Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(Br)cc3)sc2C)cc1C
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)sc2C)cc1C
Temperature: 100 °C
Yield: 50 %

Procedure:
3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (100 mg, 0.200 mmol) is dissolved in toluene (1 mL), degassed, and filled with nitrogen three times. Palladium tetrakistriphenyl phosphine (10 mg, 0.010 mmol), 3-pyridylboronic acid (31 mg, 0.250 mmol), and sodium carbonate (100 uL of a 10M solution, 0.400 mmol) are added, and the degassing procedure is repeated. Ethanol (1 mL) is added to dissolve the boronic acid. The reaction is heated to 100° C. and monitored by HPLC. Upon complete consumption of starting material, the reaction is allowed to cool to room temperature and diluted with ethyl acetate. Celite is added and the mixture is filtered and rinsed with more ethyl acetate and water. The solution is further diluted with water and the two phases are separated. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester (47 mg, 0.100 mmol) is obtained after column chromatography (50% yield).
Reaction SMILES: Br[NH-].Br[CH2:4][C@@:5]([OH:22])([CH3:21])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1)=[O:7].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>CC(C)=O.CC(O)C.O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C@:5]([OH:22])([CH3:21])[CH2:4][O:38][C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:29])[CH:37]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:16]
Reactant: N#Cc1ccc(O)cc1F
Reactant: C[C@](O)(CBr)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH-]Br
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: C[C@](O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Yield: 23 %

Procedure:
A mixture of bromoamide ((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide, R-19 (2.0 g, 5.70 mmol), anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with 2-fluoro-4-hydroxybenzonitrile (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol was heated to reflux for 3 h and then concentrated under reduced pressure to give a solid. The residue was treated with 100 mL of H2O and then extracted with EtOAc (2×100 mL). The combined EtOAc extracts were washed with 10% NaOH (4×100 mL) and brine, successively. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid.
Reaction SMILES: [C:1]([N:5]1[C:26](=[O:27])[N:8]2[CH:9]=[C:10]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[C:1]([N:5]1[C:26](=[O:27])[N:8]2[CH:9]=[C:10]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:36][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:22])[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cn2c(=O)n(C(C)(C)C)nc12
Reactant: NCCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(-c2cccc(C(=O)NCCc3ccccc3)c2)cn2c(=O)n(C(C)(C)C)nc12

Procedure:
A solution of 50 mg of the product of Step A, 33 mg of phenethylamine, 68 mg of triethylamine and 258 mg of 1-propanephosphonic acid cyclic anhydride in EtOAc (3.0 mL) was warmed to 80° C. The organic layer was washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford 3-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-N-phenethyl-benzamide as a white solid. MS (M+H+)=473.4.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:22]([Cl:40])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:40][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([F:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(N2CCc3cc(F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (140 mg, 1.25 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (150 mg, 0.8 mmol) and N-(4-Bromo-2-chloro-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide (200 mg, 0.5 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature; concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29].[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17]2([O:32][CH2:31][CH2:30][O:19]2)[CH3:18])[CH2:8][C@@H:7]1[OH:29]
Reactant: OCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1

Procedure:
2β-(3'-Chloropropoxy)-3α-hydroxy-5α-pregnane-11,20-dione (470 mg.) was added to a mixture of ethylene glycol (4 ml.), toluene-p-sulphonic acid (3 mg.) and benzene (50 ml.). The vigorously stirred mixture was refluxed under a Dean and Stark head for 17 hours. The cooled mixture was neutralised with sodium bicarbonate solution, ether (50 ml.) added and the organic mixture was washed with water (250 ml.). The organic solution was dried over anhydrous sodium sulphate and evaporated to give the title compound (520 mg.) as a white foam, [α]D + 37.5° (c 1.03).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccc(C#N)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 300 mg, 0.91 mmol) in methylene chloride (10 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.52 mL, 1.04 mmol). The reaction was stirred at 0° C. for 30 min. At this time, the reaction was concentrated in vacuo to give a light yellow oil. The residue was then treated with a solution of 2-amino-5-cyanopyridine (216 mg, 1.80 mmol) in tetrahydrofuran (5 mL) and pyridine (0.37 mL, 4.5 mmol). The reaction was then stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (15 mL) and extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyano-pyridin-2-yl)-3-cyclopentyl-propionamide (53 mg, 86%) as a colorless oil: (ES)+-HRMS m/e calcd for C21H22ClN3O3S (M+H)+ 432.1143, found 432.1147.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:32]=[CH:31][C:10]([O:11][C@@H:12]([CH3:30])[C@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[Si:23]([O:22][C@H:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C@H:12]([CH3:30])[O:11][C:10]1[CH:31]=[CH:32][C:7]([B:37]([OH:38])[OH:36])=[CH:8][CH:9]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the method described in Example 5b) from tert-butyllithium (3.95 ml, 1.7M in hexanes), (3R,4S)-3-[4-(4-bromophenoxy)-3-(tert-butyldimethyl-silanyloxy)pentyl]pyridine (2.52 g, Example 11b)) and tri-isopropylborate (1.68 ml) in tetrahydrofuran (20 ml) to afford the sub-title compound as a foam (1.22 g) after chromatography on silica eluting with ethyl acetate and then ethyl acetate:methanol (4:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OB(O)c1ccco1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Yield: 76 %

