Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH:5]([CH2:7]O)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:49])[C:37]=1[CH:38]([O:41][Si:42]([CH2:47][CH3:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:39][NH2:40].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:49])[C:37]=1[CH:38]([O:41][Si:42]([CH2:45][CH3:46])([CH2:47][CH3:48])[CH2:43][CH3:44])[CH2:39][NH:40][CH2:7][CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[O:6]1
Reactant: CC1CCC(CO)O1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cncc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC(CNCC1CCC(C)O1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 5-methyltetrahydrofuran-2-methanol in DCM was added Dess-Martin periodinane (1.2 eq.). The mixture was stirred at room temperature overnight. The crude mixture was directly added to a solution of 2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (1 eq.) in DCM followed by AcOH (1.2 eq.) and NaBH(OAc)3 (1.5 eq.). The reaction mixture was stirred at room temperature. After 2 h, the mixture was quenched with saturated aqueous Na2S2O3 and saturated NaHCO3. The reaction mixture was extracted with DCM. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 25% EtOAc in heptane to provide 2-(3,5-dichloropyridin-4-yl)-N-((5-methyltetrahydrofuran-2-yl)methyl)-2-((triethylsilyl)oxy)ethanamine (A281) as a light-yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (2H, s), 5.34-5.46 (1H, m), 3.71-3.90 (2H, m), 3.10 (1H, dt, J=12.5, 8.1 Hz), 2.90 (1H, td, J=12.1, 6.0 Hz), 2.52-2.67 (2H, m), 1.71-2.07 (3H, m), 1.47-1.64 (1H, m), 1.19-1.38 (1H, m), 1.11 (3H, t, J=6.3 Hz), 0.77-0.89 (9H, m), 0.40-0.62 (6H, m); LCMS (ESI) m/z 419.1 (M+H)+.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7]1)=O)=C.Cl>O1CCOCC1>[CH2:23]([O:22][C:20]([CH:8]1[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:10][NH:6][CH2:7]1)=[O:21])[CH3:24]
Reactant: C=COC(=O)N1CC(C(=O)OCC)C(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1CNCC1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A stirred solution of 4-(4-nitro-phenyl)-pyrrolidine-1,3-dicarboxylic acid 3-ethyl ester 1-vinyl ester (6 g, Reference Example 5) in dioxane (30 ml), at 25° C., was treated dropwise with hydrochloric acid (15 ml, 4N). After stirring for 2 hours the mixture was treated with a further aliquot of hydrochloric acid (15 ml, 4N) and stirring was continued at 25° C. for a further 2 hours. The reaction mixture was evaporated (40° C. and 2.7 kPa) and the residue was heated at reflux temperature with ethanol (30 ml) for 45 minutes. The mixture was cooled to room temperature then evaporated and the residue was triturated with diethyl ether (100 ml) for 20 hours affording the title compound (4.3 g) as a white solid. TLC: RF=25/70 [on silica plates eluting with a mixture of dichloromethane and methanol, (90:10, v/v)]. 1H-NMR [400 MHz, (CD3)2SO]: δ 1.09 (t, J=7 Hz, 3H); 3.25 to 3.85 (3 m, 6H); 4.05 (m, 2H); 7.76 (d, J=8.5 Hz, 2H); 8.24 (d, J=8.5 Hz, 2H); 9.90 (b, 2H). MS (EI): 264[M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C(C)C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Temperature: 55 °C
Yield: 83.3 %

Procedure:
To a solution of 4-bromo-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.50 g, 1.47 mmol) in ethanol (5.0 mL), was added SnCl2.2H2O (1.3 g, 5.88 mmol) and the mixture was heated at 55° C. overnight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO4 and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.38 g, 85%). LCMS m/z (%)=311 M+H+, (79Br, 100), (81Br, 96.5), 1H NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.72 (dd, J1=8.01 Hz, J2=2.78 Hz, 1H), 6.54 (d, J=2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J=6.57 Hz, 3H), 1.23 (d, J=6.57 Hz, 3H).
Reaction SMILES: [CH2:1]([O:7][C:8]([CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:36])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:9])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:7][C:8]([CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:36])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:9])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CCC=CCCOC(=O)CCC(CCCCC)OC(=O)C=Cc1ccccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC/C=C\CCOC(=O)CCC(CCCCC)OC(=O)/C=C/c1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
To a solution of 6.14 g 3-[2-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid 1-(2-hex-3-enyloxycarbonyl-ethyl)-hexyl ester in 50 ml of tetrahydrofuran, a solution of 25 ml of a 1M tetrabutylammoniumfluoride solution was added at 0° C. After stirring at room temperature for 90 minutes, the solution was quenched with water and extracted with ether. The organic phase was washed with water, dried and evaporated to dryness. The residue was purified by Kugelrohr-distillation and chromatography to yield 0.51 g of a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5](=[O:8])[N:6]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)Nc1nc(=O)[nH]cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(=O)n(C(=O)c2ccc(C)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a round-bottomed flask containing N-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide (350 mg, 2.04 mmol) in CH2Cl2 (20 mL) was added 4-methylbenzoyl chloride (316 mg, 2.2 mmol) and Et3N (454 mg, 4.5 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (30 mL), washed with saturated aqueous sodium chloride (satd aq NaCl) solution (1×15 mL), dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by reverse phase chromatography to yield N-(5-fluoro-1-(4-methylbenzoyl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide as a white solid (16 mg, 3%): mp 146.9-148.2° C.; 1H NMR (acetone-d6) δ 9.75 (s, 1H), 8.64 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 2.47 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[O:15][C:16]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:17]=4[CH:18]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[O:15][C:16]4[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=4[CH:18]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1cc3cc([N+](=O)[O-])ccc3o1)CC2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CCN(Cc1cc3cc(N)ccc3o1)CC2

Procedure:
7-Nitro-3-(5-nitrobenzofur-2-ylmethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine (0.74 g) was stirred at room temperature under a hydrogen atmosphere [344.7 kPa (50 p.s.i.)] in an ethanol solution containing 5% Pd/C for 2 hours. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give the title compound as a foam which was used without further purification, yield 0.58 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>ClCCl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:18]([C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:25])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NCCN(C)C)c1)N2
Reaction time: 0.67 h
Yield: 106 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (10.0 ml) was added N-hydroxy benzotriazole (89.2 mg, 0.66 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253.0 mg, 1.32 mmol, 3.0 eq.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then N1,N1-dimethylethane-1,2-diamine (42.7 mg, 0.48 mmol, 1.1 eq.) was added to the flask and the reaction mixture was stirred for an additional 40 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 191 mg of methyl 2-(3-(2-(dimethylamino)ethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a off-white solid, which was washed with hexane and collected by filtration to afford 162 mg product as a white solid. Yield: 89.5%.