Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
The method described in Example 3 (step 3.2.) is used. Starting from 5.3 g (26 mmol) of 4-bromo-2-fluorobenzaldehyde, 4 g (28.6 mmol) of 4-fluorophenylboronic acid, 26 ml (52 mmol) of aqueous sodium carbonate (2M) solution and 0.9 g (0.78 mmol) of palladium tetrakis(triphenylphosphine), 3.4 g of pure product are obtained in the form of a white solid, following chromatography on silica gel, eluting with a 10/90 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:26])([CH3:25])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:30]([F:47])=[C:31](/[CH:35]=[C:36](/[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[F:46])\[C:37]#[N:38])[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[C:30]=2[F:47])[C:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[F:46])([C:37]#[N:38])[CH:9]([CH2:10][C:11]([CH3:26])([CH3:25])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[NH:8]1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CCOCCO[Si](C)(C)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOCCO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 68.8 %

Procedure:
In a manner similar to the method described in Example 100b, [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 119a (0.4 g, 1 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (0.3 g, 1 mmol) prepared in Example 52a, AgF (0.2 g, 1.5 mmol), and triethylamine (0.3 mL, 2.4 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (2 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl}-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (0.49 g, 60%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:26][CH2:25]C(=O)[CH2:23][CH2:22]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:34][CH:33]4[O:35][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].CO[CH:38]([O:41][CH3:42])[O:39][CH3:40].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:42][O:41][C:38]1([O:39][CH3:40])[CH2:25][CH2:26][CH:21]([N:18]2[C:16]3=[N:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=4)=[N:13][C:14]([N:28]4[CH2:34][CH:33]5[O:35][CH:30]([CH2:31][CH2:32]5)[CH2:29]4)=[C:15]3[CH:20]=[N:19]2)[CH2:22][CH2:23]1
Reactant: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(OC)(OC)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (80 mg) (0.17 mmol) in DCM (2.0 mL) was added trimethylorthoformate and methanol in excess and a catalytic amount of p-toluene sulfonic acid along with molecular sieves and stirred at room temperature overnight. The added water and extracted 3 times with EtOAc. The organics were dried (MgSO4) and filtered off through a pad of Magnesol and concentrated in vacuo. to afford a solid. The solid was triturated with diethyl ether to give a white solid that was filtered and washed with diethyl ether to give (54 mg) MS m/z=476.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.CCOC(C)=O.O>COCCOC.O.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>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=2[Cl:26])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OCc1ccccc1
Yield: 82 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454, which is incorporated herein by reference)(5 g, 18.9 mmol) in DME/H2O, was added 2,4-dichlorophenylboronic acid (3.60 g, 18.9 mmol), Ba(OH)2 0.8H2O (5.96 g, 18.9 mmol), and Pd(PPh3)2Cl2 (0.77 g, 1.09 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 5.79 g (82%) of 2-benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine as a viscous oil: crude MS (AP) m/z 375.2 [(M+H)+, 100].
