Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].F[C:19](F)(F)[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccccc3OC)ccc2sc1=O

Procedure:
4-Hydroxy-6-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 4-trifluoromethoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.534 (s, 1H), 7.782 (d, 1H), 7.639 (d, 2H), 7.444 (d, 1H), 7.320 (d, 2H), 4.026 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1(O)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCC(C(O[C@@H]1[C@@H]2[C@@H](CC[C@H]3OC(=O)C[C@H](O)C3)[C@@H](C)C=CC2=C[C@H](C)C1)=O)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCOc2ccccc21
Agent: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC1=CCCOc2ccccc21
Yield: 99.9 %

Procedure:
14.9 g (0.1 mol) of 5-methyl-2,3,4,5-tetrahydrobenzoxepin-5-ol, 300 ml of toluene and a spatula tip of para-toluenesulphonic acid are charged to a 1 litre reactor equipped with a Denan and Stark apparatus. The combined solution is brought to reflux for 2 hours, the water being removed as it is formed. The reaction mixture is then neutralized with a 5% aqueous sodium bicarbonate solution and the organic solution is washed with water. The organic phase is subsequently dried over anhydrous sodium sulphate and concentrated under reduced pressure. 16 g of the title compound are obtained, which compound is purified by distillation, B.p. (2.5 mm Hg)=80-90° C. 10 g of a colourless liquid are obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:16]=[C:15]([C:17](=[O:19])[NH2:18])[N:14]([CH3:20])[CH:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]([CH3:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=2)[C:22]1=[O:36])(=O)C.[OH-].[Na+]>O1CCCC1.C([O-])(O)=O.[Na+].ClCCl>[C:32]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:16]=[C:15]([C:17]([NH2:18])=[O:19])[N:14]([CH3:20])[CH:13]=3)[CH:10]=[CH:9][CH:8]=1)[N:30]([CH3:31])[CH2:29]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(=O)OCc1c(-c2cc(C(N)=O)n(C)c2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1Cc2cc(C(C)(C)C)ccc2C(=O)N1c1cccc(-c2cc(C(N)=O)n(C)c2)c1CO
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(5-carbamoyl-1-methyl-1H-pyrrol-3-yl)benzyl acetate (31 mg, 63.4 μmol, Eq: 1.00) in tetrahydrofuran was added NaOH (1.0 M (aqueous) 1.0 mL, 1.00 mmol, Eq: 15.8). The reaction mixture heated at 60° C. for 4 h. The mixture was cooled to room temperature. The solution was diluted with sat NaHCO3 (aqueous) and dichloromethane. The layers were separated. The aqueous layer was extracted once with dichloromethane. The organic extracts were combined and dried over MgSO4. The solution was filtered. Concentrated in vacuo to give 4-[3-(6-tert-Butyl-3-methyl-1-oxo-3,4-dihydro-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (28 mg, 99%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26-1.40 (m, 9H) 2.56 (s, 3H) 3.95 (s, 3H) 4.53 (br. s., 2H) 5.23 (s, 2H) 6.93 (d, J=1.89 Hz, 1H) 7.14 (d, J=1.89 Hz, 1H) 7.24-7.38 (m, 3H) 7.39-7.53 (m, 1H) 7.64 (dd, J=5.67, 3.40 Hz, 1H) 8.01 (d, J=8.31 Hz, 1H). LC/MS-ESI observed [M+H]+ 447.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:8][CH3:9])[O:6][CH3:7])=[CH2:4].[O:10]1CCC[CH2:11]1>>[CH3:1][O:2][CH:3]([CH:5]([O:8][CH3:9])[O:6][CH3:7])[CH2:4][CH:11]=[O:10]
Reactant: C1CCOC1
Reactant: C=C(OC)C(OC)OC
Product: COC(CC=O)C(OC)OC
Reaction time: 6 h
Yield: 87 %

