Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OP([O-])(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N+:21]([CH2:25][CH2:26][S:27][C:28]2[CH2:34][C@H:33]3[N:30]([C:31](=[O:38])[C@@H:32]3[C@H:35]([OH:37])[CH3:36])[C:29]=2[C:39]([O:41]CC2C=CC([N+]([O-])=O)=CC=2)=[O:40])[CH:22]=[CH:23][CH:24]=1.C1COCC1.CCOCC>P([O-])([O-])([O-])=O.[Pd]>[NH2:18][C:19]1[CH:20]=[N+:21]([CH2:25][CH2:26][S:27][C:28]2[CH2:34][C@H:33]3[N:30]([C:31](=[O:38])[C@@H:32]3[C@H:35]([OH:37])[CH3:36])[C:29]=2[C:39]([O-:41])=[O:40])[CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC[n+]3cccc(N)c3)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SCC[n+]3cccc(N)c3)C[C@H]12
Reaction time: 1 h
Yield: 128.8 %

Procedure:
To a mixture of p-nitrobenzyl (5R, 6S)-3(2-(3-aminopyridinio)ethyl thio)-6-(1-(R)-hydroxyethyl)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (0.730 g, 1.0 mmol) and 10% palladium-on-charcoal (0.7 g) in 25 mL of a phosphate buffer (0.05 m, pH 7.4) was added 8 mL of THF and 20 mL of ether. This mixture was then hydrogenated (Parr) at 40 psi for 1 h. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with H2O and ether. The aqueous phase was separated, washed with ether (2x) and then residual volatiles were removed in vacuo. The aqueous solution was immediately applied to a C18 reverse-phase column which was eluted with H2O. Lyophilization of the relevant fractions afforded 0.45 g of an off-white solid. This material was repurified by reverse-phase hplc to give the desired product (0.123 g, 35%) as an ivory-colored solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:10][CH:9]2[C:11](=O)[CH:6]([C@H:7]([CH3:14])[C@H:8]2[CH3:13])[CH2:5]1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>O1CCCC1>[CH3:3][N:4]1[CH2:10][CH:9]2[C:11](=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]([C@H:7]([CH3:14])[C@H:8]2[CH3:13])[CH2:5]1
Reactant: C[C@H]1C2CN(C)CC(C2=O)[C@@H]1C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C2CN(C)CC1[C@H](C)[C@H]2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4.35 g of triethyl phosphonoacetate in tetrahydrofuran (50 ml) was added 0.85 g of sodium hydride (oily: 60-72%) under ice-cooling and the resulting mixture was stirred at 0° C. for 10 minutes. Then a solution of 2.7 g of the crude (6R*,7R*)-3,6,7-trimethyl-3-azabicyclo[3.2.1]octan-8-one in tetrahydrofuran (20 ml) was added thereto and the reaction mixture was heated under reflux for 1 hour. After adding ethyl acetate, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.6 g of the title compound as a pale yellow oily substance.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)[N:37]1[CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45].NN>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:37][CH2:42][CH2:43][S:44]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:46])=[O:45]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=C1CCC(=O)N1CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol) in DMF (3 mL) was added diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 2-(2,5-dioxo-1-pyrrolidinyl)ethanesulfonyl chloride (53 mg, 0.168 mmol). After the reaction mixture was stirred at room temperature overnight, hydrazine (4 eq) was added. The reaction mixture was stirred for 4 hrs. The solution was filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (10 mg, 17%)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][C:10]2[CH:14]=[C:13](Br)[S:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)C=C.[Na+].[I-:20].CNCCNC>O1CCOCC1.[Cu]I>[I:20][C:13]1[S:12][C:11]([CH3:16])=[C:10]([CH2:9][C:8]2[CH:17]=[CH:18][C:5]([O:4][CH3:1])=[CH:6][CH:7]=2)[CH:14]=1
Reactant: C=CCOc1ccc(Cc2cc(Br)sc2C)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cc2cc(I)sc2C)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of bromide 13 (906 mg, 2.80 mmol) in 1.4-dioxane (10 mL) were added NaI (841 mg, 5.61 mmol), CuI (54 mg, 0.28 mmol) and N1,N2-dimethylethane-1,2-diamine (0.06 mL, 0.56 mmol) at room temperature. The reaction mixture was evacuated and backfilled with nitrogen. The mixture was stirred 120° C. for 18 hours. The mixture was cooled to room temperature and filtered off through celite. The filtrate was extracted with EtOAc/H2O (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 14 was dried under high vacuum and used without further purification (846 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.Br[C:13]1[S:17][C:16]([C:18]2[N:22]3[N:23]=[C:24]([CH3:32])[CH:25]=[C:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:21]3=[N:20][C:19]=2[CH3:33])=[C:15]([CH3:34])[CH:14]=1>[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:28]([CH:27]([C:26]1[C:21]2[N:22]([C:18]([C:16]3[S:17][C:13]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[CH:14][C:15]=3[CH3:34])=[C:19]([CH3:33])[N:20]=2)[N:23]=[C:24]([CH3:32])[CH:25]=1)[CH2:30][CH3:31])[CH3:29]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cn1cccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccnn4C)cc3C)c(C)nc12
Yield: 87.3 %

