Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=2)[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:18][C:19]1[CH:24]=[C:23]([C:2]2[S:6][C:5]([C:7]3([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:22]=[C:21]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=2)[CH:20]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(=O)NS(=O)(=O)C1(c2ncc(Br)s2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NS(=O)(=O)C1(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
The product of Step 1 (109 mg, 0.322 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 122 mg, 0.322 mmol), and PdCl2(dppf).CH2Cl2 (24 mg, 0.032 mmol) were combined in a vial, sealed, and purged with nitrogen (2×). Dioxane (2.0 mL) and 2 M Na2CO3 (0.48 mL, 0.97 mmol) were added, and the reaction was purged again with nitrogen (2×). The mixture was stirred in an oil bath at 100° C. overnight. The dark brown reaction was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4), filtered and evaporated. Flash chromatography (dry load, 25-100% ethyl acetate in hexanes, then 0-10% methanol in ethyl acetate) provided an orange-brown residue. The residue was triturated with CH2Cl2, filtered, and dried to afford N-({1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}sulfonyl)acetamide (85 mg, 52%) as a colorless solid. MS ESI: [M+H]+ m/z 512.0. 1H NMR (600 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.27 (s, 1H), 8.81 (d, J=4.9, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.27 (d, J=4.9, 1H), 7.21 (s, 1H), 3.23-3.06 (m, 2H), 2.76-2.61 (m, 2H), 2.31 (s, 3H), 2.10-1.89 (m, 2H), 1.84 (s, 3H). rhSYK activity=+++
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C=O)C>O>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][N:22]2[C:18](=[O:28])[C:19]3=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]3[C:21]2=[O:23])[CH2:7]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CCOC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture comprising 30.0 g of (tetrahydro-3-furanyl)methyl tosylate, 23.0 g of potassium phthalimide and 150 ml of DMF was stirred at 80° C. for 8 hours. Water was poured into the reaction mixture, and crystals precipitated out was separated by filtration to obtain 27.0 g of N-{(tetrahydro-3-furanyl)methyl}phthalimide.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:37])[C@H:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:11][N:10]([CH3:32])[N:9]=1)#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:37])[C@H:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:11][N:10]([CH3:32])[N:9]=1)#[N:2]
Reactant: CC(C)C[C@H](Nc1nn(C)cc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1nn(C)cc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N
Reaction time: 8 h

Procedure:
To N1-(cyanomethyl)-N2-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1-methyl-1H-pyrazol-3-yl)leucinamide (144 mg, 0.283 mmol) in dry THF (0.5 mL) under dry nitrogen was gradually added a total of 5 equivalents of MeSO3H (100 μL, 1.42 mmol) over a period of 4 hours in portions of 1–2 equivalents at a time and the reaction mixture was stirred overnight. Aqueous sat. NaHCO3 was added carefully and the product was extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (NH4OH/MeOH/CH2Cl2, 1/9/90) to afford N1-(cyanomethyl)-N2-[1-methyl-4-(4-piperazin-1-ylphenyl)-1H-pyrazol-3-yl]leucinamide. MS (−ESI): 408.4 [M−1]−.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]=[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1=C(O)C(=O)N(c2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(c2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.5 %

Procedure:
To a mechanically stirred solution of the title compound of Example E (21 g, 0.085 mol) in 450 ml of pyridine was added hydroxylamine hydrochloride (8.83 g, 0.127 mol). After stirring for 4 days at room temperature the solution was concentrated in vacuo to give a solid which was chromatographed on silica gel eluting with 3% EtOH/CH2Cl2 to give the title compound (13.71 g, 61%) as a colorless powder: Anal calcd for C13H14N2O4 : C, 59.53; H, 5.40; N, 10.68. Found: C, 59.48; H, 5.47; N, 10.64. MS calcd for C13H14N2O4 262, found 262. DSC=153.2°-155.4° C. at 91.1 J/g.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[CH:16](O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:16]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:2])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc(OC)c(OC)c2)c2c(OC)c(OC)c(OC)cc2c1O
Yield: 43 %

