Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1C2N=CC=C(OC(N(C)C)=[N+](C)C)C=2N=N1.C([O:32][C:33]1[CH:38]=[C:37]([O:39]CC2C=CC=CC=2)[C:36]([Cl:47])=[CH:35][C:34]=1[C:48]1[C:52]([C:53]([OH:55])=O)=[CH:51][N:50](COCC[Si](C)(C)C)[N:49]=1)C1C=CC=CC=1.C(OC1C=C(OCC2C=CC=CC=2)C(Cl)=CC=1N1C=C(C(O)=O)CN1COCC[Si](C)(C)C)C1C=CC=CC=1.[CH3:103][C:104]([C:106]1[CH:111]=[CH:110][C:109]([NH2:112])=[CH:108][CH:107]=1)=[O:105].C(N(C(C)C)CC)(C)C.B(Cl)(Cl)Cl>ClCCl.CN(C)C=O>[C:104]([C:106]1[CH:111]=[CH:110][C:109]([NH:112][C:53]([C:52]2[C:48]([C:34]3[CH:35]=[C:36]([Cl:47])[C:37]([OH:39])=[CH:38][C:33]=3[OH:32])=[N:49][NH:50][CH:51]=2)=[O:55])=[CH:108][CH:107]=1)(=[O:105])[CH3:103]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Agent: CN(C)C(Oc1ccnc2[nH]nnc12)=[N+](C)C
Agent: C[Si](C)(C)CCOCN1CC(C(=O)O)=CN1c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)c2c[nH]nc2-c2cc(Cl)c(O)cc2O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (100 mg, 0.27 mmol) was added to a mixture of 3-(2,4-Bis-benzyloxy-5-chloro-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-4carboxylic acid and 3-(2,4-Bis-benzyloxy-5-chloro-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.27 mmol). N,N-dimethylformamide (2.5 ml) was added, followed by 4-aminoacetophenone (43 mg, 0.32 mmol) and diisopropylethylamine (0.14 ml, 0.81 mmol). The reaction mixture was heated at 100° C. for 5 minutes using microwave heating and stood at ambient temperature for 2 hours. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (8 ml) and aqueous sodium chloride solution (5 ml). Mixture was stirred vigorously for 10 minutes and the phases were separated. The organic phase was dried over anhydrous sodium sulphate and filtered and filtrate solvents were removed in vacuo to afford a brown oil. The crude amide product was re-dissolved in dichloromethane (2 ml) and placed under a nitrogen atmosphere. Boron trichloride (1.0M solution in dichloromethane, 1.35 ml, 1.35 mmol) was added drop-wise and a brown precipitate forms. Reaction mixture was stirred overnight then quenched by the cautious addition of saturated aqueous sodium bicarbonate solution (4 ml). Reaction mixture was extracted with ethyl acetate and phases separated. The organic phase was washed with brine then dried over sodium sulphate, filtered and filtrate solvents were removed in vacuo to afford brown solid which was purified by preparative HPLC to afford 3-(5-chloro-2,4-dihydroxy-phenyl)-1H-pyrazole-4-carboxylic acid (4-acetyl-phenyl)-amide (3 mg) as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(N4CCCCC4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C21H23FN6O3, 426.2
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(O)(C(F)(F)F)=O>>[F:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)[CH:22]=4)[N:6]=3)[O:9][C:10]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccc(F)cc5o4)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)nc1-c1nc2ccc(F)cc2o1
Yield: 58.1 %

Procedure:
Using analogous procedures to those described in Example 17, tert-butyl 4-[4-[5-amino-6-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (100 mg) was reacted with TFA to give 3-(6-fluoro-1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyrazin-2-amine (46 mg). NMR Spectrum: (400 MHz, MeOD) 8.60 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.90 (dd, 1H), 7.60 (dd, 1H), 7.30 (dd, 1H), 4.20 (m, 1H), 3.70 (m, 1H), 3.30 (m, 2H), 2.50 (m, 4H); Mass spectrum: M+H+ 380
Reaction SMILES: [C:1]([CH:5](O)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:12]>C1C=CC=CC=1>[C:1]([CH:5]([Br:12])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)C(O)C(C)(C)C
Solvent: c1ccccc1
Product: CC(C)(C)C(Br)C(C)(C)C
Temperature: 0 °C

