Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1)[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(#N)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([Cl:20])[CH:22]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2ccccc2N)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ccccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of 0.500 g (1.91 mmol) of [1-(2-amino-phenyl)-piperidin-4-yl]-acetic acid ethyl ester in acetonitrile (100 mL) is added 0.25 mL (1.9 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to provide 0.34 g (44%) of {1-[2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:29][O:30][C:31](=[O:57])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]#[CH:56])=[CH:51][CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C.N#N>CN(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.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:56]#[C:55][C:52]3[CH:53]=[CH:54][C:49]([C:46]4[NH:45][C:44]([CH:40]5[CH2:41][CH2:42][CH2:43][N:39]5[C:37](=[O:38])[CH:33]([NH:32][C:31]([O:30][CH3:29])=[O:57])[CH:34]([CH3:36])[CH3:35])=[N:48][CH:47]=4)=[CH:50][CH:51]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 47.4 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (947 mg, 2.11 mmol), (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.00 g, 2.53 mmol), and triethylamine (882 μl, 6.33 mmol) in DMF (13 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (244 mg, 0.21 mmol) and CuI (40 mg, 0.21 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (0-20% MeOH-EtOAc gradient) then reverse phase preparative HPLC (10-85% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (600 mg, 1.00 mmol, 47% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.84 (s, 2H), 7.75 (d, 4H), (7.56 (s, 2H), 7.47 (d, 4H), 7.28 (d, 2H), 5.06 (m, 2H), 4.06-4.04 (m, 2H), 3.80 (m, 4H), 3.54 (s, 6H), 2.14 (m, 4H) 2.00-1.90 (m, 6H), 0.89 (d, 6H), 0.84 (d, 6H). LCMS-ESI+: calc'd for C42H5N8O6: 763.4 (M+H+). Found: 763.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:10][C:9]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:17]([CH3:16])[C@H:18]3[CH2:37][N:22]4[C:23]5[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]4[CH2:20][CH2:19]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:15])[CH2:10][C:9]2([CH3:11])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC1(C)CC1(C(=O)O)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1(c2ccc(F)cc2)CC1(C)C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method B) 1-(4-fluorophenyl)-2,2-dimethylcyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 449.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:5][C:4]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[NH:52][C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44]2)=[CH:39][C:38]=1[O:54][CH3:55]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:55][O:54][C:38]1[CH:39]=[C:40]([CH:43]2[NH:52][C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44]2)[CH:41]=[CH:42][C:37]=1[O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:23][C:4]1[CH:5]=[C:6](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(/C=C\c2cc(OC)c(OC)c(OC)c2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 83.4 %

Procedure:
(Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (38a) (316.35 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (39d) (546 mg, 80% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([N+:28]([O-])=O)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[C].[Pd]>[NH2:28][C:17]1[CH:16]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:31])[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a solution mixture of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate (57 mg) in ethyl acetate (2.5 mL) and methanol (2.5 mL), 10% palladium-carbon (11 mg) was added. The resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 48 mg of tert-butyl 2-amino-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: NC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(C(N)=O)cn3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 6-bromonicotinamide (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The mixture was filtered, the obtained precipitate was washed with water and EtOAc and dried under vacuum to afford the title compound (85 mg). 1H NMR δ ppm 9.14 (d, 1 H) 8.42 (dd, 1 H) 7.97-8.25 (m, 2 H) 7.63-7.80 (m, 2 H) 7.58 (d, 1 H) 7.22 (d, 1 H) 6.98 (dd, 1H) 3.81 (s, 3 H); MS m/z 269 (M+H).
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[O-:9]P(OP([O-])([O-])=O)(=O)[O-]>>[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:9])#[N:7]
Reactant: N#CCCCCC#N
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: N#CCCCCC(N)=O
Temperature: 30 °C
Reaction time: 4 h

Procedure:
In a 20 mL glass vial, 50 mg wet cell paste of 20-5-SBN-1b (ATCC 55735) was resuspended in 1 mL of 50 mM pyrophosphate buffer, pH 7.5. Adiponitrile was added to a final concentration of 400 mM and the reaction mixture was shaken at 200 rpm at 30° C. for 4 h on a rotary shaker. Cells were removed by centrifugation and the recovered aqueous solution was diluted (1:20 with 10 mM 1,1-diethyl urea internal standard in acetonitrile) and analyzed by gas chromatography. Of the ADN substrate, 41% of the original material remained and 50% had been converted to the only observed product, 5-cyanopentanamide.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Nc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Nc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 0.9 g of 4-(4-acetamidophenylamino)-3-furfurylamino-5-sulfamoylbenzoic acid and 9 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen, cooled, filtered and the filtrate acidified with glacial acetic acid to pH= 4-5. The precipitate formed is filtered off, washed with water and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-furfurylamino-5-sulfamoylbenzoic acid melting at 232° with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2-methyl-phenol (200 mg, 0.58 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (283 mg, 0.87 mmol, 1.5 eq). The reaction mixture was stirred for 1 h at room temperature, then ethyl 2-bromoacetate (117 mg, 0.70 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 1 h then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography to give the title compound as an oil (200 mg, 80%).
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[N:40]=1)[C:35]([OH:37])=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[N:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2-chloro-6-methoxy-isonicotinic acid (CAS RN 15855-06-8). Colorless solid (21%). MS (ESI): m/z=402.10 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][NH:12]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[CH:3]=1.Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:12]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]=[C:14]([OH:16])[CH2:15]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[CH:3]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 87.3 %

Procedure:
1.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-5-oxopyrazolidine-3-carboxamide was dissolved in 10 ml of N,N-dimethylformamide, 460 mg of 2,3-dichloropyridine was added and then 350 mg of sodium hydride was added, followed by stirring for about 7 hours at about 70° C. in nitrogen atmosphere, and the reaction liquid was stood to cool. Water was added to the reaction liquid and stirred, followed by extraction with ethyl acetate, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=9/1) to obtain 1.15 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1)#[N:14].[Cl-].[Na+]>>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: N#Cc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 89.5 %

Procedure:
Reaction was carried out in the same manner as in a Reference Example 2-(d) except for using 4-fluorobenzenesulfonyl chloride (1.18 g, 6.06 mmol) in place of 3-pyridylsulfonyl chloride, and using 4-cyanobenzylamine hydrochloride (1.00 g, 5.93 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue dissolved in a small amount of methylene chloride was added hexane, and a precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure at 60° C. to afford the title compound (1.54 g) as a slightly brown solid. (Yield: 89%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]3=[N:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:27]=1[O:28][CH3:29]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.85 g, 2.5 mmol) in CH3CN (5 mL) was added 3,4,5-trimethoxyphenylboronic acid (525 mg, 2.5 mmol), bis(triphenylphosphine)-palladium(II) dichloride (250 mg, 0.35 mmol), and 1 M Na2CO3 (5 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 80° C. for 2 hr. The reaction mixture was partitioned between EtOAc and H2O, and the organic layer was separated, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 3:1 EtOAc:Hexanes to yield the title compound (640 mg, 60%). HPLC retention time: 2.51 minutes; MS ESI (m/z): 431.4 (M+1)+, calc. 430.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][CH2:13][CH:12]3[C:7]([CH3:17])([CH2:8][CH2:9][CH2:10][C:11]3([CH3:16])[CH3:15])[CH:6]1[CH2:5][CH2:4][O:3]2.C[C@@]12[C@H:28]3CC[O:31][C@:27]3(C)[CH2:26][CH2:25][C@H]1C(C)(C)CCC2>>[CH3:17][C@@:7]12[C@@H:6]([CH2:5][CH2:4][C@@:27]([OH:31])([CH:26]=[CH2:25])[CH3:28])[C@@:2]([OH:3])([CH3:1])[CH2:14][CH2:13][C@H:12]1[C:11]([CH3:15])([CH3:16])[CH2:10][CH2:9][CH2:8]2
Reactant: CC1(C)CCCC2(C)C1CCC1(C)OCCC12
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CCO[C@]3(C)CC[C@@H]12
Product: C=C[C@](C)(O)CC[C@@H]1[C@@]2(C)CCCC(C)(C)[C@@H]2CC[C@@]1(C)O

Procedure:
Dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan (occasionally referred to as “Ambroxan (trademark)”) is an aroma chemical with satisfactorily long-lasting properties that is produced via chemical conversion mainly from sclareol extracted from Salvia sclarea. FIG. 1 shows a process for producing dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan from sclareol. As shown in FIG. 1, decahydro-2-hydroxy-2,5,5,8a-tetramethylnaphthaleneethanol and sclareolide (decahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan-2(1H)-one) are known as dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan intermediates. Also, a cyclic ether compound (8α,13-oxido-12,13-dehydro-15,16-dinorlabdane) is known as a dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan intermediate, although it is not shown in FIG. 1.
Reaction SMILES: C(SCC(O)=O)CC#C.C(C1(CO)COC1)(C)(C)C.[C:20]([C:24]12[CH2:31][O:30][C:27]([CH:32]([S:34][CH2:35][CH2:36][C:37]#[CH:38])C)([O:28][CH2:29]1)[O:26][CH2:25]2)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]12[CH2:25][O:26][C:27]([CH2:32][S:34][CH2:35][CH2:36][C:37]#[CH:38])([O:28][CH2:29]1)[O:30][CH2:31]2)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#CCCSC(C)C12OCC(C(C)(C)C)(CO1)CO2
Agent: C#CCCSCC(=O)O
Agent: CC(C)(C)C1(CO)COC1
Product: C#CCCSCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(but-3-ynylthiomethyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynylthio)acetic acid and 3-t-butyl-3-hydroxymethyloxetane using the methodology described in Example I. A small amount of 4-t-butyl-1-[1-(but-3-yn-1-ylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was also present.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](SC)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[N:16]1)(=O)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[NH2:30].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[N:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: OCCOCCn1ncc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 16.5 h
Yield: 30.6 %

Procedure:
A mixture of 2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl benzoate (200 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 140° C. for 16.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (30 mL), and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 11.5 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (45 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) and recrystallized from ethanol-ethyl acetate to give the title compound (78 mg).
Reaction SMILES: C([N:8]([C:25](=[O:47])[C@H:26]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])C1C=CC=CC=1>CO.[Pd]>[C:31]([O:30][C:28]([NH:27][C@H:26]([C:25]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:47])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc1ccccc1)[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.42 h
Yield: 95.8 %

Procedure:
A slurry of Pd—C (10% wt, 117 mg) in dry MeOH (2 mL) was added to a solution of benzyl ester 50 (1.17 g, 1.76 mmol) in dry MeOH (8.8 mL). The reaction vessel was flushed with hydrogen gas and stirred with a hydrogen balloon for 2 h 25 min. The reaction mixture was then filtered over celite to remove the catalyst. After rinsing the catalyst with small portions of MeOH, the combined filtrates were concentrated to dryness, providing acid 51 as a white solid (969 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.48 (m, 36H), 1.52-1.60 (m, 2H), 1.63-1.72 (m, 1H), 2.84-2.89 (m, 4H), 3.85-3.91 (m, 1H), 4.09-4.15 (m, 1H), 6.75 (bs, 2H), 6.80 (d, J=8.1 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H).