Procedure:
40.8 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal and 17.0 g of diethyl acetylenedicarboxylate are treated in the same manner as described in Example 1-(3) to give 1-(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene. Yield: 43%
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:6][CH:5]([C:7]([O:9]C)=O)[CH2:4]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C([Mg]Cl)(C)C>C1COCC1>[CH3:17][O:16][N:15]([CH3:14])[C:7]([CH:5]1[CH2:4][C:3]([O:2][CH3:1])([O:11][CH3:12])[CH2:6]1)=[O:9]
Reactant: CNOC
Reactant: COC(=O)C1CC(OC)(OC)C1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
Methyl 3,3-dimethoxycyclobutanecarboxylate (11.65 g, 66.9 mmol) was dissolved in THF (134 mL) and treated with N,O-dimethylhydroxylamine hydrochloride (10.12 g, 103.7 mmol). The mixture was cooled to 0° C. and treated with isopropylmagnesium chloride (2 M solution in THF, 100.3 mL, 200.7 mmol) and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution (75 mL), diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 20-100% ethyl acetate in heptane to afford the desired product (9.16 g, 67%). Rf 0.06 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 3.61 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 3.15 (s, 3H), 2.39 (d, J=9.0 Hz, 4H). ESI MS found for C9H17NO4 m/z [204.1 (M+1)].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH2:24])[C:11]=1[NH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(C1C2N=C(N)[NH:36][C:35]=2C=CC=1)=O.BrC#N>CO>[CH2:1]([O:8][C:9]([C:10]1[C:11]2[N:25]=[C:35]([NH2:36])[NH:24][C:12]=2[CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1N
Agent: N#CBr
Solvent: CO
Product: Nc1nc2c(C(=O)OCc3ccccc3)cc(OCc3ccccc3)cc2[nH]1

Procedure:
2.5 g (7.2 mmol) of 2,3-diamino-5-benzyloxy-benzoic acid benzyl ester was subjected to a similar cyclization condition as illustrated in intermediate A by using 2.3 g (21.6 mmol) of BrCN in methanol to produce 2-amino-6-benzyloxy-1H-benzoimidazole-4-carboxylic acid benzyl ester. LCMS: 375 (M+1)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:25])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH3:28][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:25])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2cc(OC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc21
Reaction time: 0.5 h

Procedure:
A solution of 1 of (4-chloro-3-trifluoromethyl-phenyl)-carbamic acid -1,2,3,4-tetrahydro-quinolin-6-yl ester (0.74 g., 2 mmol) in dry dimethylformamide (5 ml) was added to a stirred suspension of sodium hydride (0.048 g., 2 mmol) in dry dimethylformamide (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 30 min. Then methyl iodide (0.224 ml, 3.6 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1.25 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using dichloromethane-hexane (20:80) as eluant to give 2q; yield: 0.42 g. (54.6%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][C:26]1[C:27](B(O)O)=[CH:28][S:29][CH:30]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:27]4[C:26]([CH3:25])=[CH:30][S:29][CH:28]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1cscc1B(O)O
Product: Cc1cscc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 54.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 4-methyl-3-thiopheneboronic acid (available from Combi-Blocks Inc.; 57 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(4-methyl-thiophen-3-yl)-benzoic acid (49 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br s, 1H), 8.47 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.20 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.13-7.26 (m, 1H), 2.54 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([NH2:24])=[O:23])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.CC1(C)C(C)(C)OB([C:33]2[S:37][C:36]([CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N>CN(C=O)C.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.COCCOC>[O:42]1[CH2:43][CH2:44][N:39]([CH2:38][C:36]2[S:37][C:33]([C:2]3[CH:3]=[C:4]([C:22]([NH2:24])=[O:23])[C:5]4[NH:6][C:7]5[CH:8]=[C:9]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][C:16]6=[O:21])[CH:10]=[CH:11][C:12]=5[C:13]=4[N:14]=3)=[CH:34][CH:35]=2)[CH2:40][CH2:41]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3=O)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)nc2c1[nH]c1cc(N3CCOCC3=O)ccc12
Temperature: 100 °C
Yield: 59.7 %