Procedure:
The procedure described for 202 was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), 2-furanylboronic acid (0.090 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 110 mg (76%) of the title compound 203 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.59 (d, J=6.0 Hz, 2H), 7.15 (d, J=6.3 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.67 (d, J=6.3 Hz, 1H), 6.55 and 6.54 (dd, J2=2.4 Hz, J2=1.2 Hz, 1H), 2.48-2.47 (m, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H). 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 357 (M−H)−.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ClSCl
Reactant: CCCCOC(=O)NC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N(C)SCl
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a solution of 45.2 g (0.44 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to -5° C. under a nitrogen atmosphere was added a solution made up of 50.9 g (0.4 mole) of n-butyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 100 ml of methylene chloride. The addition took 2 hours while the temperature was maintained at -15° C. to 0° C. After stirring for 1 hour the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Solid was removed by extracting the product with hexanes. After filtration the hexane solution was concentrated to give 57.3 g of n-butyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:44])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C@@H:29]([NH:33][C:34](=O)[O:35]CC5C=CC=CC=5)[C:30](=[O:32])[NH2:31])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(OCC)(=O)C>[O:35]=[C:34]1[NH:33][C@H:29]([CH2:28][C@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:11][CH2:10][CH:9]([N:8]([CH3:44])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:14][CH2:13]5)[C:27]=4[C:26]2=3)[C:30](=[O:32])[NH:31]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H]2NC(=O)NC2=O)CC4)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of benzyl N-[(1R)-2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-1-carbamoylethyl]carbamate (80 mg, 0.15 mmol, 1.00 equiv) in 20 mL of THF was added TBAF hydrate (134 mg, 0.51 mmol, 4.00 equiv) at room temperature. The resulting solution was stirred for 4 h at 70° C. under nitrogen. After cooling down to room temperature, the resulting solution was diluted with 50 mL of ethyl acetate and washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 60 mg (94%) of tert-butyl N-(4-[[(3R)-3-[[(4R)-2,5-dioxoimidazolidin-4-yl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH:21]=C)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C@H:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].CC(C)=[O:31].C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+]>ClCCl.[Os](=O)(=O)(=O)=O.CO.ClCCl.O1CCCC1.O.O.C(O)(C)(C)C>[CH3:1][N:2]([CH2:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH:21]=[O:31])[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C@H:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: CC(C)=O
Reactant: C=CCC(CN(C)C(=O)c1cc([C@H]2C=NN=N2)ccc1OC)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc([C@H]2C=NN=N2)cc1C(=O)N(C)CC(CC=O)c1ccccc1
Reaction time: 36 h

Procedure:
Combine (S)-N-methyl-N-(2-phenylpent-4-enyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide (1.03 g, 2.74 mmol), acetone (15 mL, t-butanol (7.5 mL), water (7.5 mL), and a solution of N-methylmorpholine N-oxide (0.74 mL, 50% in water, 3.56 mmol). Add a solution of osmium tetraoxide (1.0 mL, 4% in water). After 36 hours, evaporate in vacuo to remove most of the acetone and extract the evaporated reaction mixture with dichloromethane. Extract the organic layer with an aqueous 10% solution of sodium thiosulfate. Extract the aqueous layer five times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Combine the residue and tetrahydrofuran/water (20 mL, 4/1). Add sodium metaperiodate (0.7 g, 3.29 mmol). After 25 minutes, filter the reaction mixture, rinse the solids with tetrahydrofuran, and evaporate the filtrate to obtain a residue. Dilute the residue with dichloromethane (100 mL), extract with water, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol/dichloromethane to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38]([O:45][C:46]1[CH:47]=[N:48][C:49]([CH2:52]Cl)=[CH:50][CH:51]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:52][C:49]2[CH:50]=[CH:51][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:47][N:48]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(OCc4ccccc4)cn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 73.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-(benzyloxy)-6-(chloromethyl)pyridine (0.81 g) as starting materials, 5-benzyloxy-N-({1-[(5-(benzyloxy)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:7](=[CH2:8])[CH:6]([CH3:9])[CH2:5][C@@H:4]([OH:10])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:6]1[CH2:5][C@H:4]([OH:10])[CH2:3][C:2]([CH3:11])([CH3:1])[C:7]=1[CH3:8]
Reactant: C=C1C(C)C[C@@H](O)CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)(C)C[C@@H](O)C1
Yield: 92.5 %

Procedure:
4 g of (1R)-3,3,5-trimethyl-4-methylene-1-cyclohexanol obtained in Example 2A were dissolved in 50 ml of toluene, about 6 mg of p-toluenesulfonic acid were added and the mixture was refluxed for 45 min. It was then poured into 50 ml of water and extracted twice with 50 ml of ether. The organic phase was separated off, washed with 50 ml of saturated NaHCO3 solution, dried over MgSO4 and freed of solvent under reduced pressure. The residue was chromatographed on 150 g of silica gel with hexane/EA (4:1) to result in 3.7 g of the abovementioned product in the form of pale yellow crystals with a purity of 97% according to GC.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:5][N:4]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CCc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Yield: 68.9 %

Procedure:
Compound 110 (200 mg, 0.61 mmol) was suspended in 3 N HCl (3 mL) and the suspension heated to reflux for 30 min. Following neutralization with saturated aqueous Na2CO3 solution, the precipitated product was collected by filtration, washed with water (3×15 mL), and dried under vacuum. The residue was crystallized from MeOH to give the product (120 mg, 0.42 mmol, 69%) as a solid, mp 190-191° C.; 1H NMR (500 MHz, DMSO) δ 1.20 (3, t, J=7.5 Hz), 2.79 (2, q, J=7.5 Hz), 5.91 (2, S), 6.57 (2, d, J=8.5 Hz), 7.41 (2, d, J=8.5 Hz), 13.65 (1, s); 13C NMR (125 MHz, DMSO) δ 12.3, 23.6, 112.5, 127.1, 127.6, 152.5, 159.1, 166.8; MS (LCQ, ESI+) Calculated for C10H13N4O2S2 285.0. found 285.0 (M+H)+; HRMS (FAB+, m/z) Calculated for C10H13N4O2S2 285.0480. found 285.0478 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)([OH:3])=[O:2].Cl.[CH2:24](O)[CH3:25]>>[CH2:24]([O:2][C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)=[O:3])[CH3:25]
Reactant: CCO
Reactant: COc1cc(OCC(=O)O)ccc1-c1nc2ncccc2[nH]1
Agent: Cl
Product: CCOC(=O)COc1ccc(-c2nc3ncccc3[nH]2)c(OC)c1
Reaction time: 8 h

Procedure:
1 g of 2-(4-carboxymethoxy-2-methoxyphenyl)-imidazo(4,5-b)pyridine is dissolved in 20 ml of ethanol, the solution is saturated with HCl gas and allowed to stand overnight. After concentration and the usual work-up, 2-(4-ethoxycarbonylmethoxy-2-methoxyphenyl)-imidazo(4,5-b)pyridine is obtained; hemfumarate, m.p. 198°.
Reaction SMILES: [C:1]1([C:7]2([C:12]#N)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:26]CC)C>CCCCCCC>[C:1]1([C:7]2([CH:12]=[O:26])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccccc2)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCCC
Product: O=CC1(c2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenyl-1-cyclopentanecarbonitrile (7.0 g, 41 mmol) in n-heptane (100 ml) cooled to -30° C. was dropwise added a 1M solution of diisobutylaluminium hydride in n-heptane (82 ml, 82 mmol). The mixture was stirred at -30° C. for 1 h and at 0° C. for 1 h. The mixture was diluted with diethylether (100 ml) and silica gel (60 g) was carefully added keeping the temperature below -30° C. The mixture was then allowed to warm to room temperature and then stirred for 20 h. After filtration the filtrate was washed with water (2×100 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 3.45 g of the crude 1-phenyl-1-cyclopentanecarboxaldehyde.