Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].Cl.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:31])[N:16]=2)[CH2:11][CH2:10]1>>[NH2:31][C:17]1[N:18]=[C:19]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH2:28]3)=[CH:23][CH:22]=2)[CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]2)[N:16]=1
Reactant: CC(C)N=C=O
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared from 2-isocyanatopropane and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=410.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(F)cc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (200 mg, 0.484 mmol) in dichloromethane (2 mL) was added 4-fluorobenzoyl chloride (63 μl, 0.533 mmol) and N,N-diisopropyl ethyl amine (124 μl, 0.727 mmol). The solution was stirred for 3 h at ambient temperature. After diluting with ethyl acetate (15 mL) the solution was washed twice with water (15 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (245 mg, 95%) as a light brown oil. MS m/e: 535.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:40])[O:31][C@@H:32]1[C@H:39]2[C@H:35]([O:36][CH2:37][CH2:38]2)[O:34][CH2:33]1)[C@@H:9]([OH:28])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:42]([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([C@H:8]([NH:29][C:30](=[O:40])[O:31][C@@H:32]1[C@H:39]2[C@H:35]([O:36][CH2:37][CH2:38]2)[O:34][CH2:33]1)[C@@H:9]([OH:28])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:42]([CH3:44])[CH3:43])[CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(NS(=O)(=O)c1cccc(O)c1)OC1CCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.2 %

Procedure:
(3R,3aS,6aR)hexahydrofuro [2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.13 mmol, 75 mg) was combined with 2-bromopropane (0.26 mmol, 0.025 mL), potassium carbonate (0.65 mmol, 90 mg), tetrabutylammonium iodide (5 mg) and anhydrous DMF (1 mL). The reaction was stirred under a nitrogen atmosphere at room temperature for 72 hours. The reaction mixture was concentrated under vacuum to a residue and diluted with ethyl acetate (2 mL). The reaction was washed in distilled water and brine, and was dried over magnesium sulfate. The dried solution was then concentrated to an oil and purified by silica gel chromatography (2:1 hexanes/ethyl acetate) to yield 38 mg (48%) of a white solid. Rf=0.40 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ7.40 (1H,m), 7.33-7.10 (9H,m), 5.63 (1H,s), 5.00 (1H,m), 4.80 (2H,m), 4.58 (1H,m), 3.88 (4H,m), 3.67 (2H,m), 3.13 (1H,br.s), 3.00 (2H,m), 2.94-2.74 (2H,m), 1.88-1.71 (5H,m), 1.69-1.43 (5H,m), 1.35 (6H,d).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.C(O)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[Li+]>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=[C:2]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(nc(-c3ccccc3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.25 mmol) in 260 μL aqueous sodium carbonate (2 M), 650 μL toluene, and 110 μL ethanol was treated with commercially available phenylboronic acid (34 mg, 0.27 mmol), tetrakis(triphenylphosphine)-palladium(0) (9 mg, 0.0075 mmol), and lithium chloride (catalytic). The reaction mixture was heated to 100° C. in a sealed vial and stirred overnight The reaction mixture was cooled and separated between water and ether. The aqueous layer was extracted with ether (3×) and the combined organics were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel cartridge, Biotage, 32-63 μm, 60 Å) with 50% EtOAc:hexanes as the eluent to afford 71 mg (71% yield) of the title compound as a white solid: 1H NMR (CDCl3, 300 MHz) 7.61-7.36 (m, 5H), 7.19-7.04 (m, 2H), 6.88-6.76 (m, 1H), 5.89 (s, 2H), 3.67 (s, 3H), 3.43 (s, 3H); MS (ESP+) m/e 400 (MH+); TLC (EtOAc:hexanes/1:1) Rf=0.45.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:20](=[O:30])[NH:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])=[O:10])(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[NH:21][C:20]([C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][N:11]1[C:9](=[O:10])[C@@H:8]([NH2:7])[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindol-2-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (174 mg, 339 μmol, Eq: 1.00) in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to afford (S)-2-((S)-2-amino-2-cyclohexyl-acetyl)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: [NH2:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)(=O)C>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NS(=O)(=O)C1CCNCC1
Reaction time: 18 h

Procedure:
Benzyl 4-(aminosulfonyl)piperidine-1-carboxylate (the product from step i), 3.3 g) was dissolved in MeOH (20 ml). To this solution was added acetic acid (0.5 ml) and a catalytic amount of Pd/C. The reaction mixture was subjected to a pressure of 5 bar under an atmosphere of hydrogen gas for 18 h at RT. The reaction was filtered through celite and the filtrate was reduced in vacuo to give the subtitle compound as a white solid. Yield 1.7 g
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH:8]([OH:16])[CH2:9][S:10]([CH2:13][CH2:14][Cl:15])(=[O:12])=[O:11])(=[O:6])=[O:5].[CH:17]([S:25]([O-:27])=[O:26])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>O.CO>[Cl:15][CH2:14][CH2:13][S:10]([CH2:9][CH:8]([OH:16])[CH2:7][S:4]([CH2:3][CH2:2][S:25]([CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])(=[O:6])=[O:5])(=[O:12])=[O:11]
Reactant: O=S(=O)(CCCl)CC(O)CS(=O)(=O)CCCl
Reactant: O=S([O-])C=Cc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)(C=Cc1ccccc1)CCS(=O)(=O)CC(O)CS(=O)(=O)CCCl
Temperature: 46 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
In a 3 liter reaction vessel were placed 1 liter of distilled water, 1 liter of methanol and 157 g of 1,3-di(2-chloroethylsulfonyl)-2-hydroxypropane. The vessel was heated to 46° C. for the purpose of dissolution. Thereto, a solution of 52 g sodium styrenesulfinate dissolved in a mixture of 100 ml of distilled water and 100 ml of methanol was added dropwise over a period of about 1 hour, and the heating and the stirring were further continued for 5 hours. A crystal deposited was filtered off, washed with methanol, and dried in vacuo. Thus, 55 g of M-6 was obtained. The yield was 49%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:5])=[O:4].[C:20](Cl)(=[O:22])[CH3:21].N1C=CC=CC=1>C(Cl)Cl>[C:20]([O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][S:3]([C:2]([F:18])([F:1])[F:19])(=[O:4])=[O:5])=[CH:8][C:9]=1[CH:15]([CH3:17])[CH3:16])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(OS(=O)(=O)C(F)(F)F)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxymethyl-3-isopropylphenyl 1,1,1-trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol) in 5 mL CH2Cl2 was added acetyl chloride (75.0 mg, 0.96 mmol) and pyridine(101.0 mg, 1.38 mmols). After stirring for 3 hours at 25° C. the reaction was quenched by the addition of H2O and the resulting mixture extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The title compound, 182 mg (84%), was isolated from the residual oil by column chromatography (5-10% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>[Pd].C(O)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCN3CCOCC3)c2c1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2ccn(CCCN3CCOCC3)c2c1)c1cccs1
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A solution of compound 149 (2.0 g, 6.912 mmol) in abs. ethanol (20 mL) was treated with Pd—C (0.25 g), purged with hydrogen gas and stirred for overnight (15 h) under hydrogen atm. (balloon pressure). The reaction mixture was filtered through a celite pad and washed with abs. ethanol (2×20 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (3.94 g, 13.824 mmol) and the resulting mixture was stirred for overnight (16 h) at room temperature. The solvent was evaporated and the product was precipitated with ether (250 mL). The solid was dissolved into sat. NaHCO3 sol.: CH2Cl2 (100 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 150 (2.348 g, 92%) as a foam. 1H-NMR (DMSO-d6) δ1.83-1.91 (m, 2H), 2.19 (t, 2H, J=6.6 Hz), 2.30 (brs, 4H), 3.56 (t, 4H, J=4.8 Hz), 4.14 (t, 2H, J=6.6 Hz), 6.34-6.35 (m, 3H), 6.58 (dd, 1H, J=1.2, 8.2 Hz), 6.95 (brs, 1H), 7.09 (dd, 1H, J=3.9, 5.1 Hz), 7.21 (d, 1H, J=3.0 Hz), 7.44 (d, 1H, J=8.1 Hz), 7.59 (d, 1H, J=3.9 Hz), 7.72 (dd, 1H, J=0.9, 3.6 Hz).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:25])[NH:8][CH2:9][C:10]2([C:13]3[N:24]=[C:16]4[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20](I)[N:15]4[N:14]=3)[CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33]>COCCOC.[Cl-].[Na+].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>[CH:1]1([O:6][C:7](=[O:25])[NH:8][CH2:9][C:10]2([C:13]3[N:24]=[C:16]4[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([C:38]5[CH:37]=[CH:36][CH:35]=[C:34]([C:32]#[N:33])[CH:39]=5)[N:15]4[N:14]=3)[CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc(I)n2nc(C3(CNC(=O)OC4CCCC4)CC3)nc12
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CNC(=O)OC4CCCC4)CC3)nc12

Procedure:
In a screw cap vial [1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-carbamic acid cyclopentyl ester was dissolved in DME (0.45 mL) and 1 M K2CO3 (0.14 mL) under argon. 3-cyanophenyl boronic acid (0.021 g, 0.15 mmol) and Pd(PPh3)4 (4 mg, 0.004 mmol) were added. The suspension was shaken at 80° C. for 17 h after which brine was added, and the aqueous phase was extracted with DCM (×3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography using EtOAc:toluene 1:1->2:1 as the eluent to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6](C(=O)C(F)(F)F)[C@@H:7]([CH3:20])[CH2:8][N:9]2[C:12]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])=[CH:4][CH:3]=1.[CH:27]1([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:29][CH2:28]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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]>[CH:27]1([N:30]2[CH:34]=[C:33]([C:2]3[CH:11]=[C:10]4[C:5]([NH:6][C@@H:7]([CH3:20])[CH2:8][N:9]4[C:12]([O:14][CH:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)=[O:13])=[CH:4][CH:3]=3)[CH:32]=[N:31]2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of (S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.250 g, 0.574 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.148 g, 0.632 mmol), tris(dibenzylideneacetone)dipalladium (0.026 g, 0.029 mmol), X-Phos (0.027 g, 0.057 mmol) and cesium carbonate (0.561 g, 1.723 mmol) in 1,4-dioxane (5.0 mL) and water (1.0 mL) was heated at 100° C. for 17 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100% ethyl acetate-hexane) to afford (S)-cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.124 g, 59%) as a yellow solid. MS (ESI, pos. ion) m/z 367 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH3:25])[C:21](=[O:24])[NH:22][CH:23]=2)[CH2:5][CH2:4]1.CS(O[CH2:31][CH:32]1[CH2:35][O:34][CH2:33]1)(=O)=O>CN(C=O)C>[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH3:25])[C:21](=[O:24])[N:22]([CH2:31][CH:32]3[CH2:35][O:34][CH2:33]3)[CH:23]=2)[CH2:5][CH2:4]1
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Reactant: CS(=O)(=O)OCC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(CC2COC2)c1=O
Reaction time: 1 h
Yield: 24.8 %

Procedure:
Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL) After stirring 1 h, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04 mmol) was added and stirring continued for 18 h. EA extractive work up from 1 M HCl and preparative HPLC purification gave the title compound (24.0 mg) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 4.57 (t, J=6.4 Hz, 1H), 4.30 (d, J=7.2 Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21 (s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 404.1 (M+1)+
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:16][CH2:15][CH2:14][C@H:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCC[C@H]1C(OC(C)(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:18]1([NH:17][CH2:2][C:3]([N:5]2[CH2:16][CH2:15][CH2:14][C@H:6]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CBr
Reactant: Nc1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CNc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1-(bromoacetyl)-L-proline, 1,1-dimethylethyl ester (2.1 g., 7.5 mmole) in distilled tetrahydrofuran (40 ml.) is added aniline (1.5 g., 15 mmole) and the reaction mixture is stirred overnight under nitrogen. The reaction mixture is diluted with ethyl acetate (200 ml.), washed with saturated sodium bicarbonate (2×50 ml.) and water (twice), dried (Na2SO4), and concentrated in vacuo into a dark oily residue (4.0 g.). Flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride) affords 2.2 g. of 1-N-phenylglycyl)-L-proline, 1,1-dimethylethyl ester as a dark oil which solidifies upon drying in high vacuum.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[CH:17]=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19]N1C(=O)CCC1=O.O.C(=O)(O)[O-]>CN(C=O)C>[Cl:19][C:8]1[C:9]2[CH:14]=[N:13][C:12]([S:15][CH3:16])=[N:11][C:10]=2[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]=1[CH:17]=[O:18]
Reactant: CSc1ncc2cc(C=O)n(C3CCCC3)c2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(Cl)c(C=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
Compound 229 (3.10 g, 11.9 mmol) and N-chlorosuccinimide (1.74 g, 13.0 mmol) were dissolved in DMF (30 mL) and stirred at 100° C. After 1 h, the temperature of the reaction was reduced to 65° C. and 0.35 eq of NCS were added. After 30 min, the reaction contents were poured into water (10×) and saturated bicarbonate was added (300 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 7% ethyl acetate in hexanes) afforded 5-chloro-7-cyclopentyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (230) (1.37 g, 39% yield). 1H NMR (500 MHz, CDCl3) δ ppm 10.17 (s, 1 H) 8.91 (s, 1 H) 5.73-5.96 (m, 1 H) 2.63 (s, 3 H) 2.29-2.47 (m, 2 H) 1.97-2.16 (m, 4 H) 1.63-1.83 (m, 2 H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74]([CH2:77][CH2:78][C:79]2([OH:85])[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80]2)=[C:73]([CH3:86])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74]([CH2:77][CH2:78][C:79]4([OH:85])[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80]4)=[C:73]([CH3:86])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 32 mg, 0.139 mmol), palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.4 mg, 0.018 mmol), potassium phosphate (59 mg, 0.279 mmol) and water (0.2 mL) were added to a solution of 1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclohexanol (Example 37-(2); 46.7 mg, 0.093 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (26.5 mg, 54%).