Procedure:
A mixture of 2-bromo-7-(3-oxomorpholino)-5H-pyrido[3,2-b]indole-4-carboxamide (30 mg, 0.077 mmol), 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)morpholine (48 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (6 mg, 8 μmol) was flushed with nitrogen. DME (1.5 mL) and Na2CO3 (0.19 mL, 0.39 mmol, 2.0 N aq. solution) were added and the vial was sealed and heated at 100° C. for 2 hrs. This was diluted with DMF and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 2-(5-(morpholinomethyl)thiophen-2-yl)-7-(3-oxomorpholino)-5H-pyrido[3,2-b]indole-4-carboxamide (23 mg, 0.046 mmol, 60% yield) as a yellow solid. MS (ESI) m/z 492.15 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.67 (1H, s), 8.54 (1H, s), 8.37 (1H, s), 8.20 (1H, d, J=8.24 Hz), 7.92(1H, s), 7.74 (1H, d, J=1.83 Hz), 7.67 (1H, d, J=3.66 Hz), 7.30 (1H, dd, J=8.24, 1.83 Hz), 7.05 ( 1H, d, J=3.66 Hz), 4.27 (2H, s), 4.01-4.07 (2H, m), 3.79-3.88 (2H, m), 3.73 (2H, s), 3.63 (4H, t, J=4.73 Hz), 2.47 (4H, br. s.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:30]4/[C:29](=[O:37])[NH:28][C:36]5[C:31]/4=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Solvent: C1CCNCC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a solution of (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (927 mg, 2.44 mmol), oxindole (325 mg, 2.44 mmol) and MeOH (20 mL) was added piperidine (24 uL, 0.244 mmol) and the reaction heated to 60° C. for 4 hours. A yellow precipitate crashed out of the reaction medium which was filtered and washed with MeOH to give the title compound (960 mg, 79%) as a yellow solid. MS ESI 495.3 [M+H]+, calcd for [C29H30N4O2Si+H]+ 495.22.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[CH:23]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[C:35](=O)([O-])[OH:36].[Na+]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[C:23]([CH:35]=[O:36])=[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C([O-])O
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethylformamide (1 ml) was added dropwise with phosphorus oxychloride (66 μl, 0.712 mmol) under ice cooling, then warmed to room temperature, and stirred for 15 minutes. The reaction solution was cooled to 0° C. with ice, added with N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamide (147 mg, 0.356 mmol) dissolved in dimethylformamide (4 ml) under ice cooling, and stirred at 0° C. for 2 hours and 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate and concentrated under reduced pressure. The resulting residue was added with chloroform for extraction, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 98.2 mg of the title compound as yellow crystals in a mixture with dimethylformamide.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.F[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][N:15]=1.[H-].[Na+]>O1CCCC1>[C:1]12([CH2:11][O:12][C:14]3[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][N:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Fc1cc(I)ccn1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1ccnc(OCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
1-Adamantanemethanol (0.820 g) and 2-fluoro-4-iodopyridine (0.22 g) in tetrahydrofuran (5 mL) was treated with sodium hydride (60% in mineral oil) (0.057) at room temperature for 6 hours. The reaction was quenched with ice-water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether/ethyl acetate (20/1) to provide the title compound.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[CH2:7]([O:10][C@H:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C@@H:13]([NH2:22])[CH2:12]1)[CH:8]=[CH2:9].[O:23]1[CH2:25][C@@H:24]1[C@@H:26]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>CC#N>[CH2:7]([O:10][C@H:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C@@H:13]([NH:22][CH2:25][C@@H:24]([OH:23])[C@@H:26]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)[CH:8]=[CH2:9]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OC)ccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Temperature: 50 °C
Reaction time: 36 h
Yield: 38.8 %

