Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH:23]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[O:28]1[C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24][CH:23]1[CH2:22][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Reactant: ClCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CC3COc4ccccc4O3)c2=O)CC1
Temperature: 120 °C

Procedure:
A mixture of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (4.00 g, 14.3 mmol; from Example 48, Step 1), 2-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (2.60 g, 14.3 mmol), DMF (10 g) and potassium carbonate (4.00 g, 28.9 mmol) was heated at 120° C. for 3 h. Water (100 g) and EtOAc (200 g) were added to the reaction mixture and the layers were separated. The organic layer was concentrated and the residue purified by chromatography on a MPLC column using a continuous gradient (0-100% EtOAc in heptane) as eluent. This provided 0.60 g (15%) of the title compound as an oil. 1H NMR analysis supports the stated structure.
Reaction SMILES: [ClH:1].[CH3:2][C@:3]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=O.CSC.B>C1COCC1>[ClH:1].[ClH:1].[CH3:2][C@:3]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: C[C@@](N)(C(=O)N1CCOCC1)c1ccccc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@](N)(CN1CCOCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 156.8 %

Procedure:
Under an argon atmosphere 412 mg of (1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylamine hydrochloride (1.522 mmol) were dissolved in 30 mL of dry THF. A 2 M solution of borane dimethylsulfide (4.4 mL, 5.78 mmol) was added dropwise at 0° C. and the mixture stirred for 10 minutes at 0° C. and then allowed to reach room temperature (gas evolution). After 4 hours the reaction was quenched with methanol (added very carefully) and diluted with methanol when effervescence ceased. THF was removed under vacuo and the methanolic solution was heated at 60° C. for 30 minutes. The solvent was at last completely removed recovering 330 mg of the amine that was subsequently dissolved in 15 mL of dioxane and treated with 1.35 mL of HCl 4 N in dioxane. After 1 hour the solvent was evaporated and the product was triturated with diethylether to yield 350 mg of the expected salt.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:24]#[N:25])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[C:24]([C:10]1[CH:11]=[C:12]([C:15]2[S:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]=1[OH:8])#[N:25]
Reactant: COC(=O)c1ccc(-c2ccc(OCc3ccccc3)c(C#N)c2)s1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(O)c(C#N)c2)s1

Procedure:
Methyl 5-[4-(benzyloxy)-3-cyanophenyl]thiophene-2-carboxylate and pentamethylbenzene were stirred at room temperature in trifluoroacetic acid to obtain methyl 5-(3-cyano-4-hydroxyphenyl)thiophene-2-carboxylate. F: 258.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8][N:7]([CH3:19])[CH2:6]1)(=[O:3])[CH3:2].C([OH:22])C>C(O)(=O)C.[Pd]>[C:1]([O-:3])(=[O:22])[CH3:2].[C:1]([NH:4][CH:5]1[CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][NH:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)NC1CN(C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)NC1CNCCN(C)C1
Product: CC(=O)[O-]