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[N:13]([CH3:15])[CH3:14].[C@@H]1(N)CCCC[C@H]1N.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([C:36]([O:38][CH3:39])=[O:37])=[CH:28]1>CCCCCCCCCCCC.O1CCOCC1.ClCCl>[CH3:14][N:13]([CH3:15])[C:12]1[CH:11]=[C:10]([N:27]2[C:31]3=[N:32][CH:33]=[CH:34][CH:35]=[C:30]3[C:29]([C:36]([O:38][CH3:39])=[O:37])=[CH:28]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: CN(C)c1cccc(Br)c1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2cccc(N(C)C)c2)c2ncccc12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0.038 g (0.2 mmol) of cuprous iodide, 0.891 g (4.2 mmol) of potassium phosphate, 0.40 g (2 mmol) of 3-bromo-N,N-dimethylaniline and 0.24 cm3 (2 mmol) of trans-1,2-cyclohexanediamine were added, under an argon atmosphere, to 0.405 g (2.3 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in solution in 0.3 cm3 of dodecane and 6 cm3 of dioxane. After stirring at a temperature in the region of 110° C. for 48 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which was taken up in 20 cm3 of dichloromethane. The resulting organic solution was washed with 20 cm3 of 0.1N hydrochloric acid and filtered, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). Methyl 1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, characterized by LC/MS (m/z 296 [MH]+), was thus obtained, which was used directly in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[NH4+].[Cl-].CC[N:44](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C)C=O>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:32])[CH2:28][C:29]([NH2:44])=[O:31])[CH2:23][CH2:22]2)=[CH:38][CH:37]=1
Reactant: O=C(O)CC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 8-mL vial, was placed 3-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-3-oxopropanoic acid (20 mg, 0.03 mmol, 1.00 equip, 98%), NH4Cl (9.48 mg, 0.18 mmol, 5.00 equip), DIEA (45.7 mg, 0.35 mmol, 10.00 equip, 99%), HATU (20.2 mg, 0.05 mmol, 1.50 equip, 99%), and N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers combined. The resulting mixture was washed with water (1×20 mL) and brine (1×20 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to yield 3-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-3-oxopropanamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1)=[O:12].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(Br)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a round bottom flask was added 4-bromophenol (1.7 g, 9.8 mmol, 1.0 eq.), acetamide 21 (2.79 g, 10.3 mmol, 1.05 eq.), potassium iodide (1.7 g, 10.3 mmol, 1.05 eq.), potassium carbonate (2.7 g, 19.6 mmol, 2.0 eq.), and acetonitrile (35.0 mL). The reaction mixture was then reluxed with vigorous stirring for 2 h. The hot reaction was then filtered to remove the insoluble potassium carbonate. The filtrate was concentrated to give 3.8 g of crude bromo-phenoxy-acetamide 22 as a light brown solid. The solid was then triturated with 10 mL of cold acetonitrile, filtered, and rinsed with 5 mL of cold acetonitrile to give pure bromo-phenoxy-acetamide 22 (1.85 g, 45% yield). Note: there was still an abundant amount of crude product in the mother liquor. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 409.9 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 8.20 (d, 1H), 7.90 (dd, 1H), 7.68 (d, 1H), 7.48 (d, 2H), 6.99 (d, 2H), 4.75 (s, 2H) ppm.
Reaction SMILES: CN1CCOCC1.[C:8]([NH:11][CH:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O)(=[O:10])[CH3:9].C(OC(Cl)=O)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([NH:34][C:13](=[O:15])[CH:12]([NH:11][C:8](=[O:10])[CH3:9])[CH2:16][CH:17]=[CH2:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=CCC(NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CCC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 63.5 %

Procedure:
4-Methylmorpholine (0.55 g, 5.40 mmol) was added to a cooled (-10° to -15° C.) THF solution (60 mL) of 2-acetamido-4-pentenoic acid (0.81 g, 5.18 mmol), and then isobutylchloroformate (0.75 g. 5.70 mmol) was added leading to the precipitation of a white solid. After 2 min, a solution of benzylamine (0.61 g, 5.70 mmol) in THF (10 mL) was slowly added at -10° to -15° C. The reaction was allowed to warm (5 min) at room temperature and the insoluble salts were removed by filteration, and the filtrate was evaporated to dryness. The residue was triturated with EtOAc (10 mL), and the remaining white solid was filtered to give 0.81 g (64%) of the desired product: mp 118°-120° C. (recrystallized from ethyl acetate/cyclohexane); Rf 0.36 (4% MeOH/CHCl3); IR (KBr) 3200 (br), 3040, 2900, 1650 (br), 1540 (br), 1350, 750, 700 cm-1 ; 1H NMR (DMSO-d6) δ 1.83 (s, C(O)CH3), 2.22-2.49 (m, CH2CH=CH2), 4.26 (d, J=5.3 Hz, CH2Ph), 4.25-4.33 (m, CH), 4.99-5.09 (m, CH2CH=CH2), 5.65-5.77 (m, CH2CH=CH2), 7.21-7.29 (m, 5 PhH), 8.05 (d, J=7.6 Hz, NH), 8.46 (br s, NH); 13C NMR (DMSO-d6) 22.41 (C(O)CH3), 36.24 (CH2CH=CH2), 41.91 (CH2Ph), 52.20 (CH), 117.15 (CH2CH=CH2), 126.54 (C4'), 126.99 (2C2' or 2C3'), 128.04 (2C2' or 2C3'), 139.25 (C1'), 134.25 (CH2CH=CH2), 169.02 (C(O)CH3), 170.96 (C(O)NH) ppm; mass spectrum, m/e (relative intensity) 246 (M+, 4), 205 (4), 163 (15), 140 (8), 106 (33), 91 (77), 70 (100).
Reaction SMILES: [CH3:1][C:2]1([CH2:12][OH:13])[O:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][O:3]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[C:19]([CH3:24])[C:18]=1[CH3:25]>CS(C)=O>[CH3:24][C:19]1[C:18]([CH3:25])=[C:17]([O:13][CH2:12][C:2]2([CH3:1])[O:3][CH2:4][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:10][O:11]2)[CH:22]=[CH:21][N+:20]=1[O-:23]
Reactant: CC1(CO)OCC2(CO1)OCCO2
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)cc[n+]([O-])c1C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a dimethylsulfoxide (15 ml) solution of the (8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methanol (1.11 g, 5.82 mmol) obtained in the step (5c), sodium hydride, in oil (326 mg, 8.15 mmol as the content was regarded as 60%) was added at room temperature in a nitrogen atmosphere. The mixture was stirred for 30 minutes in the same conditions. To the reaction mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (917 mg, 5.82 mmol) was added at room temperature and the reaction mixture was stirred at 70° C. for 4.5 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol=1/0-5/2 gradient) and desired fractions were concentrated to obtain the title compound (1.20 g, 66.1% yield) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1C=C(C)N=C(C)C=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:33].[K+].[K+]>C(#N)C.O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:33])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CCCc3sc(-c4ccncc4)cc32)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C1CCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
In a 100 mL round bottomed flask was placed 4-[4-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]pyridine (821 mg, 2.52 mmol) and then dissolved in acetonitrile (10 mL) and 1,4-dioxane (10 mL). Then γ-Collidine (1.5 mL, 11 mmol) was added. To the mixture were added freshly prepared suspension of potassium persulfate (2.96 g, 10.9 mmol) and Copper(II) sulfate pentahydrate (278 mg, 1.11 mmol) in water (20 mL). The resulting mixture was stirred 6 h at 80° C. After stirring was continued for additional 1.5 h at the same temperature no increase in product formation was observed. The mixture was allowed to cool to rt and then was diluted with water (50 mL) and then extracted with EtOAc (50 mL×2). The combined organic phase was washed with freshly prepared 10% aqueous NaHSO3 (50 mL), saturated aqueous solution of NaHCO3 (50 mL), brine (50 mL), dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (24 g) column chromatography eluted with a 30% to 100% EtOAc/hexane to yield title compound (568 mg; 66.3%) as a colorless crystalline solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][C:5]1[S:6][C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][C@@H:25]4[CH2:27][O:26]4)=[C:18]([CH2:28][CH3:29])[CH:17]=3)[N:12]=2)=[CH:8][C:9]=1[CH3:10])[CH3:2].Cl.C[O:34][C:35]([CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:36]>>[CH2:1]([N:3]([CH2:4][C:5]1[S:6][C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][C@@H:25]([OH:26])[CH2:27][N:39]4[CH2:40][CH2:41][CH:37]([C:35]([OH:34])=[O:36])[CH2:38]4)=[C:18]([CH2:28][CH3:29])[CH:17]=3)[N:12]=2)=[CH:8][C:9]=1[CH3:10])[CH2:30][CH3:31])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: COC(=O)C1CCNC1
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H](O)CN1CCC(C(=O)O)C1

Procedure:
The title compound is prepared starting from diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (30 mg, 68 μmol) and rac-pyrrolidine-3-carboxylic acid methyl ester hydrochloride (56 mg, 340 μmol) in analogy to Example 203; LC-MS*: tR=0.76 min; [M+1]+=557.17; 1H NMR (D6-DMSO): δ 1.03 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 1.90-1.98 (m, 2H), 2.22 (s, 3H), 2.34 (s, 3H), 2.43-2.49 (m, 1H), 2.58 (q, J=7.0 Hz, 4H), 2.67-2.77 (m, 5H), 2.80-2.95 (m, 2H), 3.73 (s, 2H), 3.74-3.77 (m, 1H), 3.78-3.84 (m, 2H), 3.91-3.98 (m, 1H), 7.72 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:23][CH3:24])=[N:6][C:7]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:9]=1[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:2]=C.S(=O)(O)[O-:26].[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.CO.O.[Os](=O)(=O)(=O)=O>[Si:12]([O:11][CH2:10][C:9]1[CH:8]=[C:7]([C:19]([F:21])([F:22])[F:20])[N:6]=[C:5]([O:23][CH3:24])[C:4]=1[CH2:1][CH:2]=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C=CCc1c(CO[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)nc1OC
Reactant: O=S([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of 3-allyl-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridine (2.62 g, 7.25 mmol), N-methylmorphine N-oxide (849 mg, 7.25 mmol), osmium tetroxide (4 wt. % in water, 10 mL, 400 mg) in acetone/water (4:1) (100 mL) was stirred at room temperature overnight. The reaction was quenched by sodium bisulfite (3.50 g, 36 mmol). After acetone was evaporated, the mixture was diluted with water, and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was stirred with sodium periodate (1.86 g, 8.7 mmol) in MeOH/water (1:1) (60 mL) for 30 min. The reaction was filtered and concentrated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted by ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane) to yield [4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridin-3-yl]acetaldehyde (1.61 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 9.68 (t, J=1.5 Hz, 1H), 7.46 (s, 1H), 4.67 (s, 2H), 4.01 (s, 3H), 3.76 (d, J=5 Hz, 2H), 0.96 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([OH:14])[C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:10](=[O:15])[N:11]([O:14][CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C@H:12]1[CH3:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Reactant: C=CCOC(=O)CCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Reaction time: 96 h

Procedure:
To a solution of 17.3 g of (3S-trans)-3-(t-butyloxycarbonylamino)-1-hydroxy-4-methyl-2-azetidinone and 12.9 g of chloroacetic acid, 2-propenyl ester in 350 ml of dry dimethylformamide. The mixture was allowed to stand for 4 days at room temperature and subsequently worked up as described in Example 90B. Yield 25.5 g of crude ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](Cl)[CH:9]=[C:10]([CH3:12])[CH3:11].[Mg].II.BrCC1SC=CC=1.[Cl-].[NH4+]>[Cu]I.O.O1CCCC1>[CH3:11][C:10]([CH3:12])=[CH:9][CH2:8][CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1
Reactant: BrCc1ccsc1
Reactant: CC(C)=CCCl
Agent: [Cu]I
Agent: BrCc1cccs1
Agent: II
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCc1ccsc1
Temperature: 40 °C

Procedure:
217 g of 3-bromomethylthiophene, 513 g of prenylchloride, 117 g of copper (I) iodide and 2 kg of tetrahydrofuran were introduced into a 4-liter reaction flask. 750 g of magnesium shavings were then added in small portions at a rate such that the temperature of the reaction mixture did not rise above 30°. If the temperature rises were to great, the reaction mixture was temporarily cooled. The first portion of magnesium was activated by subliming an iodine crystal onto it. After all the magnesium had been added, a check was made by means of GLC as to whether bromomethylthiophene or prenyl chloride was still present. It was possibly necessary to add more magnesium. The mixture was then stirred for a further hour at 40° C. and after that poured out into a mixture of 180 g of ammonium chloride, 1 liter of water and 500 g of ice, and stirred.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 35 (415 mg, 2.07 mmol), 1 (343 mg, 2.14 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (140 mg, 2.23 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 h). The solvent was removed in vacuo. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (36).