Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)OB([C:27]2[CH:31]=[CH:30][N:29]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:28]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:31]=[CH:30][N:29]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.51 mmol) in 1,4-dioxane (5.0 mL) and water (3 drops) was added 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[tris(propan-2-yl)silyl]-1H-pyrrole (356 mg, 1.02 mmol), Pd(PPh3)4 (29.4 mg, 0.03 mmol), and sodium carbonate (108.1 mg, 1.01 mmol) with stirring for 1 hour at 90° C. under an atmosphere of nitrogen. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2-yl)amino]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate as a yellow solid (130 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3)=[O:24]
Reactant: CCCOC(=O)c1c(N)sc2c1CC1CCC2O1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCCOC(=O)c1c(NC(=O)c2ccccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 34A and commercially available 2-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (DMSO-d6, 300 MHz) δ 0.92 (t, J=7.5Hz, 3H), 1.64-1.71 (m, 3H), 1.98-2.15 (m, 3H), 2.58 (d, J=17.0Hz, 1H), 3.11 (dd, J=16.6, 4.4Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 4.69-4.74 (m, 1H), 5.14-5.16 (m, 1H), 7.80-7.94 (m, 4H), 11.40 (br s, 1H); MS (ESI+) m/z 440 (M+H)+. Anal. calcd. for C21H20F3NO4S: C, 57.40; H, 4.59; N; 3.19. Found: C, 57.44; H, 4.47; N, 3.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][CH3:14].[Br:15]N1C(=O)CCC1=O>C(#N)C.[Cl-].[Na+].O>[Br:15][C:6]1[CH:5]=[C:4]([CH2:12][CH2:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1ccc(CCC)c(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCc1cc(OC)c(CCC)cc1Br
Temperature: 60 °C
Reaction time: 20 h
Yield: 88.6 %

Procedure:
To a solution of 2-methoxy-1,4-dipropylbenzene (2.0 g, 10.4 mmol) in acetonitrile (30 mL) at room temperature was added N-bromosuccinimide (1.85 g, 10.4 mmol) in three portions. The solution was stirred at 60° C. for 20 hr and then most of the solvent was removed in vacuo. Extracton in hexanes (2×100 mL) with 50% saturated brine (75 mL) and flash chromatography with silica gel (100% hexanes) provided the title compound as a colorless liquid (2.50 g, 89% yield): 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H, J=7.5 Hz), 0.99 (t, 3H, J=7.6 Hz), 1.60 (m, 4H), 2.50 (t, 2H, J=7.7 Hz), 2.65 (t, 2H, J=7.8 Hz), 3.79 (s, 3H), 6.67 (s, 1H), 7.24 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH2:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:12]=[CH:13][C:3]=12
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: C1CCOC1
Product: Clc1ncc(Br)c2cc[nH]c12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitro-pyridine (7 g) in dry tetrahydrofuran (150 ml) at −70° C. under an atmosphere of nitrogen was added dropwise a solution of vinylmagnesium bromide (1.0M in tetrahydrofuran; 94.5 ml) over 1 h. The solution was stirred at −70° C. for 1 h and then quenched with saturated ammonium chloride (150 ml) and the aqueous was extracted twice with ethyl acetate. The combined organics were dried (MgSO4) and evaporated to give a deep red oil. The residue was triturated with diethyl ether (100 ml) and the solid was then filtered off, sucked dry then dried at 40° C. under vacuum to afford the title compound (1.75 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=1.[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:12])(=[O:11])[NH:18][C:17]2[C:16]([F:15])=[CH:22][C:21]([F:23])=[CH:20][C:19]=2[F:24])[CH:5]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1c(F)cc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1

Procedure:
2.35 g (10 mmol) of 3-chlorosulfonylbenzoic acid methyl ester is suspended in 30 ml of dichloromethane with exclusion of moisture, the suspension is cooled to -5° C and at this temperature a solution of 1.47 g (10 mmol) of 2,4,6-trifluoroaniline and 1 ml of pyridine in 20 ml of dichloromethane is instilled. When the instillation is completed, it is allowed to come to room temperature and is stirred for 12 more hours. The resulting precipitate is suctioned off and extracted with ether. The ether extract and filtrate together are concentrated by evaporation and the residue is dissolved in dichloroethane and chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 2.8 g (8.12 mmol)= 81.2% of the theoretical yield is obtained as an amorphous product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.O1CCOCC1.C(OC([N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[C:35]2[NH:34][CH:38]=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2Br)cc1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ccc[nH]2)cc1