Procedure:
Using a procedure similar to Example 25, 1-methylpyrazole (0.17 g, 2.04 mmol), 1.56 M n-Bu-Li (1.34 mL, 2.09 mmol), ZnCl2 (4.3 mL, 2.14 mmol), 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.35 g, 0.89 mmol, 88%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.28-3.38 (m, 1H), 4.05 (s, 3H), 6.42 (d, J=1.8 Hz, 1H), 6.68 (s, 1H), 7.08 (s, 1H), 7.46 (d, J=1.8 Hz, 1H). LC/MS (m/z): calcd. for C22H27N5S (M+H)+: 394.7; found: 394.2.
Reaction SMILES: C(O[C@H]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[C:21]([CH:27]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][CH:30]=3)[OH:28])[CH:20]=2)[O:7][C@@H]1COC(=O)C)(=O)C.[CH3:42][CH2:43][O:44][C:45]([CH3:47])=[O:46]>C1(C)C=CC=CC=1>[C:45]([O:44][C@H:43]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[CH2:25][O:28][CH:27]3[C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH3:36])=[CH:33][CH:34]=2)[O:7][C@@H:42]1[CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:46])[CH3:47]
Reactant: CCOC(C)=O
Reactant: CCc1ccc(C(O)c2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2CO)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(C2OCc3ccc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc32)cc1
Temperature: 90 °C
Yield: 79 %

Procedure:
Step 5) To a solution of compound 150 (500 mg, 0.87 mmol) in toluene (10.0 mL) was added p-TsCl (183 mg, 0.96 mmol) and the reaction mixture was heated to 90° C. for 12 h. The resulting mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide (2R,3R,4R,5S,6S)-2-(Acetoxymethyl)-6-(3-(4-ethylphenyl)-1,3-dihydroisobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (151, 380 mg, 79%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[Li]C(C)(C)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](OCC)=[O:30])=[N:27][CH:28]=1.O>CCOCC.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:30])=[N:27][CH:28]=1
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(Cl)cn1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cccc(C(=O)c2ccc(Cl)cn2)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 57.4 %

Procedure:
To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (548 mg, 2.454 mmol) in ether (6 mL) under N2 was added t-BuLi (3.2 mL, 5.44 mmol). After stirring for 2.5 h, the reaction mixture was cooled to −78° C. To the reaction mixture was added a solution of ethyl 5-chloropicolinate (564.5 mg, 3.04 mmol) in ether (12 mL) dropwise via cannula over 5 min. The reaction mixture was stirred for 60 min, and then warmed to room temperature. After 1.5 h, to the reaction mixture was added H2O with vigorous stirring. The reaction mixture was diluted with EtOAc, and the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1 H, dd, J=2.3, 0.6 Hz), 8.08 (1 H, dd, J=8.4, 0.7 Hz), 7.80 (1 H, dd, J=8.4, 2.4Hz), 7.16-7.25 (2 H, m), 7.06 (1 H, dd, J=7.5, 2.2Hz), 6.90 (1 H, s), 3.92 (3 H, s), 1.28 (9 H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.[CH3:18][NH:19][NH2:20]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:19]([CH3:18])[N:20]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Reactant: CNN
Solvent: CCO
Product: CN1N=C(c2ccccc2)CC1c1cccc(O)c1
Yield: 96.9 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stirrer and reflux condensor was charged 1.0 g (0.0045 moles) of 3-hydroxychalcone, and 25 mls of absolute ethanol. To this solution was then added 0.21 g (0.0045 moles) of methyl hydrazine in one portion. The reaction was then heated to reflux for two hours, then cooled. The solvent was removed under reduced pressure to afford 1.1 g of 5-(3-hydroxyphenyl)-1-methyl-3-phenyl-2-pyrazoline as a thick brown oil. 97% yield.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(NC(C)C)(C)C.Br[CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25].O>C(#N)C>[CH2:13]([O:12][C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:23][C:24]([N:26]3[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]3[C:32]#[N:33])=[O:25])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)=[O:11])[CH3:14]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Solvent: CC#N
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (92.0 mg) was dissolved in acetonitrile (2 mL) and diisopropylamine (100 μL) was added to the solution. While the mixture was chilled in an ice bath, (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (100 mg) in acetonitrile (1 mL) was added dropwise. The mixture was stirred for 1.5 hours while chilled in the ice bath. Subsequently, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:ethyl acetate:methanol=5:1) to give (2S,4S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (132 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6]N(C)C)=[C:4]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:22]C(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][Cl:22])=[C:4]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc(CSc2cc(Cl)ccc2CN(C)C)cc1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CSc2cc(Cl)ccc2CCl)cc1
Temperature: 2.5 °C
Yield: 97.8 %

