Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][Si:10]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23])([CH3:12])[CH3:11].CI>C1COCC1>[CH3:11][Si:10]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:2])[C:22]([O:24][CH3:25])=[O:23])([CH3:12])[CH3:9]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 M LDA solution (1.24 mL, 2.48 mmol) was added to solution of methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I10) (0.306 g, 1.24 mmol) in THF (10 mL) at −78° C. and the mixture stirred for 30 minutes. Methyl iodide was then added (0.155 mL, 2.48 mmol) and the reaction mixture slowly warmed to room temperature over 1.5 hours. The reaction mixture was then left to stir at room temperature for 18 hours before quenching with a saturated solution of NH4Cl (20 mL). EtOAc (20 mL) was then added and the layers separated. The aqueous layer was further extracted with EtOAc (2×20 mL). The solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (0-5% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I50) (0.297 g, 92%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ7.49-7.44 (m, 1H), 7.33-7.24 (m, peaks obscured by CDCl3), 7.21-7.17 (m, 1H), 4.25 (q, J=7.2 Hz, 1H), 3.67 (s, 3H), 1.51 (d, J=7.2 Hz, 3H), 0.26 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[C:8](=[CH:18]\[N:19](C)C)/[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.O.[NH2:23]N>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:23][NH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)/C=C(/C(=O)c1ccc(F)cc1)c1ccnc(Cl)n1
Reactant: NN
Solvent: O
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Yield: 48.1 %

Procedure:
A solution of the compound prepared in step 3 (4.4 g) and hydrazine hydrate (0.82 g, 0.014 mol) was stirred at room temperature for 6 hours. The yellow precipitate was collected by filtration and air-dried to give 1.85 g of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine as a yellow solid, mp: 204-205° C.; Anal. Calc'd for C13H8ClFN4: C, 56.84; H, 2.94; N, 20.40; Cl, 12.91. Found: C, 56.43; H, 2.76; N, 20.02; Cl, 12.97.
Reaction SMILES: CO.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:13]([OH:32])[C:12]2=[O:33])=[CH:7][CH:6]=1)=O.[Cl-].[CH3:35][O:36][NH3+:37].C([O-])(=O)C.[Na+]>O>[OH:32][C:13]1[C:12](=[O:33])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:3]=[N:37][O:36][CH3:35])=[CH:10][CH:9]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(C=O)cc3)C2c2ccccc2)cc1
Reactant: CO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1ccc(N2C(=O)C(O)=C(C(=O)c3ccc(OC)cc3)C2c2ccccc2)cc1
Yield: 2.9 %

Procedure:
To the 0.1M methanol solution of 1-(4-formylphenyl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydropyrrol-2-one (1 mL, 0.1 mmol) was added O-methylhydroxylammonium chloride (0.025 g, 0.3 mmol) and sodium acetate (0.025 g, 0.3 mmol). The mixture was stirred under reflux for 3 hr. Water (50 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitate was collected by filtration and dried to give 3-hydroxy-4-(4-methoxybenzoyl)-1-(4-methoxyiminomethylphenyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (1.3 mg, 3%) as slightly yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[C:6](\[Cl:13])/[C:7](=[O:12])[O:8][CH2:9][CH2:10][CH3:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>C(Cl)(Cl)Cl>[CH3:17][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Cl:13])/[C:7](=[O:12])[O:8][CH2:9][CH2:10][CH3:11])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: CCCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-propoxy-1-propenyl]-cyclopropane-1-carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-propoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+22.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [CH:1]1([C:5]2[C:15]3[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[CH:8]=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:29]>C(OCC)(=O)C>[ClH:29].[CH:1]1([C:5]2[C:15]3[O:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(C3CCC3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A mixture of tert-butyl 9-cyclobutyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (40.0 mg, 0.132 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (25.0 mg, 79.1%) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([F:34])[F:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([F:34])[F:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Reactant: O=C(O)Cc1c[nH]cn1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using (1H-imidazol-4-yl)-acetic acid and (S)3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 3.14 min, [M+1]+ 457. Potency class C.
Reaction SMILES: [ClH:1].[C:2]([CH2:6][CH2:7][C:8](=[NH:11])OC)([O:4][CH3:5])=[O:3].[NH3:12]>CO>[ClH:1].[C:2]([CH2:6][CH2:7][C:8]([NH2:11])=[NH:12])([O:4][CH3:5])=[O:3]
Reactant: COC(=N)CCC(=O)OC
Reactant: N
Agent: Cl
Solvent: CO
Product: COC(=O)CCC(=N)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a suspension of 16.5 g. (0.09 mole) of methyl β-carbomethoxypropionimidate hydrochloride in 20 ml. of methanol at ice bath temperatures is added 12 ml. of the same solvent containing 1.7 g. of dissolved ammonia gas. The reaction mixture is allowed to stir at room temperature for 2 hrs., followed by filtration of some insoluble material and concentration of the filtrate to near dryness. The residual white solids are treated with ethanol, filtered and dried, 7.8 g. (51.5% yield), m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]=[C:10]([S:17][CH2:18][C:19]#[N:20])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]=[C:10]([S:17][CH2:18][C:19](=[N:24][OH:25])[NH2:20])[N:9]=2)=[CH:21][CH:22]=1
Reactant: CCCc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(NCc2ccc(Cl)cc2)nc(SCC(N)=NO)n1