Procedure:
The alcohol is dissolved in benzene and stirred at 0° C. under argon. A solution of phosphorus tribromide in benzene is added and the mixture is stirred for 2 hours and then heated to 60° C. for 4 hours. The mixture is cooled, poured into ice and extracted with ether. The organic layer is washed with saturated NaHCO3, dried over MgSO4 and evaporated to give di-t-butylmethyl bromide.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH:20](OC1C=CC([N+]([O-])=O)=CC=1)=[O:21].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C1COCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH:20]=[O:21])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(NC=O)c(F)c2)C(=O)O1
Yield: 85.1 %

Procedure:
A solution of 5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]-oxazolidine-2-one (0.200 g, 0.748 mmol), p-nitrophenyl formate (0.188 g, 1.12 mmol), and 2,6-di-(tert-butyl)pyridine (0.336 mL, 1.50 mmol) in THF (4 mL) was stirred at 65° C. overnight. Solvent was removed under vacuum and the residue purified by PTLC (30% acetone in DCM) to give product as a white solid (0.188 g, 85%). M.p. 196-8° C.; MS (m/z): [M+H]+=296.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][CH:27]=[C:6]2[C:7]([N:9]([CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=3)[CH2:13][C:14]#[N:15])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:29]=[CH:28][CH:27]=[C:6]2[C:7]([N:9]([CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=3)[CH2:13][C:14]#[N:15])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: [H][H]
Reactant: CCOc1cc(C(CC#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC#N)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 49.3 %

Procedure:
To a solution of 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.2 g, 0.5 mmol) in 30 mL of ethyl acetate was added 0.05 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow oil. The crude product was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride). The resulting yellow solid was then dried in vacuo (60° C., <1 mm) to afford 0.09 g (50%) of 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile: mp 171°-172.5° C.; 1H NMR (CDCl3) δ7.47-7.356 (m, 1H); 7.19-7.00 (m, 3H), 6.90-6.29 (m, 2H), 5.56 (dd, J=6.6 10 Hz, 1H), 5.24 (s, 2H), 4.09 (q, J=7 Hz, 2H), 3.84 (s, 3H) 3.77 (dd, J=10, 16.8 Hz, 1H), 3.27 (dd, J=6.6, 16.8 Hz, 1H), 1.45 (t, J=7 Hz, 3H); 3C NMR (CDCl 3) δ169.4, 167.9, 149.6, 148.5, 145.5, 135.5, 132.1, 129.4, 121.3, 120.0, 117.1, 113.0, 112.2, 111.4, 110.6, 64.5, 55.9, 50.7, 21.1, 14.7; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 40/60, acetonitrile/0.1% aqueous phosphoric acid) 4.5 min, 100%; Anal. Calcd. for C20H19N3O4. Theoretical: C, 65.74,H, 5.24, N, 11.50. Found: C, 65.54; H, 5.23; N, 11.23.
Reaction SMILES: C(O[N:5]1[C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:17])[N:7]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[C:6]1=[O:30])(=O)C.Cl.F[C:33](F)(F)[C:34]([OH:36])=[O:35].ClCCl>>[CH3:16][C:9]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH2:33][C:34]([OH:36])=[O:35])[C:6](=[O:30])[N:7]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[C:8]1=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)ON1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl (5-methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinyl acetate (400 mg) was dissolved in a 20% trifluoroacetic acid/dichloromethane solution (10 mL), and the mixture was stirred at room temperature overnight. After 0.5N hydrochloric acid was added, and the solution was extracted twice using chloroform (100 mL). The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further recrystallization from IPE afforded 276 mg of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].[CH3:39][N:40](C)[CH:41]=O.CNC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH3:39][N:40]([CH3:41])[C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18]
Reactant: CN(C)C=O
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.026 g, 0.000049 mol;) was dissolved in N,N-Dimethylformamide (2 mL, 0.03 mol;) and 2.0 M of Dimethylamine in Tetrahydrofuran (0.243 mL) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.024 g, 0.000063 mol;) was added. The reaction was allowed to stir for 2 hours and LC-MS showed disappearance of starting material and appearance of product at 1.28 562.10. The reaction was purified by Gilson Preparative HPLC and the pure fractions were concentrated. ES (+) MS m/e=562.10; NMR (400 MHz, DMSO-d6) δ ppm 2.79 (s, 3H), 3.00 (s, 3H), 3.06 (d, 2H, J=7 Hz), 5.22 (d, 2H, J=5 Hz), 5.7 (m, 1H), 6.60 (t, 1H, J=8 Hz), 7.00 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.54 (t, 1H, J=8 Hz), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.29 (d, 1H)
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([NH3+:14])[C:7]2=[O:15].C(N(C(C)C)CC)(C)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([NH:14][C:25](=[O:27])[O:28][CH2:29][CH3:30])[C:7]2=[O:15]
Reactant: COc1ccc2c(c1)C(=O)C([NH3+])CO2
Reactant: CCOC(C)=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.82 g (12.3 mmol) of 6-methoxy-4-oxochroman-3-aminium chloride were dissolved in tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. with an ice bath. Diisopropylethylamine and ethyl carbononochloridate were added. The mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution (2×) and water (1×). The organic phase was washed dried over MgSO4, and concentrated in vacuo to give 3.5 g (13.2 mmol, quant.) of crude material.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][NH2:16].O.C(Cl)Cl.CO>CCO.ClCCl>[CH3:15][NH:16][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: CN
Solvent: O
Solvent: CO
Solvent: CCO
Product: CNc1nc2ccccc2n2ccnc12
Temperature: 25 °C
Yield: 93 %

Procedure:
Compound 12 (0.110 g, 0.54 mmol) is solubilized in EtOH (10 ml), and then a solution of methylamine in water (40% by weight) (0.15 ml, 1.74 mmol) is introduced. The mixture is left under stirring in an autoclave, at room temperature, for at least 15 h. The product, initially insoluble, is solubilized shortly thereafter. The progression of the reaction is controlled by TLC, eluent: CH2Cl2/MeOH (95/5). At the end of 15 h, 1.5 eq (0.06 ml) of methylamine are added. After 5 h of stirring, the reaction progresses no further. The solvent is evaporated dry under vacuum. The yellowish residue obtained is solubilized in dichloromethane (10 ml). This organic phase is washed using a saturated sodium bicarbonate solution (10 ml) and then water (10 ml). It is then dried on Na2SO4 and then evaporated under vacuum. A white solid is recovered. The residue is purified on a silica gel column in order to eliminate traces of the starting product, eluent: CH2Cl2/AcEt (70/30). A white solid (0.99 g, 93%) is obtained; 1H NMR (300 MHz, DMSO-d6) δ: 7.92 (s, 1H, C—CH—N), 7.75 (dd, J1=1.22 Hz, J2=8.17 Hz, 1H, ArH), 7.65 (dd, J1=1.26 Hz, J2=8.06 Hz, 1H, ArH), 7.52 (s, 1H, N—CH—C), 7.4 (t, 1H, ArH), 7.25 (t, 1H, ArH), 6.15 (s, 1H, NH), 3.25 (d, 3H, —CH3); 13C NMR (200 MHz, DMSO-d6) δ: 142.25, 139.17, 131.99, 129.40, 128.17, 127.20, 125.14, 124.34, 114.14, 113.89, 29.20. Analysis calculated for C11H10N4: C, 66.65; H, 5.08; N, 28.26. Experimental: C, 66.26; H, 5.53; N, 28.23.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:21]>CO>[ClH:21].[CH3:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: Cc1ncccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
tert-Butyl 4-(2-methyl-3-pyridyl)piperidine-1-carboxylate (100 mg, 0.36 mmol) was dissolved in methanol (4 ml) and combined with hydrochloric acid (4N in dioxane, 10 ml) and the mixture was stirred at room temperature for two hours. The volatiles were removed under reduced pressure to yield 54 mg of a beige solid (0.25 mmol, 69%) MS (ESI) m/z=177.1 [M+1]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.C(OC(=O)[N:34]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[C:37]([F:43])[N:36]=1)(C)(C)C.[Cl-].[NH4+]>O1CCCC1>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=3)[NH:4][CH:3]=2)=[C:37]([F:43])[N:36]=1
Reactant: COc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c2c1
Temperature: 5 °C
Yield: 160 %