Temperature: 130 °C
Yield: 28.8 %

Procedure:
To a solution of 5-bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole (94.0 mg, 0.257 mmol) in 4:1 dioxane:water (3.0 mL) was added 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (57 mg, 0.27 mmol), cesium carbonate (251 mg, 0.771 mmol), and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The solution was degassed with argon and heated in a microwave reactor at 130° C. for 105 minutes. The reaction was concentrated in vacuo and the residue taken up in DCM (25 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→80/20) followed by HPLC purification (formic acid method) to give 26 mg of the title compound as a yellow solid (29% yield). LC/MS (FA) ES+ 352. 1H NMR (300 MHz, d4-MeOH) δ: 8.62-8.60 (m, 2H), 7.90-7.88 (m, 2H), 7.66-7.55 (m, 1H), 7.26-7.24 (m, 2H), 7.20-7.17 (m, 2H), 6.92 (dd, 1H, J=2.7, 1.5 Hz), 6.32 (dd, 1H, J=3.5, 1.5 Hz), 6.21 (dd, 1H, J=3.5, 2.7 Hz), 4.28 (s, 2H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.O1CCOCC1>[C:1]([CH2:2][CH2:3][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:4]
Reactant: C=CC#N
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Solvent: O
Solvent: C1COCCO1
Product: N#CCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 80 °C

Procedure:
1.6 ml of Triton B at 40% in water and 4 ml of acrylonitrile are mixed in 40 ml of dioxane, and 9.44 g of benzyl 2-indolecarboxylate are then added with stirring. The mixture is heated at 80° C. for 24 hours and is then poured into 500 ml of ice-cold water. The precipitate formed is filtered off, taken up in EtOAc and this solution is then dried over Na2SO4 and concentrated to give 10.1 g of the expected compound, which crystallizes: m.p.=98-100° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:14]2[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15]2)=[C:6]2[CH2:13][CH2:12][CH2:11][C:7]2=[N+:8]([O-])[CH:9]=1)([O-:3])=[O:2].[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>>[C:33]([O:35][CH:11]1[C:7]2=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([N:14]3[CH2:19][C@H:18]([C:20]([F:21])([F:23])[F:22])[CH2:17][C@H:16]([NH:24][C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[CH2:15]3)=[C:6]2[CH2:13][CH2:12]1)(=[O:34])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A mixture of tert-butyl [(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.100 g, 0.224 mmol) in Ac2O (1.5 mL, 16 mmol) was stirred at 90° C. for 1 h. The solution was allowed to cool to room temperature, then concentrated under reduced pressure at 60° C. The residue was diluted with EtOAc (5 mL), washed quickly with 1N NaOH. The aqueous phase was extracted with EtOAc twice. The combined organic phases were condensed and columned on 20 g silica gel, eluting with 0-50% EtOAc in hexanes to give the sub-title compound as a brown solid (0.085 g, 78%). LCMS calc. for C21H28F3N4O6 (M+H)+ m/z=489.2. found: 489.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(Br)cc(C(F)(F)F)c1=O
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (6 g, 25 mmol) stirred at rt in THF (5 mL) was added NaH (1.5 g, 37 mmol, 60% in mineral oil). After stirring for 30 min, methyl iodide (7.1 g, 50 mmol) was added. After stirring at rt for 3 h, the reaction mixture was treated with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (6 g, 97%) as a tan solid. The solid was carried forward without any further purification. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 3.60 (s, 3H). LCMS (M+H)+=256.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:12]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-pyridine-3-sulfonyl chloride (5.0 g, 0.024 mol) was dissolved in a 0.5M solution of ammonia in dioxane (125 mL) at −5° C. The mixture was allowed to warm to room temperature and the mixture stirred for 1 hour. The mixture was filtered through celite, washed twice with dioxane and concentrated in vacuo to afford 6-choro-pyridine-3-sulfonic acid amide as an off white solid 4.55 g (98% yield). LC@UV215 nm; Rt 1.05: 100%, m/z (ES+): 193/195 (400 MHz; d6-DMSO) 8.79 (1H, d), 8.21 (1H, dd), 7.75 (1H, d) 7.70 (2H, br S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[C:13]3[C:14]([CH3:36])=[C:15]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:38])[CH3:37])=[CH:5][CH:4]=1>CCCCCC.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:36])=[C:15]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:38])[CH3:37])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(O)c3c(C)c(N4CCC(c5ccc(OC)c(OC)c5)CC4)c(C)c(C)c3OC2(C)C)cc1
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C2c3c(C)c(N4CCC(c5ccc(OC)c(OC)c5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 82 %

Procedure:
Using 3-(4-methoxyphenyl)-5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 85, the title compound was synthesized in the same manner as in Example 46. Yield 82%. mp. 154–156° C. (hexane-methanol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ncnc21
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
To a 250 mL oven dried three-neck round bottom flask equipped with a stir bar, condenser, septa, nitrogen inlet and thermocouple was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 26 mL, 0.320 mol). The mixture was chilled to 0-5° C. To a oven dried 100 mL round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (42 mL, 0.520 mol), and the resulting slurry was then added portion wise via large bore canula over 15 minutes to the sodium hydride (NaH) suspension in THF. The reaction temperature rose to 6.8° C. after the addition of the substrate. The reaction mixture was stirred at 0-5° C. for 40 minutes before being charged neat triisopropylsilyl chloride (6.6 g, 7.24 mL, 0.0342 mol, 1.05 equiv) via syringe over 5 minutes. The cooling bath was removed and the reaction mixture was warmed to reflux for 4 hours. The reaction was monitored by TLC (80% hexane/ethyl acetate). When the reaction was deemed complete, the reaction mixture was cooled to room temperature and dilute with ethyl acetate (100 mL) and 20% aqueous brine (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with 1M sodium bicarbonate (NaHCO3) aqueous solution (100 mL) and 20% aqueous brine (100 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexane gradient elution) to afford 4-chloro-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (3d, 10.0 g, 10.10 g theoretical, 99%) as an amber oil. For 3d: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.61 (s, 1H), 7.67 (d, 1H, J=3.7 Hz), 6.76 (d, 1H, J=3.5 Hz), 1.86 (m, 3H), 1.02 (d, 18H, J=7.5 Hz); C15H24ClN3Si (MW, 309.91), LCMS (EI) m/e 310/312 (M++H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:18]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:11][O:12][C:34](=[O:36])[N:13]1[C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[N:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC[C@H](COCc1ccccc1)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC[C@H](COCc2ccccc2)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
(R)-3-Benzyloxy-2-[4-(4-bromo-phenyl)-thiazol-2-ylamino]-propan-1-ol (110 mg, 0.26 mmol), prepared in the previous step, was dissolved in methylene chloride (10 mL), cooled to 0° C. and triethylamine (0.36 mL, 2.6 mmol) was added followed by triphosgene (0.19 g, 0.65 mmol). The mixture was stirred for 3 h, diluted with methylene chloride and washed with saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone in hexane) afforded the title compound (35 mg, 30%). HRMS: calcd for C20H17BrN2O3S+H+, 445.02160; found (ESI, [M+H]+), 445.0201; Analytical HPLC: purity 100% at 210-370 nm, 11.1 min; 93.8% at 238 nm, 11.1 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: O[CH2:2][CH:3]([C:7]1[S:8][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:10][N:11]=1)[CH2:4][C:5]#[N:6].CS(Cl)(=O)=O.[C-:34]#[N:35].[Na+]>C(Cl)Cl.O>[N:15]1[C:14]2[NH:18][CH:19]=[CH:20][C:13]=2[C:12]([C:9]2[S:8][C:7]([CH:3]([CH2:2][C:34]#[N:35])[CH2:4][C:5]#[N:6])=[N:11][CH:10]=2)=[N:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(C(CO)CC#N)s3)ncnc21
