Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.O.[OH-].[Li+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][CH2:20][C:21](N(C(OC(C)(C)C)=O)C2C3C(=CC=C(OC)C=3)N=CC=2)=[O:22])[C@@H:15]([CH:43]=[CH2:44])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].S([O-])([O-])=[O:46].[Na+].[Na+]>O1CCCC1.O>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][CH2:20][C:21]([OH:22])=[O:46])[C@@H:15]([CH:43]=[CH2:44])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)N(C(=O)OC(C)(C)C)c1ccnc2ccc(OC)cc12
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)O
Reaction time: 16 h

Procedure:
2.26 cm3 of an aqueous solution of hydrogen peroxide at 9.8 mol/l and 0.310 g of lithium hydroxide monohydrate are added successively, at a temperature in the region of 20° C., under an argon atmosphere, to 2 g (3.7 mmol) of (3R,4R)-1-tert-butyloxycarbonyl-4-{3-[tert-butyloxycarbonyl-(6-methoxyquinolin-4-yl)amino]-3-oxopropyl}-3-vinylpiperidine in solution in 56 cm3 of tetrahydrofuran and 18 cm3 of water. After stirring for 16 hours, 50 cm3 of a saturated aqueous sodium sulfite solution are added and the tetrahydrofuran is then evaporated off under reduced pressure (2.7 kPa). The aqueous phase is filtered and the residue is washed with 3 times 30 cm3 of water. The filtrates are pooled, acidified to a pH in the region of 3.5 by adding acetic acid and then extracted with 3 times 40 cm3 of dichloromethane. The organic phases are pooled, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.9 g of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-carboxyethyl)-3-vinylpiperidine in the form of a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:18](=[C:19]([O:21]C)[CH:20]=1)[O:17][CH2:16][C@H:15]1[C@@:6]2([CH3:26])[CH2:7][CH2:8][C@@H:9]2[C@:14]1([CH3:23])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:25])[CH3:24].B(Br)(Br)Br>C(Cl)Cl>[CH3:26][C@@:6]12[CH2:7][CH2:8][C@@H:9]3[C@:14]([CH3:23])([CH2:13][CH2:12][CH2:11][C:10]3([CH3:24])[CH3:25])[C@H:15]1[CH2:16][O:17][C:18]1[C:5]2=[CH:4][C:3]([OH:2])=[CH:20][C:19]=1[OH:21]
Reactant: COc1cc(OC)c2c(c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC[C@]2(C)[C@H]3COc4c(O)cc(O)cc4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (1R,10R,11S,16S)-4,6-dimethoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 42) (0.69 g, 1.9 mmol) in CH2Cl2 (20 mL), cooled to 0° C., and a BBr3 solution (7.3 mL, 1 M in CH2Cl2, 7.3 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 6 h. The reaction was quenched with MeOH (20 mL) and concentrated. The quenching and concentration steps were repeated six times. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-4,6-diol (Compound No. 43) (0.42 g, 66%) as a pale pink solid. 1H NMR (CDCl3): δ 6.28 (d, 1H), 6.17 (d, 1H), 5.48 (br s, 1H), 4.40 (m, 1H), 4.25 (br s, 1H), 4.15 (t, 1H), 2.20 (m, 1H), 1.80-1.35 (m, 7H), 1.28 (s, 3H), 1.25-1.00 (m, 4H), 0.92 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H). MS m/z 331 (C21H30O3+H+).
Reaction SMILES: O.C[N+]1([O-])CCOCC1.[Cl:10][CH:11]=[C:12]1[CH:18]=[CH:17][C:16]2[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13]1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:10][CH:11]=[C:12]1[CH:18]=[CH:17][C:16]2[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13]1
Reactant: OCc1ccc2c(c1)C=CC(=CCl)CO2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
84 mg (0.62 mmol) of 4-methylmorpholine N-oxide monohydrate and 207 mg of 4 Å molecular sieve are added to 92 mg (0.415 mmol) of [3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]methanol, prepared according to example 71, in solution in 1 ml of dichloromethane. 14.6 mg (0.041 mmol) of tetrapropylammonium perruthenate are added to the suspension at 0° C. After stirring at ambient temperature for 1 hour, the reaction medium is purified by chromatography on silica gel (ethyl acetate/heptane 30/70) to give 70 mg (76%) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carbaldehyde in the form of a mixture of 2 Z/E isomers in an 85/15 ratio; 1H NMR (300 MHz, CDCl3) Z isomer: 4.90 (s, 2H), 6.41 (m, 3H), 7.14 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 and 2 Hz, 1H), 7.75 (d, J=2.07 Hz, 1H), 9.91 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)Cl.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(Br)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(Br)c1