Procedure:
To 3-iodo-5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5, 0.49 g, 1.14 mmol) in 6.8 mL of tetrahydrofuran at −50° C. under nitrogen, isopropylmagnesium chloride (0.569 mL, 2.0 M in tetrahydrofuran, 1.14 mmol) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, then cooled to −60° C. and (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (48, 0.23 g, 0.63 mmol) in 30.0 mL of tetrahydrofuran was added. The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a white solid (176, 0.400 g). MS (ESI) [M+H+]+=669.4.
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:12]([O-])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:14])[NH:8]2.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:14])[NH:8]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2ccc(=O)[nH]c2cc[n+]1[O-]
Agent: Cl
Product: CC(=O)OCc1nccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture containing 38.2 g of 5-methyl-1,6-naphthyridin-2(1H)-one-6-oxide hydrochloride and 300 ml of acetic anhydride was refluxed with stirring on a steam bath for 48 hours and then the reaction mixture was cooled to room temperature. The separated product was collected, recrystallized from dimethylformamide and dried in vacuo at 80° C. to produce 10.5 g of 5-[(acetyloxy)methyl]-1,6-naphthyridin-2(1H)-one as its hydrochloride, m.p. 162°-165° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:65][CH2:66][CH2:67][C:68]1[CH:69]=[CH:70][C:71]2[C:75]([CH3:77])([CH3:76])[O:74][B:73]([OH:78])[C:72]=2[CH:79]=1>CN(C=O)C.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:30])([F:28])[F:29])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([NH:65][CH2:66][CH2:67][C:68]5[CH:69]=[CH:70][C:71]6[C:75]([CH3:76])([CH3:77])[O:74][B:73]([OH:78])[C:72]=6[CH:79]=5)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(CCNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.9 mmol) and HATU (513 mg, 1.35 mmol) in DMF (18 mL), DIPEA (350 mg, 2.7 mmol) can be added. The reaction mixture can be stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) can be added. The reaction mixture can be continued to stir overnight. Water can be added and the mixture can be extracted three times with ethyl acetate. The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I.C(OCC)(=O)C>CN(C)C(=O)N(C)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:20][CH2:19][CH2:18][Cl:17])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: ClCCCI
Reactant: COc1ccc2c(c1)CCNC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(CCCCl)C(=O)C2
Reaction time: 2 h

Procedure:
First, 7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.15 g, 6 mmol) is dissolved in absolute tetramethylurea (30 ml), mixed with 55% sodium hydride dispersion in oil (300 mg) and stirred for 2 hours at 20°-25° C. under a nitrogen atmosphere. The resulting reaction mixture is added dropwise, with stirring, at 15°-20° C. under a nitrogen atmosphere to 1-chloro-3-iodopropane (1.6 g, 7.8 mmol) dissolved in tetramethylurea (20 ml) and stirred for 3 hours at ambient temperature. Then, ethyl acetate (300 ml) are added and the mixture is extracted six times with water. The organic solution is dried over magnesium sulphate, concentrated by evaporation and the residue is purified oer a silica gel column with methylene chloride and increasing amounts of ethanol (up to 2%). Yield: 410 mg. IR spectrum (methylene chloride): 1650 cm-1 (C=O).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH2:11][CH:10]1[CH3:24])[CH:7]=[CH2:8]>CO>[CH2:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:11][CH:10]1[CH3:24])[CH:7]=[CH2:8]
Reactant: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1C
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: C=CCN1CCN(c2ccc(N)cn2)CC1C
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
4.975 g (22.05 mmol) of tin(II) chloride dihydrate were added to a solution of 707 mg (2.45 mmol) of 1-allyl-2-methyl-4-(5-nitropyridin-2-yl)piperazine from Example 13.2 in 50 ml of methanol and the resulting mixture was stirred at 70° C. for 90 minutes. After the solvent had been evaporated down to dryness, water was added to the resulting residue and the mixture was made alkaline using a dilute aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction and the phases were separated. The aqueous phase was extracted with dichloromethane. After that, the combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness. The resulting title compound was used in the next step without any further purification.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:13]=3[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH3:20][N:17]1[CH2:18][CH2:19][C:13]2[CH:12]=[CH:11][NH:10][C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1
Reactant: CN1CCc2ccn(S(=O)(=O)c3ccccc3)c2C(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2cc[nH]c2C(c2ccccc2)C1

Procedure:
A mixture of 1-phenylsulphonyl-1,4,5,6,7,8-hexahydro-6-methyl-8-phenylpyrrolo[2,3-d]azepine (0.48 g), 50% sodium hydroxide (25 ml) and ethanol (50 ml) was refluxed for 75 minutes. The solution was evaporated to half its original volume, diluted with water and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give an oily solid, which was chromatographed over silica, eluting with dichloromethane and increasing amounts of methanol (1-10%) in dichloromethane to give the title product as a solid, m.p. 90°-91° C. (cyclohexane).