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CCC(CC#N)c1ncc(-c2ncnc3[nH]ccc23)s1
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A solution of the above prepared 4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrile in DCM (12 mL) at 0° C. was treated sequentially with TEA (130 μL, 0.94 mmol) and methanesulfonyl chloride (73 μL, 0.94 mmol). After 1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was added. After 30 minutes, the mixture was diluted with water, extracted with ether, washed with water, brine and dried over sodium sulfate. Concentration and purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS (ES): 425 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O>N1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:28][C:14]1[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:13]=1[CH3:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCCN1CCOCC1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixuture of 5-bromo-1,3-dihydroindol-2-one (212 mg, 1.0 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (250 mg, 1.0 mmol) and 3 drops pyrrolidine in 2.0 ml of ethanol was refluxed at 90° C. for 4 hours and then cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane and dried in a vacuum oven overnight to give 399.8 mg (90%) of 5-bromo-3-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a red solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[CH:17]=[CH:16]1>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[C:18](=[O:19])[CH:17]=[CH:16][C:15]3=[O:20])[C:7]=2[N:8]=1
Reactant: Nc1cccc2oc(C(F)(F)F)nc12
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1cccc2oc(C(F)(F)F)nc12
Yield: 57.2 %

Procedure:
Compound 476B (0.500 g, 2.48 mmol) was dissolved in acetic acid (10 mL) and maleic anhydride (0.267 g, 2.72 mmol) was added. The mixture was heated at reflux for 3 h, cooled and the solvent removed in vacuo to give a tan solid. The crude product was purified by flash chromatography on silica gel eluting with 2% MeOH/CH2Cl2 to give compound 476C (0.40 g, 57%) as an off-white solid. HPLC: 89.7% at 2.38 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 283.21 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]1=[O:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C>[OH:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]2=[O:12])[CH2:15][CH2:16]1
Reactant: OCC1CCNCC1
Reactant: CC(C)n1ccn(CCCl)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ccn(CCN2CCC(CO)CC2)c1=O
Temperature: 70 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of 1-(2-chloroethyl)-1,3-dihydro-3-(1-methylethyl)-2H-imidazol-2-one (12 g), 4-piperidinemethanol hydrochloride (9.1 g), N,N-diethylethanamine (21 ml) and KI (catalytic amount) in DMF (200 ml) was stirred for 20 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3)95/5). The pure fractions were collected and the solvent was evaporated, yielding 6.9 g (43%) 1,3-dihydro-1-[2-[4-(hydroxymethyl)-1-piperidinyl]ethyl]-3-(1-methylethyl)-2H-imidazol-2-one (intermediate 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26](Cl)=[O:27])=[C:19]2[N:18]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([NH:13][C:12]3[C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH3:15])=[N:9][N:10]([CH3:14])[CH:11]=3)=[O:27])=[C:19]2[N:18]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cc1ccc(Cl)cc1-c1nn(C)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2ccc(Cl)nc12
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of 3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-amine (182.9 mg, 0.4826 mmol, 1.2 equiv) in dichloromethane (5 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (91.2 mg, 0.411 mmol, 1.0 equiv) and triethylamine (0.30 mL, 2.2 mmol, 5.2 equiv) at room temperature. After 16 hours, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 143.1 mg (87%) of 5-chloro-N-(3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was carried forward without purification. LCMS (ESI) m+H=401.0.