Procedure:
Step V (1): Lithium perchlorate (838 mg, 7.88 mmol) was added to a solution of (1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine (765 mg, 3.49 mmol, from Step U(2)) and benzyl (S)-1-((S)-oxiran-2-yl)-2-phenylethyl-carbamate (1.04 g, 3.49 mmol) in CH3CN (50 mL). The reaction mixture was stirred at 50° C. for 36 h. The reaction mixture was poured into brine/NaHCO3 solution. Extracted with EtOAc, washed combined extracts with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (1-10% MeOH (with 0.1% triethylamine)/chloroform, linear gradient) to give 700 mg (39% yield) of benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. LC-MS (M+H)+=517.06; HRMS (M+H)+=517.2700; [α]D +14.45 (c=6.50 mg/mL, dichloroethane); 1H NMR (500 MHz, CDCl3) δ ppm 1.59 (s, 3H) 1.82-1.93 (m, 1H) 2.58-2.75 (m, 2H) 2.80-2.93 (m, 2H) 2.97-3.07 (m, 1H) 3.44-3.54 (m, 1H) 3.78 (s, 3H) 3.88 (t, 1H) 4.09 (t, J=5.19 Hz, 2H) 4.76 (s, 1H) 4.84-4.94 (m, 1H) 5.02 (s, 2H) 5.18 (d, J=10.38 Hz, 1H) 5.31 (dd, J=17.24, 1.37 Hz, 1H) 5.89-6.01 (m, 1H) 6.79-6.92 (m, 2H) 7.14-7.37 (m, 11H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:25]>O1CCOCC1>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([C:10]2[C:3]3[C:2]([NH2:25])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: N
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1N
Solvent: C1COCCO1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyaniline (0.45 g, 1.31 mmol), ammonia (115 ml, SG 0.88) and 1,4-dioxane (115 ml) was heated and stirred at 120° C. in a pressure vessel overnight. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate twice. The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as brown solids (0.32 g, 0.99 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.09 (s, 1H), 7.24 (s, 1H), 6.88 (d, 1H), 6.79 (dd, 1H), 6.71 (d, 1H), 6.01 (broad, 2H), 5.06 (m, 1H), 4.79 (broad, 2H), 3.81 (s, 3H), 2.10 (m, 2H), 1.87-1.92 (m, 4H), 1.68 (m, 2H); MH+324.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:20])=O>O1CCCC1>[Cl:20][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[N:10]=1
Reactant: OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-c2csc(CCl)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound (4.14 g) obtained in Example 103a was dissolved in tetrahydrofuran (100 mL), and thionyl chloride (3.5 mL) was added. The reaction mixture was stirred at room temperature for 24 hr, and heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (3.19 g) as a colorless solid.
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18])SC)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:20]1([CH2:26][C:27]([NH2:29])=[NH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:20]1([CH2:26][C:27]2[NH:29][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[CH3:18])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)C(C#N)=C(Nc1cnccc1C)SC
Reactant: N=C(N)CC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccncc1Nc1nc(CC2CCCCC2)[nH]c(=O)c1C#N
Temperature: 90 °C

Procedure:
0.4 g (1.51 mmol) of methyl 2-cyano-3-[(4-methyl-3-pyridinyl)amino]-3-(methylsulfanyl)-2-propenoate are dissolved with 0.29 g (1.67 mmol) of 2-cyclohexylethanamidine hydrochloride and 0.46 g (3.3 mmol) of potassium carbonate in 5 ml of DMF and heated at 90° C. for 7 days. After cooling and filtration, the product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A; water, eluent B: acetonitrile, gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) purified. 433 mg (88% of theory) of the product are obtained.