Procedure:
A solution of 4-chloro-2-(4-methoxybenzylthio)-N,N-dimethylbenzylamine (D19) (2.49 g, 7.7 mmol) in dry toluene (80 ml) was cooled in ice whilst ethyl chloroformate (0.9 ml, 9.4 mmol) was added dropwise. A solid slowly separated, and after 1 h at 0-5° C. the mixture was heated under reflux for 2 h. The solvent was removed in vacuo, then the residue was repeatedly dissolved in toluene and evaporated to dryness (3 times) to give the title compound as a light brown oil (2.36 g, 98%).
Reaction SMILES: [CH3:1][S:2]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][NH:10][CH3:11])=[O:3].Cl[C:16]1[NH:17][C:18]2[C:23]([C:24](=[O:26])[N:25]=1)=[C:22]([CH3:27])[C:21]([O:28][CH3:29])=[C:20]([O:30][CH3:31])[CH:19]=2.CCN(CC)CC.O>CS(C)=O>[CH3:1][S:2]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][N:10]([CH3:11])[C:16]1[NH:17][C:18]2[C:23]([C:24](=[O:26])[N:25]=1)=[C:22]([CH3:27])[C:21]([O:28][CH3:29])=[C:20]([O:30][CH3:31])[CH:19]=2)=[O:3]
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(C)c1OC
Reactant: CNCc1cccc(OCS(C)=O)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2[nH]c(N(C)Cc3cccc(OCS(C)=O)c3)nc(=O)c2c(C)c1OC
Temperature: 120 °C

Procedure:
Compound from step 4 (213 mg, 1.00 mmol) and 2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (254 mg, 1.00 mmol) were dissolved in dry DMSO. Et3N (0.14 mL, 1.00 mmol) was added, and the mixture was heated to 120° C. overnight. Upon cooling, the mixture was poured into water and extracted with diethyl ether. The ethereal extracts were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from MeOH to give 54 mg (12.53%) of the above Example F-2 as a white crystalline powder. mp 191.0–193.5° C.; 1H NMR (DMSO-d6, 2.49) δ 2.59 (s, 3 H), 2.60 (s, 3 H), 3.03 (s, 3 H), 3.62 (s, 3 H), 3.84 (s, 3 H), 4.79 (s, 2 H), 5.02 (d, 1 H, J=10.6), 5.22 (d, 1 H, J=10.6), 6.64 (s, 1 H), 6.90 (d, 1 H, J=7.6), 7.01 (m, 2 H), 7.30 (t, 1 H, J=7.9); 13C NMR (DMSO-d6, 39.50) δ 13.90, 34.66, 35.59, 51.90, 55.93, 60.23, 84.92, 104.81, 108.46, 114.18, 115.02, 121.22, 130.13, 131.94, 140.10, 142.90, 150.63, 150.97, 157.71, 157.97, 163.67; MS (ES+) m/z 432 (M+H); Anal. (C21H25N3O5S)C: calcd, 58.45; found, 58.32; H: calcd, 5.84; found, 5.74; N: calcd, 9.74; found, 9.77.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11].[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([O:9][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11]
Reactant: CCCCOC(=O)N1C[C@@H](O)C[C@H]1C(=O)OC
Reactant: Oc1cccc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOC(=O)N1C[C@H](Oc2cccc(Cl)c2)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a mixture of N-α-butoxycarbonyl-cis-4-hydroxy-L-proline methylester 123 mg (0.50 mmol), 3-chlorophenol 0.058 ml (0.55 mmol), triphenylphosphine 184 mg (0.70 mmol) and tetrahydrofuran 2 ml was added diisopropyl azodicarboxylate 0.150 ml (0.75 mmol) dropwise under ice-cooling and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and the residue was purified by a column chromatography on silica gel (eluted with a mixed solvent of ethyl acetate and hexane) to give 155 mg (0.44 mmol) of the title compound (yield: 87%).
Reaction SMILES: C(N(N=O)[C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH:11]1[CH2:13][CH2:12]1)C1C=CC=CC=1.[OH2:35].[OH-].[Li+].OO.Cl>O1CCCC1.O.C(O)(=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:15]2[N:14]([CH:10]([CH:11]3[CH2:13][CH2:12]3)[C:9]([OH:32])=[O:35])[C:18]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=3[N:16]=2)=[CH:26][CH:27]=1
Reactant: O=NN(Cc1ccccc1)C(=O)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 56 %

