5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1H-pyrazole-3-carboxylic acid (Example 104, 220 mg, 0.373 mmol) in DMF (5 mL) was added cyclopropylamine (26 mg, 0.448 mmol) and DIPEA (241 mg, 1.87 mmol, 0.325 mL) followed by HATU (213 mg, 0.560 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water (70 mL) and extracted with 2-MeTHF (50 mL). The organic layer was washed with brine (50 mL) dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-25% EtOAc in DCM and the residue was dissolved in DCM (5 mL). Boron trichloride (1M in DCM, 1.72 mL, 1.72 mmol) was added at 0° C. and the reaction was stirred at this temperature for 40 minutes. The reaction was quenched by the addition of MeOH (1 mL) and stirred for 20 minutes. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with 2-6% MeOH in DCM to afford the title compound (103 mg, 79%).
Reaction SMILES: C([O:5][P:6]([O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:31][C:32]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][N:35]=[C:34]([NH:42][C:43]4[CH:57]=[CH:56][C:46]([CH2:47][P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])=[CH:45][C:44]=4[O:58][CH3:59])[N:33]=3)=[C:24]3[C:28]=2[CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[CH2:16][CH2:15]1)([O:8]C(C)(C)C)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH3:59][O:58][C:44]1[CH:45]=[C:46]([CH:56]=[CH:57][C:43]=1[NH:42][C:34]1[N:33]=[C:32]([NH:31][C:23]2[CH:22]=[CH:21][C:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([O:13][P:6]([OH:7])([OH:8])=[O:5])[CH2:19][CH2:18]3)=[C:28]3[C:24]=2[C:25](=[O:30])[N:26]([CH3:29])[CH2:27]3)[C:37]([C:38]([F:40])([F:41])[F:39])=[CH:36][N:35]=1)[CH2:47][P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(OC(C)(C)C)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl [4-({4-[(7-{trans-4-[(di-tert-butoxyphosphoryl)oxy]cyclohexyl}-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino)-3-methoxybenzyl]phosphonate (Compound 228A, 38.5 mg, 0.044 mmol) in THF (2 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. Solvents were then removed in vacuo and the residue was purified by MDP (formic acid conditions) to obtain 31.9 mg of the desired product (yield: 95%). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.6 Hz, 6 H), 1.41-1.46 (m, 2 H), 1.66-1.76 (m, 4 H), 2.12-2.15 (m, 2 H), 2.49 (m, 1 H), 3.04 (s, 3 H), 3.29 (d, J=21.20 Hz, 2 H), 3.73 (s, 3 H), 3.96-4.03 (m, 4 H), 4.12 (m, 1 H), 4.47 (s, 2 H), 6.89 (d, J=7.6 Hz, 1 H), 7.05 (s, 1 H), 7.36 (d, J=8.8 Hz, 1 H), 7.43 (s, br, 1 H), 8.36 (d, J=0.8 Hz, 1 H), 8.98 (s, 1 H), 10.54 (s, 1 H). MS (ES+): m/z 758.21 [MH+]. HPLC: tR=1.27 min (UPLC TOF, polar—3 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CC1(c2ccc(N)cc2)CCCCC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 1-(4-nitro-phenyl)-cyclohexanecarbonitrile (0.500 g, 2.17 mmol, as prepared in the previous step) in EtOH (6 mL) and water (6 mL) was treated with NH4Cl (1.16 g, 21.7 mmol) and Fe powder (606 mg, 10.9 mmol) and heated to 50° C. for 2 h. The cooled mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvents were evaporated in vacuo. The residue was partitioned between water (50 mL) and EtOAc (75 mL), and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (488 mg, 100%) as an orange oil. The compound was used in the following step without purification. Mass spectrum (ESI, m/z): Calcd. for C13H16N2, 201.1 (M+H), found 201.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[OH-].[Na+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21]>CN(C)C=O>[OH:23][C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC(C)(O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CCCCC(C)(C)O
Temperature: 110 °C

Procedure:
83 g (0.5 mol) of 3-methylxanthine are dissolved in 500 ml of 1N sodium hydroxide solution (0.5 mol) under the influence of heat. The mixture is filtered, the water is distilled off under reduced pressure and the sodium salt which remains is dried under a high vacuum. After addition of 1.5 liters of dimethylformamide and 75.3 g (0.5 mol) of 1-chloro-5-hydroxy-5-methylhexane, the mixture is heated at 110° C. for 6 hours, while stirring, filtered hot and evaporated under reduced pressure, the residue obtained is taken up in 1 liter of hot 1N sodium hydroxide solution, the hot solution is filtered and, after cooling to room temperature, 6N hydrochloric acid is added dropwise, with stirring, until a pH of 9 is reached. The precipitate is filtered off with suction, washed neutral and dried in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: CCc1ccncc1
Reactant: Clc1ccc(CCBr)cc1
Product: CC(CCc1ccc(Cl)cc1)c1ccncc1
Yield: 59.6 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.05 g (9.35 mmol) of 4-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.37 g of the desired compound (yield: 59.8%).