Procedure:
A 10 1 magnetic lift stirred autoclave is charged with 1,015 g of 2,3,3-trimethoxyprop-1-ene together with 3,000 g of tetrahydrofuran and 500 mg of Rh2 (COD)2Cl2 as hydroformylation catalyst. The oxo reaction is carried out under a pressure of 500 bar (CO/H2 =1:1) at 40° C. for 6 hours, at 60° C./550 bar for another 6 hours and at 80° C./600 bar for a further 6 hours. According to gas chromatography, this way of carrying out the reaction gives a conversion of 94%. The desired compound 3,4,4-trimethoxybutanal (bp=135° C./110 mbar) is obtained in the yield of 87% following fraction-ation. Preparation of methyl 2-methoxyacrylate
Reaction SMILES: C[C:2]1([CH3:27])[CH2:7][CH2:6][NH:5][S:4](=[O:9])(=[O:8])[N:3]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:26].[C:28]1(I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:12]1[CH:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22]2)[CH:15]=[CH:16][C:11]=1[CH2:10][N:3]1[CH:2]([CH3:27])[CH2:7][CH2:6][N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:4]1(=[O:9])=[O:8]
Reactant: Ic1ccccc1
Reactant: CC(=O)N1CCN(c2ccc(CN3C(C)(C)CCNS3(=O)=O)c(F)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CN3C(C)CCN(c4ccccc4)S3(=O)=O)c(F)c2)CC1
Temperature: 100 °C
Yield: 25.1 %

Procedure:
A mixture of methyl 2-{[4-(4-acetylpiperazin-1-yl)-2-fluorophenyl]methyl}-3-methyl-1λ6,2,6-thiadiazinane-1,1-dione (200 mg, 0.52 mmol), PhI (212 mg, 1.04 mmol), Pd2(dba)3 (48 mg, 0.052 mmol), Xantphos (60 mg, 0.104 mmol), and Cs2CO3 (170 mg, 1.04 mmol) in 1,4-dioxane (3 mL) was heated at 100° C. in a microwave oven for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound as light yellow oil (60 mg, 25%). 1H NMR (500 MHz, CDCl3) δ 7.54 (t, 1H), 7.35-7.41 (m, 4H), 7.27-7.29 (m, 1H), 6.69 (dd, 1H), 6.54 (dd, 1H), 4.49 (d, 1H), 4.28-4.35 (m, 2H), 3.90 (td, 1H), 3.76 (t, 2H), 3.61 (t, 2H), 3.53 (td, 1H), 3.14-3.20 (m, 4H), 2.14 (s, 3H), 1.98-2.02 (m, 1H), 1.75-1.78 (m, 1H), 1.25 (d, 3H); LCMS (ESI): m/z=461.7 [M+H]+.
Reaction SMILES: BrC1C=CC2[NH:10][CH:9](C)OC(C)(C)C=2C=1.C(OC(N1C=CC=C1B(O)O)=O)(C)(C)C.[C:30]([O:34][C:35]([N:37]1[C:41]([C:42]2[CH:43]=[CH:44][C:45]3[NH:50][CH:49]([CH3:51])[O:48][C:47]([CH3:53])([CH3:52])[C:46]=3[CH:54]=2)=[CH:40][CH:39]=[CH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[C:30]([O:34][C:35]([N:37]1[C:41]([C:42]2[CH:43]=[CH:44][C:45]3[NH:50][CH:49]([CH3:51])[O:48][C:47]([CH3:53])([CH3:52])[C:46]=3[CH:54]=2)=[CH:40][CH:39]=[CH:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32].[C:9]([C:38]1[N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:36])[C:41]([C:42]2[CH:43]=[CH:44][C:45]3[NH:50][CH:49]([CH3:51])[O:48][C:47]([CH3:53])([CH3:52])[C:46]=3[CH:54]=2)=[CH:40][CH:39]=1)#[N:10]
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Agent: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: CC1Nc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2C(C)(C)O1
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Nc2ccc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)cc2C(C)(C)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 1.78 %

Procedure:
tert-Butyl-5-(2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate was prepared according to the coupling procedure for Example 17 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 1-t-butoxycarbonylpyrrol-2-yl boronic acid. To a solution of tert-butyl-5-(2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate (1 g, 2.9 mmol) in anhydrous THF (20 mL) was added at −78° C. under nitrogen chlorosulfonyl isocyanate (0.35 mL, 4.0 mmol). The mixture was kept stirring at −78° C. under nitrogen for 2 hours, treated with anhydrous DMF (5 mL), and allowed to warm to room temperature. Aqueous ammonium sulfate solution (50 mL) and ethyl acetate (100 mL) was added and organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/4:1) to afford the title compound as a white solid (0.019 g, 1.78%): 1H-NMR (DMSO-d6) δ 7.48 (d, 1H, J=2.0 Hz), 7.36 (dd, 1H, J=8.3, 2.0 Hz), 7.32 (d, 1H, J=3.6 Hz), 7.14 (d, 1H, J=8.3 Hz), 6.46 (d, 1H, J=4.0 Hz), 5.35 (q, 1H, J=5.2 Hz), 1.58 (d, 3H, J=5.6 Hz), 1.56 (s, 3H), 1.51 (s, 3H), 1.38 (s, 9H); MS (ESI) m/z 366 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([Cl:11])[C:3]=1[CH3:12].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:12][C:3]1[C:4]([Cl:11])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl

Procedure:
To a solution of 1,3-dichloro-2-methyl-4-nitro-benzene (19) (6.18 g, 30 mmol) and AIBN (200 mg) in CCl4 (75 mL), NBS (7.96 g, 45 mmol) was added under stirring and reflux. The reaction was monitored by 1H-NMR (CDCl3). Additional NBS (5×7.96 g, total of 270 mmol) was added till the starting material was consumed. The reaction mixture was filtered hot, and the filtrate was evaporated to dryness. The crude was column chromatographed (SiO2, hexanes:EtOAc, 9:1 to 8.5:1.5). The product was obtained as a low melting white solid: yield 6.869 g, 80%. 1H-NMR (CDCl3) δ 4.75 (s, 2H), 7.45, d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz); MS (CI) m/z 285 (M+H). Anal Calcd for C7H4BrCl2NO2 : C, 29.51; H, 1.42; N, 4.92. Found: C, 29.09; H, 1.43; N, 4.71.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40].C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:45]5[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 60 °C
Yield: 34.5 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added 1-methane sulfonyl piperazine (181 mg, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (85 mg, 35%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.55-7.20 (m, 5H), 6.50 (s, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.15 (m, 4H), 2.55 (m, 6H), 2.00 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 670 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=2)[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=1.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>CN(C=O)C>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([NH:25][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[N:27][CH:28]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)cn1
Yield: 42.7 %

Procedure:
3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14 g, 9.5 mmol), 2-amino-5 methylpyrazine (2.08 g, 19.0 mmol) and HATU (4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL, 19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL) and extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a pale yellow gum (1.70 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30]([CH3:31])=[O:41])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 8 supra) (800 mg, 1.8 mmol) in a mixture of dichloromethane and methanol (200 mL, 1:1) was added m-CPBA (710 mg, 1.8 mmol) slowly. The reaction mixture was stirred at room temperature for 25 minutes. The solvent was then removed under reduced pressure and the residue was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford {4-[3-(2-Methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 440 mg, 53.1%).
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[OH-].[Na+]>COCCOC.CCOC(C)=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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Yield: 60.1 %