Procedure:
To a ice-cold suspension of 10.15 g (21.11 mmol) N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-acetamide in 60 ml tetrahydrofuran and 15 ml water were added dropwise over 30 min. a solution of 8.86 g (211 mmol) lithium hydroxide monohydrate in 43.1 ml (422 mmol) hydrogen peroxide 30% solution and 30 ml water. After stirring for 2.25 h at room temperature the pH was adjusted to 3 using 70 ml acetic acid and 25% aqueous hydrochloric acid. The resulting light yellow solution was extracted three times with ethyl acetate. The organic layers were washed with water, aqueous saturated sodium bicarbonate solution and brine. After drying over magnesium sulfate and filtration, the solution was evaporated until a suspension formed. This suspension was filtered and washed with ethyl acetate to give the compound as a white solid (56%). MS (Turbo Spray): m/z=363.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:6]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:8](OC)[O:9]C)[CH3:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(=O)CC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:6]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7][CH:8]=[O:9])[CH3:5]
Reactant: COC(=O)[C@H](C)N(CC(OC)OC)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Yield: 108.8 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2,2-dimethoxy-ethyl)-amino]-propionic acid methyl ester (26.0 g, 80.0 mmol) and pyridinium toluene-4-sulfonate (10.0 g, 40.0 mmol) in 2-butanone (260 mL) and water (8.6 mL, 0.48 mol) was heated under reflux for 16 h, then the solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (24.3 g), which was directly used in the next step. Yellow oil, MS (ISP)=348.3 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=3)[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][N:17]=1.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.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>[CH3:30][N:28]1[CH:29]=[C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:13]3[C:12]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:17][CH:16]=[CH:15][N:14]=3)[CH2:23][CH2:22]2)[C:26]([CH3:31])=[N:27]1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccccc2F)CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
Add 2-fluorobenzeneboronic acid (215 mg, 1.5 mmol) to a nitrogen purged solution of 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (200 mg, 0.65 mmol) in dry N,N-dimethylacetamide (4 mL), deoxygenated water (2 mL), potassium carbonate (215 mg, 1.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0035 mmol) and stir at 110° C. for 16 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3×20 mL). Concentrate the combined DCM extracts and purify by reverse phase HPLC to give the title compound (0.130 g, 54%). MS (ES): m/z=367 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.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]>[C:13]([C@@:10]1([CH:15]2[CH2:17][CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[CH:24]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(N)cn2)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Temperature: 90 °C
Reaction time: 10 h
Yield: 58.4 %

Procedure:
To a solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (300 mg) obtained in Step E of Example 103, tert-butyl 3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate (300 mg) obtained in Step B of Example 131, cesium carbonate (740 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg) in tetrahydrofuran (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (105 mg), and the mixture was stirred at 90° C. for 10 hr under argon atmosphere. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (310 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([CH2:10][S:11][C:12](=N)N)[NH:7][C:8]=1[CH3:9])#[N:2].Cl.ClC[C:32]1[CH:33]=[NH+:34][CH:35]=[CH:36][CH:37]=1.[Cl-].[OH-].[K+]>C1C=CC=CC=1>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:12][S:11][CH2:10][C:6]2[NH:7][C:8]([CH3:9])=[C:3]([C:1]#[N:2])[CH:4]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:5]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:33]=1
Reactant: ClCc1ccc[nH+]c1
Reactant: CCOC(=O)C1=C(CSC(=N)N)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(CSCc2cccnc2)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (-)-S-[(5-cyano-3-carboethoxy-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridin-2-yl)methyl]isothiourea (mg 500), 3-chloromethylpyridinium hydrochloride (mg 190), benzylthriethylammonium chloride (BTEAC mg 80), KOH (4M, ml 2) and benzene (ml 5) is stirred at room temperature for 15 minutes to separate a precipitate that is filtered and triturated with diethyl ether to give mg 450 of (-)-2-(3-pyridinylmethylthio)methyl-5-cyano-3-carboethoxy-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine.