Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(COC(=O)c2c(Cl)ncnc2Cl)cc1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(COC(=O)c2c(N)ncnc2Cl)cc1
Temperature: 0 °C
Yield: 119.4 %

Procedure:
4-Methoxybenzyl 4,6-dichloropyrimidine-5-carboxylate (732 m g, 1.97 mmol) was dissolved in dioxane (14 ml) and cooled in an ice bath. Ammonia (1.41 ml, 7N in MeOH, 9.87 mmol) was dropwise added and the mixture was stirred at 0° C. and then stirred at room temperature overnight. The solvent was removed to give 691 mg (94% yield) of the title compound, that was used in the next step without further purification. Purity 79%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Li]CCCC.CCCC(C)C.C(NC(C)C)(C)C.[I:27]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:27])[C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCC(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1cc(I)c(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
A solution of 2,5-dichloropyridine (10 g, 67.57 mmol) in THF (17 mL) was added dropwise to a stirred solution of n-BuLi in isohexane (33.8 mL, 67.57 mmol) and diisopropylamine (9.63 mL, 67.57 mmol) in THF (68.0 mL) cooled to −78° C., over a period of 1 hour under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 30 minutes and then a solution of I2 (17.49 g, 68.92 mmol) in THF (17.0 mL) was added dropwise. The resulting solution was stirred at −78° C. for 1 hour and then quenched with water (75 mL) and allowed to warm to room temperature. The mixture was extracted with Et2O (3×100 mL) and the combined organic layers were dried over MgSO4, and then evaporated. The residue was triturated with CH2Cl2 to give a solid which was dried under vacuum to afford 2,5-dichloro-4-iodopyridine (9.72 g, 53% yield). The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 50-100% CH2Cl2 in isohexane. Fractions containing product were combined and evaporated and the residue triturated with MeOH to leave a second crop of 2,5-dichloro-4-iodopyridine (5.74 g, 31% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 7.85 (1H, s), 8.34 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].[Na].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:15]([C:16]([OH:18])=[O:17])[CH:19]([CH3:21])[CH3:20])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)c(F)c1)C(=O)O

Procedure:
Following the procedure of Example 38, 3-fluoro-4-trifluoromethylaniline is reacted with the sodium salt of α-bromoisovaleric acid to yield N-(3-fluoro-4-trifluoromethylphenyl)valine, which is esterifed to yield the m-phenoxybenzyl ester of N-(3-fluoro-4-trifluoromethylphenyl)valine.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])[CH2:3][OH:4].[CH:25](OC)(OC)OC.CO.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:25][O:4][CH2:3][C:2]([CH3:1])=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CO
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: COCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Reaction time: 8 h

Procedure:
To a solution of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene-1-ol (1.6 g, 5 mmol), 1.06 g (10 mmol) of trimethyl orthoformate and 160 mg (5 mmol) of dry methanol in 5 ml of dry THF is added dropwise a solution of 40 μL of trifluoroacetic acid in 1 ml of dry THF over a 1 minute period at room temperature. After overnight standing, the reaction mixture is poured into cold aqueous 5% NaHCO3 and extracted with chloroform three times. The combined organic extract is washed with water, dried over Na2SO4 and evaporated in vacuo to give a residue, which is purified by HPLC (4% ether in hexane, silica gel column) to afford of 1-methoxy-2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene as an oil.
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[F:9][C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[O:36][CH3:37])=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([CH2:23][S:24]([CH3:27])(=[NH:26])=[O:25])[CH:20]=[C:19]([F:28])[CH:18]=2)=[N:14][CH:15]=1>N1C=CC=CC=1>[CH3:6][O:5][CH2:4][CH2:3][O:2][C:1](=[O:7])[N:26]=[S:24]([CH2:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:12]=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[O:36][CH3:37])[C:10]([F:9])=[CH:15][N:14]=2)[CH:18]=[C:19]([F:28])[CH:20]=1)([CH3:27])=[O:25]
Reactant: COCCOC(=O)Cl
Reactant: COc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CS(C)(=N)=O)c2)ncc1F
Solvent: c1ccncc1
Product: COCCOC(=O)N=S(C)(=O)Cc1cc(F)cc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methoxyethyl carbonochloridate (18 μL; 0.15 mmol; Sigma-Aldrich Corporation) was added dropwise to a stirred solution of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methyl-sulfonimidoyl)methyl]phenyl}pyrimidin-2-amine (Example 15; 50.0 mg; 0.12 mmol) in pyridine (1.1 mL) at 0° C. The mixture was stirred at RT for 24 hours before the batch was concentrated. Ethyl acetate and aqueous sodium chloride solution were added. The batch was extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[C:33]([O:45][CH3:46])[CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[O:56])=[C:33]([O:45][CH3:46])[CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(OC)c2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(OC)c2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.42 g) was dissolved in methylene chloride (12.6 ml), and a solution of m-chloroperbenzoic acid (133 mg) in methylene chloride (8.4 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 255) (0.18 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH2:14])[CH:10]=[C:11]([NH2:13])[CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[NH2:14][C:9]1[CH:10]=[C:11]([NH:13][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])[CH:12]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(N)cc(N2CCOCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc(NC(=O)C2CC2)cc(N2CCOCC2)c1

Procedure:
A solution of 5-morpholinobenzene-1,3-diamine (0.074 g, 0.383 mmol), triethylamine (0.080 mL, 0.574 mmol), cyclopropanecarbonyl chloride (0.035 mL, 0.383 mmol), and DCM (2 mL) was stirred at 23° C. for 3 h, then concd. The concentrate was partitioned between EtOAc and water, and the products were extracted twice with 25% 2-propanol in chloroform. The combined organics were dried over magnesium sulfate and concd, affording N-(3-amino-5-morpholinophenyl)cyclopropanecarboxamide as a brown amorphous solid. Mass Spectrum (ESI) m/e=262.2 (M+1).
Reaction SMILES: 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.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:75])[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C>[CH2:68]([O:67][C:66](=[O:75])[NH:65][CH2:64][CH2:63][NH:62][C:47](=[O:49])[CH2:46][C@@H:45]([NH:44][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
549.7 mg (1.446 mmol) of HATU and 339.7 mg (2.629 mmol) of N,N-diisopropylethylamine are added to a solution of 500 mg (1.31 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 333.5 mg (1.446 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.O>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (25.0 g) synthesized in Example 3 and heptylamine (10.0 g) were dissolved in dichloromethane (250 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (18.0 g) and hydroxybenzotriazole (HOBT) monohydrate (16.6 g) were successively added thereto, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (30.0 g) as a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: COc1ccc2c(-c3ccc(C(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetyl-phenylboronic acid to give 1-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 373(MH+).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[CH:44]1[C:52]2[C:51]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:50]=3[O:49][C:48]=2[CH:47]=[CH:46][C:45]=1[NH2:58]>>[CH:44]1[C:52]2[C:51]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:50]=3[O:49][C:48]=2[CH:47]=[CH:46][C:45]=1[NH:58][C:38]([C@@H:37]1[CH2:41][CH2:42][CH2:43][N:36]1[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:40]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 37.6 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-L-proline (0.29 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl (2S)-2-[(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)carbonyl]pyrrolidine-1-carboxylate (0.18 g). MS (ESI) m/z 399 ([M+H]+); MS (ESI) m/z 397.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:20][N+:17]([O-:19])=[O:18])=[CH:9][N:10]=1
Reactant: O=Cc1ccc(Oc2ccccc2F)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2F)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 6-(2-fluoro-phenoxy)-pyridine-3-carbaldehyde (210 mg, 0.97 mmol) described in Manufacturing Example 74-1-2 and acetic acid (3 mL) were added nitromethane (0.39 mL, 7.3 mmol) and ammonium acetate (220 mg, 2.9 mmol), which was stirred for 3 hours at 100° C. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and was concentrated under a reduced pressure. A mixture of dimethyl sulfoxide (3 mL) and acetic acid (0.2 mL) was added to the resulting residue, and sodium borohydride (58 mg, 1.5 mmol) was added to the reaction mixture at room temperature while cooling appropriately. The reaction mixture was stirred for 10 minutes. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (150 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:19][C:20]1([CH3:36])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[O:21]1>C1COCC1.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([B:22]3[O:23][C:24]([CH3:25])([CH3:26])[C:20]([CH3:36])([CH3:19])[O:21]3)=[CH:35][CH:34]=2)[CH:3]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Reactant: Cc1ccnc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.4 %

Procedure:
To a stirred solution of 4-methylpyridin-2-amine (7.86 mmol, 850 mg) in THF (50 mL) was added dropwise a solution of 1M LiHMDS in THF (8.0 mmol, 8 mL) at room temperature. After the reaction mixture turned dark green, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (9.6 mmol, 2.56 g) in dichloromethane (55 mL) was added dropwise. The mixture was stirred at room temperature for 2.5 h and was then concentrated. 3% aq. Citric acid solution (18 mL) was added and the mixture was extracted with dichloromethane (2×15 mL). The combined organic layer was washed with 3% aq. citric acid solution, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in THF (15 mL) and 6M NaOH solution (15 mL) was added. The mixture was stirred for 4 h. at room temperature. Ethyl acetate was added and the layers were separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: DCM/MeOH=98/2 to DCM/MeOH=95/5) to yield 1.1 g of N-(4-methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (40.7%).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCCCC)CCC.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[NH2:15][CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1([N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CC1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: CO
Solvent: C1CCOC1
Product: NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Yield: 38 %

Procedure:
The title compound (2.31 g; 38%) was prepared from 1-[bis(phenylmethyl)amino]cyclopentanecarbonitrile D32 (4.0 g; 13.8 mmol), and phenyllithium in di-n-butylether (8.4 ml of 1.8M solution; 15.2 mmol) in THF (80 ml), followed by reaction with sodium borohydride (1.57 g; 41.4 mmol) in methanol (80 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS), API+: Found 371 (MH+). C26H30N2 requires 370. Ret. time 2.62 min.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1>O.CC(C)=O>[S:1]([CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1)[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(CSC#N)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenyl-acetamido)penam-3carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with water and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C.
Reaction SMILES: [C:1]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)(=[O:5])[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.CCOCC.O>[C:1]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:36])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCn1c(SCc2nccc3ccsc23)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCC(=O)OCn1c(S(=O)Cc2nccc3ccsc23)nc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 318.0 mg (0.800 mmol) of 1-butyryloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-6) in 30 ml of CHCl3 was added 224.3 mg (1.04 mmol) of 80% m-CPBA at -10° to -15 ° C., and the mixture was stirred for 1 hr. To the solution were added 3 ml of saturated aqueous NaHCO3 and 0.6 ml of 10% aqueous sodium sulfite. After bringing back to room temperature, the solution was mixed with water and extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby brown viscous liquid was obtained. After silica gel column chromatography, the crystals were dispersed with ether, followed by filtration and washed with ether, whereby 169.8 mg (Yield : 51.3%) of the objective compound (Ic-12), 1-butyryloxymethyl-2-[(thieno[2, 3-c]pyridin7-yl)methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: [CH:1]1[C:2]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:3]=2[NH:4][C:5](=[O:10])[C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:23]O>>[CH:1]1[C:2]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:3]=2[NH:4][C:5](=[O:10])[C:6]=1[C:7]([O:9][CH3:23])=[O:8]
Reactant: O=C(O)c1cc2c([nH]c1=O)OCc1ccccc1-2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
Add 6.0 gm of 4,6-dihydro-3H[2]benzopyrano[3,4-b]pyridin-3-one-2-carboxylic acid to 100 ml of methanol. Dropwise, at 0° C., add 10 ml of thionyl chloride to the system. Heat the system at reflux for 6 hours. Remove the solvent by stripping. Isolate the title compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:15])/[CH:12]=[CH:13]\I>>[C:1]1([C:7]#[C:8]/[CH:13]=[CH:12]\[C:11]([O:10][CH3:9])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C\I
Reactant: C#Cc1ccccc1
Product: COC(=O)/C=C\C#Cc1ccccc1

Procedure:
The general procedure was used to convert phenylacetylene and (Z)-methyl-3-iodoacrylate to the title product. Purification by flash chromatography (15% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a light yellow oil (336 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.35 (m, 3H), 6.36 (d, J=11.39, 1H), 6.14 (d, J=11.41, 1H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.25, 132.16, 129.28, 128.42, 127.79, 123.22, 122.63, 101.45, 86.37, 51.55. Anal. Calc'd. for C12H10O2: C, 77.40; H, 5.41; Found C, 77.41; H, 5.35.