Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C>[N:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH:24][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:27]=1
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Yield: 68.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinyimethoxy)pyridine from Example 69a (1.18 g, 3 mmol), 4-ethenylpyridine (0.39 mL, 3.6 mmol), Pd(OAc)4 (62.5 mg), tris(o-tolyl)phosphine (312.5 mg), and triethylamine (6.25 mL) in acetonitrile (15 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (852 mg, 69% yield). MS (CI/NH3) m/z 416 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.48 (s, 9H), 1.92 (m, 2H), 2.02 (m, 2H), 3.42 (m, 2H), 3.97 (m, 1H), 4.13 (m, 2H), 7.43 (m, 2H), 7.56 (m, 1H), 8.05 (m, 1H), 8.62 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:7][C:6]=2[CH:24]=1.[Li]CCCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C.O>C1COCC1>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:8]2[S:7][C:6]3[CH:5]=[C:4]([B:34]4[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]4)[CH:3]=[CH:2][C:24]=3[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2sc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2-c2ccc(C)cc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, in a 500 ml round-bottomed flask, 5 g (12.75 mmol) of 6-bromo-2,3-di-p-tolyl-benzo[b]thiophene was dissolved in 150 ml of THF, and 6.12 ml (15.31 mmol) of n-BuLi 2.5M (hexane) was added thereto at −78° C. The resulting solution was stirred at −78° C. for 2 hours. Then 3.4 ml (16.58 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added thereto and stirred at room temperature for one hour. The reaction was ended by adding 50 ml of water. Then an organic layer was extracted with brine and methylene chloride. The extracted organic layer was dried with anhydride magnesium sulfate, filtered and removed of solvent. The organic layer was purified through chromatography (silica, hexane), and 4.8 g (yield 79%) of white solid product was obtained by increasing the polarity of the developing solvent.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[Br:7][C:8]1[C:9]([Cl:16])=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=1>O.C([O-])([O-])=O.[Na+].[Na+]>[Br:7][C:8]1[C:9]([Cl:16])=[CH:10][C:11]([C:14]([OH:1])=[O:15])=[N:12][CH:13]=1
Reactant: OCc1cc(Cl)c(Br)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)c(Br)cn1
Reaction time: 2 h

Procedure:
KMnO4 (174 mg, 1.1 mmol) in H2O was added dropwise to a solution of (5-bromo-4-chloro-2-pyridinyl)methanol (187 mg, 0.846 mmol) in 10% Na2CO3 (1 mL). After 2 h, the solution was filtered through Celite®, adjusted to pH ˜4 and the resulting precipitate was filtered then azeotropically dried with toluene affording the title compound (135 mg, 68%) as a white powder: LCMS (ES) m/z=237 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][CH:30]=2)[CH:23]=[C:22]([C:34](O)=[O:35])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[NH2:54][CH:55]([CH3:58])[CH2:56][OH:57]>C(Cl)Cl>[OH:57][CH2:56][CH:55]([NH:54][C:34]([C:22]1[CH:21]=[C:20]([C:14]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[F:12])[CH:25]=[C:24]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][CH:30]=2)[CH:23]=1)=[O:35])[CH3:58]
Reactant: CC(N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3C(C)C)c2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NC(C)CO)cc(-c3ccnn3C(C)C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (77.4 mg, 0.229 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH2Cl2 (5 mL) at 0° C. After the reaction stirred at the same temperature for 1 hour, 2-amino-propan-1-ol (54 mg, 0.72 mmol) was added. The mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide as white solid (54 mg, 46%). MS (N+H)=396.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Cl)[N:3]=1.[CH2:14]([NH2:23])[C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH2:12][N:23]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=3)[C:6](=[O:8])[C:5]2=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3nc(Cl)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of crude methyl 6-chloro-2-(chloromethyl)nicotinate (10 g, 45.4 mmol) in THF (150 mL) was added PMBNH2 (15.5 g, 113.5 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 16 hours before it was concentrated under reduced pressure to give a crude product. After washing with MTBE (100 mL×3), the title compound was obtained (8.8 g, yield 67%) as a white solid. MS: 288.8 (M+H+, 10).
Reaction SMILES: C(O)C.[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27]([C:36]([O:38]C)=[O:37])=[CH:26][C:25]4=[O:40])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27]([C:36]([OH:38])=[O:37])=[CH:26][C:25]4=[O:40])[CH2:20][CH2:21]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(C(=O)O)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To 1 mL of an ethanol solution containing 0.12 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 0.5 mL of 5 mol/L aqueous sodium hydroxide solution was added and stirred for 1 hour. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 6 mol/L hydrochloric acid, and the resulting solid was filtered to afford 40 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: [Na+].[OH:2]C1C=CC(S([O-])(=O)=O)=CC=1[N+]([O-])=O.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1(=O)N(NCCCCCC(O)=O)C(=O)C=C1>CN(C)C=O>[C:23]([NH:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1O
Agent: O=C(O)CCCCCNN1C(=O)C=CC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (2.24 g) of 4-hydroxy-3-nitrobenzene sulfonic acid sodium salt (HNSA) was mixed together with one molar equivalent (2.06 g) of dicyclohexylcarbodiimide and one molar equivalent (2.10 g) of N-maleimido-6-aminocaproic acid in 25 ml of dimethylformamide (DMF) at room temperature overnight. A white precipitate of dicyclohexylurea was formed. The precipitate was filtered and 300 ml diethyl ether was added to the mother liquor. After about 10 minutes to 4 hours a gummy solid precipitated from the mother liquor. This solid was found to contain 58% of active HNSA ester and 42% of free HNSA.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]([CH3:26])([CH3:25])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][C:5]([CH3:25])([O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH3:26])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (32 mg, 89.5 μmol) was combined with DCM (1.0 mL) to give a colorless solution. To this solution was added triethylamine (25.0 μL, 179 μmol) and acetyl chloride (7.00 μL, 98.5 μmol) and the reaction mixture was stirred 18 hours at room temperature. After concentrating the mixture in vacuo the residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title compound (19 mg, 53%) as white foam; LC-MS (UV peak area, ESI) 97%, 400.2348 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:21][C:22](=[O:24])[CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:21][C:22](=[O:24])[CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1N)(NC(C)=O)C(=O)OCC

Procedure:
A mixture of 1.0 eq. of 79 and 0.1 wt/wt eq. of 10% Pd on carbon in EtOH was hydrogenated at 10-60 psi of hydrogen for a time sufficient for reaction completion. The reaction mixture was filtered through Celite. The filtrate was concentrated by rotary evaporation. The crude material was dried under vacuum to give product 80.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=C(C=CCC(C2C=CC(C)=CC=2)(C)C)C=CC=1)C1C=CC=CC=1.[H][H]>C([O-])(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([CH3:18])[CH3:19])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(C)(C)C=CCc2cccc(Oc3ccccc3)c2)cc1
Reactant: [H][H]
Agent: CC(=O)[O-]
Agent: Cc1ccc(C(C)(C)CC=Cc2cccc(Oc3ccccc3)c2)cc1
Product: Cc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 3 h

Procedure:
To 30 ml of ethyle acetate, 1.9 g of a mixture of 50% 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-2-pentene and 50% 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-pentene was added and dissolved, and thereto 0.4 g of 5% pd-C was added, and the mixture was stirred under a pressure of 20 kg/cm2G with hydrogen gas at room temperature. After three hours, pd-C was removed by filtration, and ethyl acetate was evaporated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=5[F:28])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(F)cc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,4-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.91 min; Mass spectrum (ESI+): m/z=491 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1>C(Cl)Cl.[Pd]>[C:25]([O:24][C:23](=[O:29])[NH:22][C@@H:19]1[CH2:20][CH2:21][N:17]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=3)[CH2:3][CH2:4]2)[CH2:18]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)s1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a Parr hydrogenation bottle was added 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone (0.50 g, 2.09 mmol) and tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.373 g, 2.0 mmol), dissolved in CH2Cl2 (20 mL), followed by the addition of 10% Pd/C (0.12 g). This mixture was hydrogenated at 35 psi for 24 hour. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo and chromatographed using MeOH/EtOAc/Et3N (1:9:0.1) to give 0.62 g of title compound in 76% yield. MS (EI) calcd: (M+1)+=409.2; found: 410.2.
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=O)[CH2:4][CH2:3]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([SH:28])[CH2:26][SH:27].O>C(O)(=O)C>[CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH:9]=[C:8]1[CH2:7][C:5]1([S:28][CH2:25][CH2:26][S:27]1)[CH2:4][CH2:3]2
Reactant: CC12CCC(=O)C=C1CCCC2=O
Reactant: SCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC12CCC3(CC1=CCCC2=O)SCCS3
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To a solution of Wieland-Miescher ketone (5.87 g, 33.0 mmol) in glacial acetic acid (40 mL) was added p-toluenesulfonic acid (2.94 g) followed by dropwise addition of 1,2-ethanedithiol over a 1 hour period. The reaction mixture was stirred at room temperature for another 4 hours, poured into 30 mL water, and stirred for 15 minutes. The white solid was filtered off, washed successively with water, diluted with NaHCO3 solution and water, and then dried to yield thioketal 239 (7.33 g, 87.3 %) as a white solid. 1H NMR (CDCl3) δ 1.50-2.70 (m, 10H), 3.20-3.40 (m, 4H), 5.67 (s, 1H); 13C NMR (CDCl3) 212.92, 141.23, 128.04, 64.81, 49.43, 40.11, 39.62, 37.92, 37.57, 30.81, 30.69, 24.73, 24.57.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]([F:20])=[C:8]([O:21][CH3:22])[N:7]=1)=[CH2:5])C.C(#N)C.C(=O)(O)[O-].[Na+].[F:31][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>O>[F:20][C:9]1[CH:10]=[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([C:4](=[O:5])[CH2:3][F:31])=[N:7][C:8]=1[O:21][CH3:22]
Reactant: C=C(OCC)c1nc(OC)c(F)cc1NC(=O)OC(C)(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(C(=O)CF)c(NC(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl [2-[1-(ethyloxy)ethenyl]-5-fluoro-6-(methyloxy)-3-pyridinyl]carbamate (6.72 g, 21.54 mmol), acetonitrile (70 ml), and saturated aqueous sodium bicarbonate solution (15 ml) was treated portionwise over 5 minutes at 0° C. under argon with [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™) (8.9 g, 25.05 mmol). After the addition the mixture was stirred at room temperature for 0.5 hour then treated with saturated aqueous sodium bicarbonate solution (50 ml), stirred for 10 minutes, then diluted with water (100 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed eluting with 0-50% dichloromethane in hexane affording the product as a white solid (3.72 g, 57%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2].[N+](=[CH2:20])=[N-]>O1CCOCC1.C(OCC)C>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:16][O:17][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)C(=NO)c1nccc(NC=O)n1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)C(=NOC)c1nccc(NC=O)n1

Procedure:
Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g.) was dissolved in dioxane (200 ml.) under heating and the resultant solution was cooled to ambient temperature in an ice bath, and then thereto was added a solution of diazomethane in diethyl ether with stirring until complete consumption of the starting materials. The reaction mixture was concentrated to give a brown oil, which was purified by column chromatography on silica gel (140 g.) using benzene as an developing solvent and a mixture of benzene and ethyl acetate (3:1) as an eluent to give a pale brown semisolid of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.4 g.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1.N1C=CC=CC=1>COCCOC>[CH:9]1([C:12]([NH:14][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:13])[CH2:11][CH2:10]1
Reactant: NC(=O)C1CC1
Reactant: O=C(Cl)CCCCBr
Solvent: c1ccncc1
Solvent: COCCOC
Product: O=C(CCCCBr)NC(=O)C1CC1
Yield: 40 %

Procedure:
A solution of 7.96 g. of 5-bromovaleric acid chloride, 3.40 g. of cyclopropanecarboxamide, 3.16 g. of pyridine, and 20 ml. of 1,2-dimethoxyethane was heated to reflux under nitrogen for 1.5 hours, then was concentrated by rotary evaporation. The resultant semi-solid was triturated with methylene chloride (2X). The combined methylene chloride layers were washed with saturated brine, were dried (anhydrous magnesium sulfate), were treated with activated charcoal, and were filtered. The filtrate was concentrated on a steam-bath with addition of hexane until crystallization started. Thus, 3.98 g. (40% yield) of white, crystalline N-cyclopropanecarbonyl-5-bromovaleramide was obtained melting at 114°-115°C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188d) (20 mg, 0.07 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (15 mg, 0.07 mmol) were dissolved in DMA (2 ml). WSC hydrochloride (40 mg, 0.21 mmol) and HOBt (10 mg, 0.07 mmol) were added, and the mixture was stirred at 70° C. for one hour and at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0, 9, 17%) to obtain 16 mg of the title compound as a glassy solid. mass spectrum (ESI): m/z 441 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:12])[C:10](=[O:11])[C:5]2=[C:4]([O:13][CH3:14])[C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Li]CCCC.CCCCCC.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37](OC)=[O:38].Cl>C1COCC1>[CH3:14][O:13][C:4]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([C:37]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][N:31]=2)=[O:38])[N:6]2[CH2:7][CH2:8][N:9]([CH3:12])[C:10](=[O:11])[C:5]=12
Reactant: COC(=O)c1cnccn1
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)CCN(C)C2=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(OC)c2n(c1C(=O)c1cnccn1)CCN(C)C2=O
Temperature: 25 °C

Procedure:
To a cold (−78° C.) solution of ethyl 6-bromo-8-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.5 g, 1.51 mmol; Example 7, steps 1 to 6, substituting benzyl bromide with iodomethane in step 5) in anhydrous THF (15 mL) under an atmosphere of dry nitrogen, a solution of n-BuLi in hexane (1.81 mL, 1.81 mmol, 1 M) was added. The resultant mixture was stirred at −78° C. for 15 minutes, and treated with methyl pyrazine-2-carboxylate (0.21 g, 1.51 mmol). The reaction mixture was allowed to warm up to room temperature, treated with dilute hydrochloric acid, and concentrated under vacuum. The residue was extracted with ethyl acetate. The organic extracts were combined, washed with aqueous sodium carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 0 to 10% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5]/[CH:6]=[C:7](/[C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([Cl:26])=[CH:20][CH:19]=1)\[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.O>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8](/[C:7](/[C:18]2[CH:19]=[CH:20][C:21]([Cl:26])=[C:22]([O:24][CH3:25])[N:23]=2)=[CH:6]\[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [C-]#N
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(/C(=C/CC#N)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.3 %

Procedure:
Sodium cyanide (137 mg) was added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (500 mg) in ethanol (10 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a 2 M sodium hydroxide solution and brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give the title compound as a yellow oil (230 mg, 53%).