Procedure:
6-Acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine (20 g) is dissolved in ethanol (400 ml) and acetic acid (70 ml), and hydrogeneated over 10% palladium on carbon (2 g) at about 50° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give acetate of the title compound (30 g) as an oil.
Reaction SMILES: O1CCCCC1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C(C(CCCC(O)COC1C=CC(F)=CC=1)CC#CCCCC(O)=O)(=O)C>>[C:22]([O:21][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)/[CH:10]=[CH:9]/[CH2:8][OH:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Agent: CC(=O)C(CC#CCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Product: CC(=O)OC(/C=C/CO)COc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 4, Step B-5 except that an equivalent quantity of 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-trans-2-pentene is substituted for the 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)pentane of Example 4, Step B-5. The product is obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][CH:25]([N:30](C)[C:31](=O)C(F)(F)F)[CH2:24]5)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][CH:25]([NH:30][CH3:31])[CH2:24]5)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)C(F)(F)F)C1Cc2ccc(C(=O)Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC1Cc2ccc(C(=O)Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
A mixture of the compound (70 mg) obtained in Example 15, potassium carbonate (53 mg), water (0.5 ml), methanol (1 ml) and tetrahydrofuran (1 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (60 mg) as a colorless powder.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CNC[C@H]1O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of (±)-1,1-dimethylethyl trans-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (4.44 g, 12.7 mmole) in DCM (75 mL) was added TFA (25 mL). After stirring for 2 h, the reaction contents were concentrated under vacuum and the residue dissolved in DCM (150 mL). MP-carbonate resin (18.8 g, 50.8 mmole) was added and the reaction contents were stirred vigorously overnight. The reaction contents were filtered through a scinter-glass funnel and the resin washed with MeOH. The filtrate was concentrated and dried under vacuum to give an off-white foam: LC-MS (ES) m/e 251 (M+H)+.
Reaction SMILES: [OH2:1].[Br:2]N1C(=O)CCC1=O.[CH3:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]=[CH:14]2>CS(C)=O>[Br:2][CH:15]1[CH2:16][C:17]2[C:13](=[CH:12][C:11]([CH3:10])=[CH:19][CH:18]=2)[CH:14]1[OH:1]
Reactant: O
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C=CC2
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)C(O)C(Br)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Water (0.6 ml) and N-bromosuccinimide (6.1 g) was added to a solution of 5-methyl-1H-indene (4.4 g) in dimethylsulfoxide (50 ml), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was poured into ice-cooled water, and extracted with ether. The organic layer was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting crystals were washed with hexane to obtain, by filtration, 2-bromo-6-methylindane-1-ol (4.4 g). To a solution of 2-bromo-6-methylindane-1-ol in toluene (50 ml) was added p-toluene sulfonic acid monohydrate (0.1 g), and the mixture was stirred for 20 minutes. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-bromo-5-methyl-1H-indene (1.7 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C.Cl>O1CCCC1>[CH3:14][O:15][C:16](=[O:17])[NH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(C2CC2)nc(N)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C)cc(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 53.7 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 1000 ml of tetrahydrofuran is added portionwise, under a nitrogen atmosphere, 42.8 g of 50% sodium hydride while cooling the reaction flask in an ice-water bath. After stirring one hour at 25° C. 58.5 g of dimethylcarbonate is added dropwise at 5° to 25°. The suspension is stirred about 16 hours at ambient temperatures, then 80 ml of concentrated hydrocloride acid is added dropwise under a nitrogen atmosphere while maintaining a reaction temperature of 20° to 25° with external ice-bath cooling. The suspension is stirred 0.5 hour, filtered, and the filtrate is dried over sodium sulfate and concentrated in vacuo to give the subject compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10](=[CH2:14])C(O)=O)=[CH:7][C:6]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19].[C:27](OCC)(=[O:29])C>>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][C:8]2[O:9][CH:10]=[CH:14][C:27](=[O:29])[C:15]=2[CH:16]=1
Reactant: CCOC(C)=O
Reactant: C=C(Oc1ccc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)c1)C(=O)O
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
30 g of polyphosphoric acid was added to 1.0 g of trans-3-[4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenoxylacrylic acid. The mixture was stirred for 1 hour at 55°-65° C. The reaction mixture was introduced into 200 ml of ice water. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 0.4 g (yield: 42.0%) of 6-(2,4-difluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. Melting point: 182.2°-182.8° C. (recrystallized from ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[C:9]2[C:8]([CH3:10])=[CH:7][S:6][C:5]=2[S:4][C:3]=1[CH:11]=O.[CH3:13][N:14]1C2C(=CC=CC=2)C=C1C=O>>[CH3:1][C:2]1[C:9]2[C:8]([CH3:10])=[CH:7][S:6][C:5]=2[S:4][C:3]=1[CH2:11][NH:14][CH3:13]
Reactant: Cc1csc2sc(C=O)c(C)c12
Reactant: Cn1c(C=O)cc2ccccc21
Product: CNCc1sc2scc(C)c2c1C
Yield: 53 %

Procedure:
According to the procedure of Preparation 24 (a), except substituting 3,4-dimethylthieno[2,3-b]thiophene-2-carboxaldehyde (0.5 g, 2.5 mmole) for the 1-methylindole-2-carboxaldehyde, the title compound (0.28 g, 53%) was prepared as a colorless oil: MS (ES) m/e 212 (M+H)+.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:60])/[C:31](/[C:35]3[N:36]=[C:37]([NH:40][C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:38][CH:39]=3)=[N:32]\[O:33][CH3:34])[C:27](=[O:61])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:62].[Na+]>CC(C)=O.C(OCC)(=O)C>[I:62][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:60])/[C:31](/[C:35]3[N:36]=[C:37]([NH:40][C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:38][CH:39]=3)=[N:32]\[O:33][CH3:34])[C:27](=[O:61])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: [I-]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of diphenylmethyl 3-[(Z)-3-chloro-1-propen-1-yl]-7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylate (IXb) (392 mg, 0.45 mmol) and sodium iodide (204 mg, 1.36 mmol) in acetone (3.9 ml) was stirred at room temperature for 2 hours and diluted with ethyl acetate. The organic solution was successively washed with an aqueous sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated to afford 394 mg (91% yield) of the title product.
Reaction SMILES: [CH2:1]([C:14]1[S:15][C:16]([CH3:19])=[N:17][N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:20][N:21]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]1[CH:29]=O.C(OC(=O)C)(=O)C>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:14]1[S:15][C:16]([CH:19]=[CH:29][C:22]2[N:21]([CH3:20])[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=2)=[N:17][N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1nnc(C)s1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCc1nnc(C=Cc2ncc([N+](=O)[O-])n2C)s1
Yield: 56.6 %

Procedure:
8.45 g of 2-tridecyl-5-methyl-1,3,4-thiadiazole, 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of zinc chloride are heated in 40 ml of acetic acid and 15 ml of acetic anhydride for 24 hours at reflux temperature. After the solvent has been removed, the residue is recrystallized from alcohol. 7.1 g of product is obtained, corresponding to 61% of the theory. The melting point is 91° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of racemic trans-1,1-dimethylethyl [2-(4-bromophenyl)cyclopropyl]carbamate (Intermediate 4) (1.25 g) in 71.5 mL of DCM was cooled to 0° C. TFA (17 mL) was added dropwise and the solution was stirred at this temperature for 1 h. Then the mixture was evaporated in vacuo to obtain 1.83 g of title material as a yellow solid which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][CH2:17][O:18]S(C1C=CC(C)=C([N+]([O-])=O)C=1)(=O)=O.[C:32]([O:36][C:37](=[O:55])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][C:41]=1[CH2:47][NH:48][C:49]([O:51][CH:52]([CH3:54])[CH3:53])=[O:50])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:55])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:18][CH2:17][CH2:16][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:42][C:41]=1[CH2:47][NH:48][C:49]([O:51][CH:52]([CH3:53])[CH3:54])=[O:50])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc([N+](=O)[O-])cc3)oc2C)cc1[N+](=O)[O-]
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Product: Cc1oc(-c2ccc([N+](=O)[O-])cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1

Procedure:
4-Methyl-3-nitro-benzenesulfonic acid 2-[5-methyl-2-(4-nitro-phenyl)-oxazol-4-yl]-ethyl ester (Preparation 7) and 3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester were coupled by Standard procedure A to give the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:28])=[C:12]([N:16]2[CH2:21][CH2:20][CH:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.ClCCCl.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:28][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:17][CH2:18][CH:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:33](=[O:35])[CH3:34])[CH2:24][CH2:23]2)[CH2:20][CH2:21]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCC(C3CCNCC3)CC2)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)N1CCC(C2CCN(c3cccc(CO)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4,4′-bipiperidine (125 mg) and TEA (0.15 ml) were mixed with DCE (3 ml), and acetyl chloride (39 mg) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1M TBAF/THF solution (0.6 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous ammonium chloride solution and EtOAc, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-{1′-[2-fluoro-3-(hydroxymethyl)phenyl]-4,4′-bipiperidin-1-yl}ethanone (84 mg).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:5][N:4]([C:6]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:2]1([F:1])[CH2:5][N:4]([C:6]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:7][CH2:8][C:9]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH2:22][CH2:23]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(c1ccccc1)(N1CC(F)(F)C1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CN(C2(c3ccccc3)CCC3(CCNCC3)CC2)C1
Reaction time: 3 h

Procedure:
tert-Butyl 9-(3,3-difluoroazetidin-1-yl)-9-phenyl-3-azaspiro[5.5]undecane-3-carboxylate (300 mg, 0.714 mmol) was taken up in DCM (24 ml) and TFA (6 ml) was added. The resulting mixture was stirred for 3 h. The TLC revealed completion of the reaction and the solvent was removed under reduced pressure. The compound was azeotroped (2-3×) with DCM and used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=C)=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1.[OH2:23]>C(Cl)(Cl)(Cl)Cl.CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:23])=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: C=Cc1ccc(CCC(=O)OC)cc1P(=O)(OCC)OCC
Reactant: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1C=O
Yield: 76 %

Procedure:
3-(3-Diethoxyphosphoryl-4-vinyl-phenyl)propionic acid methyl ester (200 mg, 0.61 mmol) was dissolved in 3.9 mL CCl4 and 3.9 mL of MeCN. NaIO4 (388 mg, 1.81 mmol) was dissolved in 6 mL H2O and was added. The mixture was stirred vigorously and RuCl3 (10 mg, 0.05 mmol) was then added and the mixture was stirred for 1 hr at rt The reaction was diluted with DCM, organic layer was separated, dried Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (4/1 EtOAc/hexane, Rf=0.37) to give pure product as an oil, 153 mg (yield 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (3.87 g, 10.81 mmol), 1-naphthaleneboronic acid (2.79 g, 16.22 mmol), triethylamine (4.5 mL, 32.44 mmol), palladium (II) acetate (72.8 mg, 0.324 mmol), and tri-o-tolylphosphine (204.1 mg, 0.670 mmol) in dry N,N-dimethylformamide (43 mL) was heated at 100° C. under nitrogen for 1 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl ester (3.51 g, 90%) as a yellow oil: EI-HRMS m/e calcd for C25H26O2 (M+) 358.1933, found 358.1930.