Procedure:
A mixture of 6.60 g. (0.02 mole) of [4-(p-chlorobenzylamino)-6-propyl-2-pyrimidinylthio]acetonitrile, 2.76 g. (0.04 mole) of hydroxylamine hydrochloride and 8.48 g. (0.08 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for three and one-half hours. The mixture was filtered, diluted with 250 ml of water and extracted with 100 ml of ether. The ether layer was dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. The residue was dissolved in ethanol, diluted with petroleum ether and cooled in ice. The precipitate which formed was collected and recrystallized from a mixture of ethanol-petroleum ether to give the analytical sample, m.p. 50° dec.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Li])CCC.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
i)—A solution of 6-nitroindole (25 g, 154 mmol) in dry tetrahydrofuran (900 ml) was cooled to −78° C. and treated with n-butyllithium (2.5 M solution in hexanes, 67.0 ml, 169 mmol). After 20 min. stirring, chloro-triisopropyl-silane (33.0 ml, 155 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 2 h. The mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 95:5) afforded 6-nitro-1-triisopropylsilanyl-1H-indole (41.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([N:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CC1CNC1
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A 25 mL round-bottomed flask was charged with (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid (0.475 g, 2.17 mmol), azetidine-3-carbonitrile hydrochloride (314 mg, 2.65 mmol) and HATU (832 mg, 2.19 mmol). Then added DMF (3.6 mL) followed by N,N-diisopropylethylamine (1.5 mL, 8.67 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-100% EtOAc) to afford 288 mg (47%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a viscous colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH3:23])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Reactant: CI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccn(C)c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=325.2, 327.1 (M+H+), was prepared in accordance with the general method of example 2 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one and methyl iodide.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(I)cc1)CCNC2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(I)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-iodobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue purified by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 89-90 ° C.).
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].[Cl:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>>[C:2]([O:7][CH2:8][CH2:9][NH:10][S:14]([CH2:13][CH2:12][Cl:11])(=[O:16])=[O:15])(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: O=S(=O)(Cl)CCCl
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Product: C=C(C)C(=O)OCCNS(=O)(=O)CCCl

Procedure:
2-Aminoethyl methacrylate hydrochloride is condensed with 2-chloroethanesulfonyl chloride to produce the 2-(2-chloroethylsulfonylamino)ethyl methacrylate. ##STR23##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=2[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3cccc(Cl)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 17 from 3-chlorophenyl boronic acid and 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine. A orange solid: mp 144-146° C.; 1H-NMR (CDCl3) δ 7.50 (t, 1H, J=1.78 Hz), 7.40 (dt, 1H, J=7.61, 1.45 Hz), 7.33 (t, 1H, J=7.76 Hz), 7.29-7.22 (m, 4H) 6.72 (d, 1H, J=8.24 Hz), 4.90 (q, 1H, J=5.45 Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.4 6 (d, 3H, J=5.5 Hz); MS (ES) m/z 288/290 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]([C@H:26]5[CH2:29][C@H:28](OS(C)(=O)=O)[CH2:27]5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C-:43]#[N:44].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[C:43]([C@@H:28]1[CH2:29][C@H:26]([CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[CH:19]=2)=[O:22])[CH3:25])[CH2:27]1)#[N:44]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](C#N)C1
Temperature: 100 °C

Procedure:
To a solution of methanesulfonic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester (crude from step 1, 97 mg, 0.16 mmol) in DMSO (1.5 mL) at room temperature was added potassium cyanide (41 mg, 0.63 mmol) and 18-crown-6 (8 mg, 0.03 mmol). The reaction mixture was heated at 100° C. overnight then cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified via chromatography with 20% to 50% EtOAc/hexanes to isolate 34 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-cyano-cyclobutyl)-ethyl]-amide as a yellow foam.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:17][C:18]1[N:19]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]#[N:34])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>ClCCl>[C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[S:17][C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:24][CH:25]=1)#[N:34]
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Reactant: CCOC(=O)C(F)(F)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(F)(F)Sc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (1.1 eq), followed by ethyl 2-bromo-2,2-difluoroacetate (1.05 eq) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (prepared as described herein, 1 eq) in dichloromethane and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M), 50% saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. Hexanes were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH:59]=O)[CH:54]=1>>[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][N:48]([CH2:59][C:55]5[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=5)[CH2:47][CH2:46]4)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]3=[O:42])=[O:33])=[CH:51][CH:52]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(C4CCN(Cc5cccnc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 45 %

Procedure:
Following procedures analogous to that used in reaction (9), the compound from Example 29 was reacted with 3-pyridinecarboxaldehyde for 2 days to provide the title compound (7.3 mg, 45%). MS found: (M−H)−=605.5.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1cccs1
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: COCCOC
Product: Cc1ccc(-c2cccs2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
A mixture of 2-thiopheneboronic acid (0.483 g, 3.78 mmol), 2-bromo-5-methylpyridine (0.5 g, 2.91 mmol), a solution of Na2CO3 (1M in H2O, 7.8 mL, 7.8 mmol) and a catalytic amount of Pd(PPh3)4 in DME (10 mL) was heated at the reflux temperature for 3 h., then allowed to cool to room temperature and poured onto ice. The resulting mixture was stirred for 10 min and extracted with CH2Cl2 (2×25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (70% EtOAc/hex) to give 2-(5-methyl-2-pyridyl)thiophene (0.499 g, 98%): GC-MS m/z (rel abundance) 176 (MH+, 100%); 1H NMR (CDCl3) δ 1.39 (s, 3H), 7.15 (m, 1H), 7.39 (m, 1H), 7.61-7.43 (m, 3H), 8.41 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[CH3:20][O:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([NH2:31])[CH:29]=2)[NH:24][N:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([NH:31][C:28]1[CH:29]=[C:30]2[C:22]([O:21][CH3:20])=[N:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:6]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: COc1n[nH]c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
2,6-Difluoro-3-(N-propylsulfamoylamino)benzoic acid (0.095 g, 0.32 mmol), 3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (0.053 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol), and EDCI (0.062 g, 0.32 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (30 mL) and washed with a mixture of 1:1:1 water:bicarbonate:brine (3×20 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography eluting with 1:1 then 8:2 EtOAc:hexanes to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(N-propylsulfamoylamino)benzamide (0.090 g, 0.20 mmol, 63% yield). 1H NMR (400 MHz, CD3OD) δ 8.57-8.60 (m, 1H), 8.47-8.49 (m, 1H), 7.63-7.70 (m, 1H), 7.04-7.11 (m, 1H), 4.07 (s, 3H), 2.94-3.30 (m, 2H), 1.45-1.56 (m, 2H), 0.85-0.90 (m, 3H); m/z (APCI-pos) M+1=441.1.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:33][CH2:32][N:31]3[C@@H:26]([CH2:27][O:28][CH2:29][CH2:30]3)[CH2:25]2)[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl.O1CCOCC1>CO>[Cl:34][C:19]1[N:20]=[C:21]([N:24]2[CH2:33][CH2:32][N:31]3[C@@H:26]([CH2:27][O:28][CH2:29][CH2:30]3)[CH2:25]2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NNc1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Reaction time: 72 h
Yield: 64.7 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (4.34 g, 7.20 mmol) in MeOH (18 mL) was added 4 N HCl in dioxane (18 mL, 72 mmol). The solution was stirred for 3 days, and then concentrated in vacuo. The residue was dissolved in water (50 mL) and the solution was adjusted to pH 10 with 20% aq. K2CO3. The mixture was extracted with DCM (2×100 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (9aR)-8-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (1.41 g, 65%) as an orange solid. LCMS: (M+H)+: 303.1.