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][N:28]=[C:27]2[NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)=[C:37]([Cl:49])[CH:36]=1>C(Cl)Cl>[Cl:49][C:37]1[CH:36]=[C:35]([NH:34][C:27]2[C:26]3[C:31](=[CH:32][CH:33]=[C:24](/[CH:23]=[CH:22]/[CH2:21][NH:20][C:1](=[O:4])[CH3:2])[CH:25]=3)[N:30]=[CH:29][N:28]=2)[CH:40]=[CH:39][C:38]=1[O:41][C:42]1[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CN)cc34)cc2Cl)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)NC/C=C/c1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c2c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A mixture of 14.4 μL (0.25 mmol) of acetic acid and 40.3 mg (0.33 mmol) of dicyclohexylcarbodiimide in 2 mL of methylene chloride were stirred for 10 minutes and treated with 100.3 mg of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine. The reaction was allowed to stir at room temperature overnight. The precipitate which formed was filtered and chromatographed on silica gel, eluting with 6-10% methanol/chloroform to afford 106 mg of the title compound; mp 254-256° C.; 1H NMR (d6 DMSO): δ 9.88 (s, 1), 8.58 (s, 1), 8.48 (m, 1), 8.20 (m, 3), 7.95 (m, 1), 7.83 (m, 1), 7.71(d, J=8.7 Hz, 1), 7.24 (m, 2), 7.19 (d, J=8.7 Hz, 1), 6.61 (d, J=16.2 Hz, 1), 6.48 (m, 1), 3.90 (m, 2).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[F:15][C:16]1[CH:31]=[CH:30][C:19]2[NH:20][C@@H:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][O:23][C:18]=2[CH:17]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC1OCCC1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([C:12]([C:9]3[CH:10]=[CH:11][C:5]4[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:14])[C@@H:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][O:23][C:18]=2[CH:17]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)C[C@H]1COc2cc(F)ccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 20 °C
Reaction time: 72 h

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (2.219 kg, 11.44 mol; 99.6 mass %) was charged to a 100 L glass-lined vessel followed by toluene (9 L). Ethyl [(3S)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 10a, 2.970 kg, 10.39 mol, 83.7 mass %) was charged and the mixture was stirred at 20° C. A solution of T3P in 2-MeTHF (11.6 L, 20.8 mol, 55.7 mass %) was then charged to the vessel within 5 minutes. Toluene (3.1 L), Pyridine (2.5 L) and toluene (3 L) were charged and the resulting mixture heated at 80° C. for 20 h then cooled to 20° C. and held for 3 days. The mixture was heated to 50° C. and washed with water (15 L). The organic phase was retained and the separated aqueous phase extracted with toluene (14.8 L). The combined organic phase was washed with aqueous sodium bicarbonate solution (14.8 L, 11.3 mol, 6.00 mass %) then water (15 L) at 39-50° C. The organic phase was cooled to 21° C., filtered to remove particulates, and a small amount of collected solid was washed with toluene (3 L). The filtrate was then concentrated to 4 relative volumes by distillation under reduced pressure to yield a solution of ethyl {(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate in toluene. The organic phase was filtered once more and a solution of methylamine (33% w/w) in ethanol (13 L, 104 mol, 33.3 mass %) was added and the mixture stirred at 20° C. for 3 days. The mixture was evaporated to dryness under reduced pressure, then treated with 2-propanol (5 L) and re-evaporated. The 2-propanol treatment was repeated once more; 10 Lt was used to rinse the 100 Lt vessel and this was added to the collected product in the rotary evaporator vessel and the mixture evaporated to dryness. The collected solid was further dried in a vacuum oven under reduced pressure (10 mBar). The dried solid (3.985 Kg) was charged to a clean dry vessel, followed by 2-propanol (24.5 L), the mixture was stirred and heated to 80° C., held at 80° C. for 2 h then cooled to 10° C. and held at 10-11° C. for 4 days then filtered. The product cake was washed with 2-propanol (5 L) then dried in a vacuum oven at 45° C. to afford the title product (3.636 Kg; 99.4% w/w assay, 87.1% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3OC)[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)([O-])[O-])=CC=3[Cl:93])N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CC3(CO)COC3)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[Cl:93])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)([O-])[O-])cc2Cl)ncc1C(F)(F)F
Agent: CC1(C)OB(c2cnn(CC3(CO)COC3)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(Cl)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1

Procedure:
Prepared analogously to Compound 44A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-chlorobenzyl)phosphonate (Compound 58B, 200 mg, 0.321 mmol) and (3-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}oxetan-3-yl)methanol (Compound 44B, 99.0 mg, 0.337 mmol) to afford 160 mg of the title compound as a racemic mixture (56%). MS (ESI): m/z=899.74/901.72 [M+H]+. UPLC: tR=1.64 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:20][OH:21])[CH:15]=[CH:14][C:13]=2[C:12]2[N:22](COCC[Si](C)(C)C)[N:23]=[C:24]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:20][OH:21])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:22][N:23]=[C:24]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH2:27]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=NO)ccc3c21
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=NO)ccc23)CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 44.1 %

Procedure:
A 50 ml round-bottomed flask equipped with a septum having a top-mounted argon intake is charged with 180 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime in 15 ml of DCM. After cooling to 0° C. using an ice bath, 1.8 ml of TFA are added and the mixture is stirred at RT for 6 h. The mixture is concentrated under RP and the solid obtained is taken up in 50 ml of water and 2 ml of 0.75M aqueous ammonia solution. It is extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. Chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (92.5/7.5 by vol.), gives 63 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime (lemon yellow solid). MS (E/I): m/z=500 (M+); 1H NMR: 1.67 (m, 2H); 2.11 (m, 2H); 2.87 (s, 3H); 2.89 (m, 2H); 3.56 (m, 2H); 3.79 (m, 1H); 6.06 (d, J=7.8 Hz, 1H); 7.32 (broad t, J=7.6 Hz, 2H); 7.67 (m, 1H); 7.84 (broad s, 1H); 8.14 (broad d, J=8.5 Hz, 1H); 8.30 (s, 1H); 8.41 (d, J=8.5 Hz, 1H); 11.43 (s, 1H); 12.81 (s, 1H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][CH3:10])[S:7][CH:8]=1.[CH:11]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[ClH:2].[ClH:1].[ClH:2].[CH:11]([N:24]1[CH2:29][CH2:28][N:27]([CH2:3][C:4]2[N:5]=[C:6]([NH:9][CH3:10])[S:7][CH:8]=2)[CH2:26][CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CNc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 70 °C
Yield: 44.5 %

Procedure:
A mixture of 4-chloromethyl-2-methylaminothiazole monohydrochloride (2.2 g), 1-benzhydrylpiperazine (2.5 g) and potassium carbonate (2.7 g) in N,N-dimethylformamide (15 ml) was stirred at 70° C. for an hour. After the reaction mixture was poured into ice-water, it was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give an oil, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (1.2 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-methylaminothiazole trihydrochloride, mp 225°-228° C. (dec.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([I:20])=[C:12](Cl)[N:11]=1.Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1.CCOC(C)=O.CO>[Cl:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([I:20])=[C:12]([O:1][C@@H:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[N:11]=1
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1I
Reactant: O[C@@H]1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc(Cl)nc(O[C@@H]2CCOC2)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of (R)-(−)-3-hydroxy-tetrahydrofuran (0.214 g, 2.42 mmol) in anhydrous THF (10 mL) at 0° C. was added NaH (60% in mineral oil, 103 mg, 2.58 mmol). The mixture was stirred at 0° C. for 30 min, then methyl 2,6-dichloro-5-iodopyrimidine-4-carboxylate (0.539 g, 1.62 mmol) was added to the mixture at −10° C. The reaction mixture was stirred at the same temperature for 30 min, and then allow warm to r.t. for 4 h. The reaction was then diluted with EtOAc and acidified with 2 N HCl. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in ether (8 mL) and MeOH (2 mL), and then trimethylsilyldiazomethane (2 M, 2 mL, 4 mmol) was added at 0° C. The reaction was stirred at r.t. for 1 h, and then quenched by 2 N HCl and concentrated in vacuo. The residue was purified by ISCO chromatography (24 g silica gel, 1-10% EtOAc in hexanes in 40 min) to give the title compound (0.140 g, 26%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 5.69-5.66 (m, 1H), 4.10 (dd, 1H), 4.05-3.92 (m, 6H), 2.38-2.30 (m, 1H), 2.24-2.18 (m, 1H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13]1[O:15][CH2:14]1>CS(C)=O>[CH2:14]1[O:15][CH2:13]1.[OH:15][CH2:14][CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1CO1
Product: OCCn1ccc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of NaOH (4.4 gm, 0.011 tool) in DMSO (175 ml) was stirred at 100° C. for 5 hours at which time it was cooled to 20° C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm).