Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:14]O.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O>C(Cl)Cl>[Cl:27][CH2:14][C:3]1[C:2]([CH3:1])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1c(CO)cccc1N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CCl)cccc1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(2-methyl-3-morpholinophenyl)methanol (0.468 g, 2.26 mmol) was dissolved in dry DCM (14 mL) with triethylamine (0.669 mL, 4.82 mmol) and this stirred solution was cooled at 0° C. in an ice bath. Mesyl chloride (0.415 g, 3.62 mmol) was added dropwise and the reaction was allowed to reach rt overnight. The mixture was diluted in DCM (25 mL), washed with water (20 mL) and the water re-extracted with DCM (20 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed under vacuum to afford 4-(3-(chloromethyl)-2-methylphenyl)morpholine as a crude oil (0.5 g, 98% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[C:10]([CH3:17])[CH:9]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([Cl:47])[C:41]=1[O:48][CH2:49][CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58]I)=[CH:54][CH:53]=1>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH2:50][CH2:49][O:48][C:41]3[C:42]([Cl:47])=[CH:43][C:44]([CH3:46])=[CH:45][C:40]=3[Cl:39])=[CH:53][CH:54]=2)[C:15]#[N:16])=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(-c2ccccc2Cl)ccc1CC#N
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(-c4ccccc4Cl)cc3C)cc2)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution (2′-chloro-3-methylbiphenyl-4-yl)acetonitrile (1 eq.) from step 1 in THF (0.10M) at −78° C. was added hexamethylphosphoramide (HMPA; 4 eq.) then lithium hexamethyldisilazide (LiHMDS; 1.2 eq.). The reaction mixture was stirred 30 min at −78° C. To the resulting solution was cannulated over 10 min a solution of 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1; 1.05 eq.). The final mixture was allowed to warm slowly to 0° C., stiffed an extra 2 h, poured in saturated aqueous NH4Cl and finally extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 20% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: NCCO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-aminoethanol (6.37 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 18 min, product retention=17.9 min (20 mL/min, 220 nM) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (25 mg, 0.047 mmol, 68.2% yield): LCMS=475.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.25 (1 H, t, J=5.94 Hz), 8.09-8.19 (2 H, m), 7.58-7.84 (7 H, m), 5.14 (1 H, s), 3.60-3.67 (2 H, m), 3.34-3.44 (2 H, m); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.043 g) in dichloromethane (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.029 g, 6%). MS (ISP) 514.3 [(M+H)+]; mp 292° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:8])[CH:4]([OH:7])[CH2:5][Cl:6].O1CC[CH2:12]OO1.S(=O)(=O)(O)O>ClCCCl>[Cl:1][CH2:2][CH:3]1[CH:4]([CH2:5][Cl:6])[O:7][CH2:12][O:8]1
Reactant: OC(CCl)C(O)CCl
Reactant: C1COOOC1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: ClCC1OCOC1CCl
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A three-neck 500-mL flask equipped with a thermometer, a mechanical stirrer, an addition funnel, a condenser, and a positive nitrogen atmosphere was charged with 1,4-dichloro-2,3-butanediol (50.0 g, 0.314 mole), trioxane (9.43 g, 0.314 mole), and 1,2-dichloroethane (EDC) (300 mL). The 1,4-dichloro-2,3-butanediol was not totally dissolved. Concentrated sulfuric acid (46.3 g, 0.455 mole) was then added dropwise over eight minutes. During the addition period, a slight exotherm was noticed and the flask was immersed in an ice bath to maintain the reaction temperature at 21.5° C. to 25.5° C. for 2.1 hours. The reaction mixture was permitted to settle overnight. The acid layer was removed, washed once with 30 mL EDC, and discarded. The combined EDC solutions were quenched with 2% NaHCO3 (600 mL), washed with deionized water (400 mL), 1% NaHCO3 solution (400 mL), deionized water (400 mL, twice), and stripped in vacuo. The resulting light yellow liquid weighed 48.9 g (89.5% yield), and contained 1.8% EDC and 98.2% dl- and meso-(4,5-dichloromethyl)-1,3-dioxolane, as determined by GC analysis and proton NMR (CDCl3) δ (s, --OCH2O--), 4.1 (m, ClCH2CHCHCH2Cl), 3.6(d, ClCH2CHCHCH2Cl).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH:6]([NH:8]S(C(C)(C)C)=O)[CH3:7])[N:3]=[CH:2]1.[ClH:15]>CO>[ClH:15].[ClH:15].[O:1]1[CH:5]=[C:4]([CH:6]([NH2:8])[CH3:7])[N:3]=[CH:2]1
Reactant: CC(NS(=O)C(C)(C)C)c1cocn1
Agent: Cl
Solvent: CO
Product: CC(N)c1cocn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round-bottomed flask, 2-methyl-propane-2-sulfinic acid (1-oxazol-4-yl-ethyl)-amide (585 mg, 2.57 mmol) was dissolved in methanol (4.5 ml) and hydrogen chloride (4.0 M in 1,4-dioxane, 1.3 ml, 5.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 15 min then concentrated to give 1-oxazol-4-yl-ethylamine dihydrochloride as a viscous orange oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:24][O:25][CH3:26])[N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)[N:5]=[C:4]([CH2:24][O:25][CH3:26])[N:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COCc1nc(Cl)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCc1nc(-c2cccc(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1

Procedure:
Combine 4-chloro-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (388 mg, 1 mmol), 3-chlorophenylboronic acid (157 mg, 1 mmol), Pd(P(Ph)3)4 (100 mg, 0.09 mmol), 2M aqueous sodium carbonate (1 mL), and 1,2-dimethoxyethane (5 mL) under nitrogen. Reflux for 16 hours. Evaporate and add water (5 mL), and extract with EtOAc. Dry the organic layer with sodium sulfate and purify by liquid chromatography, to obtain 4-(3-chloro-phenyl)-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]#[N:30])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)(C)C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C(C)(C)C1
Temperature: 100 °C
Yield: 85 %

Procedure:
Tetrakis (triphenylphosphine)palladium (0) (4.10 g, 0.0035 mol) was added to a suspension of N-tert-butyloxycarbonyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (36.37 g, 0.089 mol) and zinc cyanide (10.44 g, 0.089 mol) in anhydrous dimethyl formamide (280 ml) under argon. The resultant was heated at 100° C. for 4 hours, cooled and poured into water (800 ml). The mixture was filtered through kieselguhr and the filter cake washed with ethyl acetate. The bilayered filtrate was separated and the aqueous layer extracted into ethyl acetate (4×500 ml). Combined organics were washed with water (3×250 ml), brine (250 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using 0-15 % ethyl acetate in hexane gradient elution to afford the title compound as a colourless oil (21.75 g, 85%).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:15]=[C:16](SC)[NH:17][C:18](=[O:23])[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CN1C(=O)CCC1.C(O)C>C(OCC)(=O)C.O>[CH3:35][N:34]([CH3:36])[C:28]1([CH2:27][NH:26][C:16]2[NH:17][C:18](=[O:23])[C:19]([C:20]([NH2:22])=[O:21])=[C:14]([NH:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:15]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CSc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(N)=O)c(=O)[nH]1
Reactant: CN(C)C1(CN)CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NCC2(N(C)C)CCCCC2)[nH]c(=O)c1C(N)=O
Temperature: 180 °C
Yield: 53 %

Procedure:
A mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 294) (200 mg), 1-(aminomethyl)-N,N-dimethylcyclohexylamine (409 mg) and NMP (1 mL) was heated at 180° C. for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated crystal was collected by filtration and washed with ethyl acetate to give a white solid. To the white solid, a mixed solvent of ethanol and water was added, heated and then cooled, and the precipitated solid was collected by filtration to give 2-({[1-(dimethylamino)cyclohexyl]methyl}amino)-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (136 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:43][C:40]4[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccncc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccncc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.23 g) synthesized in Example A155(1) was dissolved in tetrahydrofuran (5 mL), and 4-pyridinemethanol (62 mg), tributylphosphine (0.21 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.21 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr, then hexane (5 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.18 g, 64%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C@H:13]1[CH2:16][C@H:15]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][N:25]=[C:20]3[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[CH:11][C:2]=1[NH:12][C@H:13]1[CH2:16][C@H:15]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][N:25]=[C:20]3[C:19]([CH3:26])([CH3:27])[C:18]2=[O:28])[CH2:14]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2nccnc21
Reactant: Clc1ccc2cccnc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ccc4cccnc4n3)C2)c2nccnc21
Temperature: 100 °C

Procedure:
2-chloro-1,8-naphthyridine (89 mg, 0.54 mmol), 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (100 mg, 0.431 mmol), and cesium carbonate (202 mg, 0.620 mmol) were suspended in dry dimethylformamide (0.86 mL) under nitrogen and heated to 100° C. for 18 h. The mixture was cooled and extracted with ethyl acetate and water. The phases were separated and the organic was dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using the ISCO (0-100% EtOAc in hexane), gave the desired 5-(trans-3-((1,8-naphthyridin-2-yl)amino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (32 mg, 0.089 mmol, 21% yield) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.45 (s, 6 H) 2.42 (ddd, J=13.88, 9.28, 3.29 Hz, 2 H) 3.44-3.62 (m, 2 H) 5.22-5.38 (m, 2 H) 6.71 (d, J=8.92 Hz, 1 H) 7.16 (dd, J=7.82, 4.46 Hz, 1 H) 7.79-7.98 (m, 2 H) 8.11 (q, J=3.12 Hz, 2 H) 8.84 (dd, J=4.38, 1.90 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH:30]4[C:35](OC)=[O:36])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][C@H:31]([OH:34])[C@@H:30]4[C:35]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:36])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1[C@@H](O)CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)[C@H]1[C@@H](O)CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (292 mg, 2.61 mmol) in dry THF (12 mL) was added 2M solution of isopropylmagnesium chloride in THF (1.3 mL, 2.60 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of (3S)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (250 mg, 0.65 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford (2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide (10 mg). Compound No. 11a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Compound No. 11b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Separation by chiral HPLC provided additional diastereomers 11c and 11d.
Reaction SMILES: Br/[C:2](/[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH2:17]2)=[C:12]([O:19][CH3:20])[N:11]=1)=[CH:3]\[C@@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(OCC)(=O)C.O.O1CCOCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25](/[C:2](/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:18][CH2:17]3)=[C:12]([O:19][CH3:20])[N:11]=2)=[CH:3]\[C@@H:4]2[NH:8][C:7](=[O:9])[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1C1CC1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1C1CC1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
1,4-Dioxane (4 mL) and water (0.4 mL) were added to a mixture of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-24 (170 mg), 4-chlorophenylboronic acid (160 mg), tris(dibenzylideneacetone) dipalladium (45 mg), tri(2-furyl)phosphine (69 mg) and cesium carbonate (492 mg), and the mixture was stirred at 90° C. for 2.5 hours. Water and ethyl acetate were added to the reaction solution and the insoluble matter was filtered off through celite, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→0:100) to give (5R)-5-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a crude product (250 mg).
Reaction SMILES: ClC([SiH3])(Cl)Cl.BrC(Br)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].I[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:26]2>CC(N(C)C)=O.[Zn].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].ClCCl.[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[CH:27]=[CH:26]3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(I)ccc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C3CN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
In an inert atmosphere, zinc dust (300 mg, 4.59 mmol) was vigorously stirred in dimethylacetamide (1.6 ml) and heated to 65° C. Subsequently, trichloromethylsilane (70 μl, 0.57 mmol) and dibromoethane (50 μl, 0.57 mmol) were added, and the reaction mixture was stirred for another 30 minutes at 65° C. 3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.53 mmol) in dimethylacetamide (2 ml) was added dropwise to the above prepared solution at 65° C., and then the reaction mixture was allowed to cool to room temperature. 5-Iodo-1-triisopropylsilanyl-1H-indole (855 mg, 1.98 mmol) in dimethylacetamide (4 ml) was added to the reaction mixture. Subsequently, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichlormethane (52.4 mg, 0.06 mmol) and copper(I)iodide (24.4 mg, 0.13 mmol) were added. The reaction mixture was heated to 80° C. for 2 hours, cooled to room temperature and quenched with water (150 ml). Ammonium chloride (2 g) was added, and the reaction mixture was extracted twice with diethylether (150 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure to give an oil (1.1 g, 64% purity).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.CO.[ClH:36]>O1CCOCC1>[ClH:36].[ClH:36].[Br:1][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate was dissolved in 1:1CH2Cl2:methanol and 4N HCl in dioxane was added and stirred at room temperature for 1 hour. The solvents were removed to afford the title compound. 1H NMR (d6-DMSO) δ 10.98 (bs, 1H), 8.90 (bs, 1H), 8.70 (bs, 1H), 8.23 (d, 1H), 7.45 (m, 2H), 7.40 (d, 1H), 7.22 (m, 1H), 7.12 (m, 2H), 6.76 (s, 1H), 3.31 (m, 2H), 2.98 (m, 2H), 2.89 (m, 1H), 2.10 (m, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z=431.2, 433.2 (M+H-2HCl).