Procedure:
A solution of 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (0.25 g, 0.9 mmol) and p-fluorophenyl-boronic acid (0.15 g, 1.04 mmol), in DME (10 mL) is purged with argon. The solution is treated with NaOH (0.07 g, 1.7 mmol) and (PPh3)4Pd (0.05 g, 0.04 mmol) then heated at reflux overnight. The reaction is then cooled, diluted in EtOAc, and washed with water and brine. The organic solution is dried over MgSO4 and the solvent removed in vacuo. The residue is purified by silica gel column chromatography using a mixture of hexanes/EtOAc to afford 0.164 g (62%) of desired product as a white solid. UV (95% EtOH) λmax 248 nm (ε 20386). TOF MS ES+ exact mass calculated for C19H14FN3 (p+1): m/z=304.1250. Found: 304.1249. Anal. Calcd for C19H14FN3: C, 75.23; H, 4.65; N, 13.85. Found: C, 75.10; H, 4.76; N, 13.70.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[CH3:15][C:16]([CH3:18])=[O:17]>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:16]([OH:17])([CH3:18])[CH3:15])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)O)ncc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
2,5-Dibromo-4-methylpyridine (4.0 g, 15.94 mmol) was dissolved in toluene (60.0 mL) and the reaction was cooled to −78° C. Butyllithium (7.01 mL, 17.54 mmol) was added dropwise and the reaction was allowed to stir for 30 min. Acetone (4.69 mL, 63.8 mmol) was then added and the reaction was allowed to warm to rt and stir for 16 h. The reaction was quenched with saturated ammonium chloride, extracted into ethyl acetate (3×200 mL) and washed with water followed by brine. The organics were dried over magnesium sulfate and volatiles removed under reduced pressure. The compound was purified on silica gel chromatography (0-50% ethyl acetate in hexanes) to afford 2-(5-bromo-4-methylpyridin-2-yl)propan-2-ol (2.33 g, 10.13 mmol, 63.5% yield). MS (ESI) m/z 230.3 [M]+, 232.3 [M+2]+.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:11])=[C:7]([CH3:19])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1cc(C2CCC2)c(-c2nnc[nH]2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CCC2)c(-c2nnc[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a 4-mL vial was added 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound 202.3, 31 mg, 0.12 mmol, 1.0 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 27 mg, 0.12 mmol, 1.0 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83 μL, 0.48 mmol, 4 equiv). The mixture was stirred at room temperature for 4 hours then diluted with ethyl acetate (10 mL) and washed with 1 M NaH2PO4 (5 mL). The aqueous was back extracted with ethyl acetate (3 mL) and the combined organics was washed with brine (5 mL), saturated NaHCO3 (5 mL) and brine (5 mL). The organics were dried (Na2SO4), filtered and removed in vacuo. The crude residue was purified by preparative TLC (DCM/8% MeOH) to obtain the title compound as a white solid (23 mg, 46%). m/z (ES+) 426 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39]C(=O)OC(C)(C)C)[CH2:35][CH2:34]1>>[NH2:39][CH:36]1[CH2:37][CH2:38][N:33]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:34][CH2:35]1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCC(N)CC2)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl piperidin-4-ylcarbamate (Aldrich, Cat. No. 540935). LCMS (M+H)+: m/z=419.2.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[N+:18]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].C(OCC)(=O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:12]([NH2:18])=[C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Br)cc1CS(=O)(=O)c1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1CS(=O)(=O)c1ccccc1
Yield: 100.6 %

Procedure:
This compound was prepared by catalytic hydrogenation of 5-bromo-2-nitrobenzyl phenyl sulfone (0.23 g, 0.64 mmol) in the presence of Raney nickel and hydrogen (45 psi) in ethyl acetate (30 ml) for 1 hour. The reaction mixture is filtered through celite and concentrated in vacuo to give the title compound as a light brown solid (0.21 g, 99%). Mp: 140-141° C. MS (ES+): 326 (M+H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:20]4)[CH:14]=[C:8]2[C:7]1=[O:33]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:27]1([C:25]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[C:15]([C:13]4[CH:14]=[C:8]5[C:7](=[O:33])[NH:6][CH2:11][CH2:10][N:9]5[CH:12]=4)[CH:16]=[CH:17][CH:18]=3)[N:23]=2)=[O:26])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: COc1ccc(CN2CCn3cc(-c4cccc5ccc(C(=O)N6CCOCC6)nc45)cc3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCn2cc(-c3cccc4ccc(C(=O)N5CCOCC5)nc34)cc21
Yield: 31 %

Procedure:
The above-obtained brown solid 2-(2,4-dimethoxybenzyl)-7-(2-(morpholine-4-carbonyl)quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Example 167c) in 1 mL of TFA and 1 mL of DCM was heated in an oil bath at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The orange residue was partitioned between 50 mL of EtOAc and 5 mL of 2 N NaOH. The EtOAc layer was washed with 10 mL of brine and concentrated. Purification of the brown residue on a silica gel column (1-10% MeOH in EtOAc) gave 7-(2-(morpholine-4-carbonyl)quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (80 mg, 0.213 mmol, 31% yield for 3 steps) as a tan crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (1H, d, J=8.6 Hz), 8.07 (1H, dd, J=7.3, 1.3 Hz), 7.94 (1H, d, J=1.6 Hz), 7.86 (1H, m), 7.75 (2H, d, J=8.4 Hz), 7.67 (1H, t, J=7.7 Hz), 7.36 (1H, d, J=1.8 Hz), 4.23 (2H, m), 3.75 (4H, m), 3.64 (4H, m), 3.57 (2H, m). m/z (ESI, +ve) 377.0 (M+H)+.