Procedure:
prepared by reaction of 3-(3-bromo-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=1.00 min; [M+H]+=312.0.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21]([CH2:33][CH2:34][CH3:35])=[C:22]([CH:30]=[CH:31][CH:32]=1)[O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCC.O.CN(C=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]2[C:21]([CH2:33][CH2:34][CH3:35])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:10]([CH2:11][CH:12]=[CH2:13])[C:2]=1[OH:1])=[O:5]
Reactant: CCCc1c(OCCCCl)cccc1OCC(=O)OCC
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(N)=O)c1O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy-3-(2-propenyl)benzamide(193 mg 1.0 mmol), ethyl [3-(3-chloropropoxy)-2-propylphenoxy]acetate(386 mg, 1.0 mmol), sodium iodide (276 mg, 2.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) were added to 2.0 ml of DMF, and the reaction mixture was heated in an oil bath at 40° C. overnight. The temperature was raised to 60° C., and the reaction mixture was again heated overnight. The reaction mixture was poured into 15 ml of water and extracted three times with ethyl acetate. The combined extracts were washed twice with water, dried and filtered. The solvent was removed under vacuum to give the crude product as a solid. Chromatography of the crude product on silica gel with 50/50 ethyl acetate/hexane as eluant gave the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1.C(=O)(O)[O-].[Na+].[I-].[Na+].[ClH:46]>C(O)CCC.C(Cl)Cl>[ClH:24].[ClH:46].[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCO
Product: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCN(CCCOc3ccc4ccccc4c3)CC2)cc1
Yield: 59.8 %

Procedure:
A mixture of 4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine (4.70 g, 0.0147 mol), 2-(3-chloropropyloxy)naphthalene) (3.23 g, 0.0147 mol), and sodium bicarbonate (5.53 g, 0.0658 mol) in 350 mL of 1-butanol containing sodium iodide was heated at reflux for 24 h. The butanol was removed by rotary evaporator and the residue partitioned between chloroform and water. The chloroform layer was washed with 5% sodium hydroxide, dried (Na2SO4) and filtered. Chloroform was removed to give a brown oil. This oil was dissolved in methylene chloride and placed on a 300 g silica gel column for flash chromatography. Elution was accomplshed using methylene chloride, 1% methanol-methylene chloride, and 2% methanol-methylene chloride. Fractions of similar purity were combined and solvents removed to give a dark brown oil. This material was converted to the HCl salt and recrystallized from methanol-diethyl ether. A white solid was isolated and dried 16 h in vacuo at 80° C. This procedure produced 5.08 g (59.8%) of white crystalline solid, mp 225°-226° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][OH:8])[CH3:4].Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1.O>CN(C)C=O>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])[N:11]=1
Reactant: CCOCCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1cccc(Br)n1

Procedure:
1.7 g of 60% oily sodium hydride was suspended in 20 ml of N,N-dimethylformamide, followed by adding a solution of 10 ml of N,N-dimethylformamide containing 4.1 ml of 2-ethoxyethanol thereto with stirring under ice-cooling. After stirring for 20 minutes, a solution of 10 ml of N,N-dimethylformamide containing 5 g of 2,6-dibromopyridine was added thereto and the mixture was further stirred at room temperature for one hour. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5% ethyl acetate/hexane as an eluent for separation and purification, to give 4.8 g of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[NH:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[N:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][NH:20][N:21]=2)=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(-c2cc[nH]n2)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2cc[nH]n2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(1H-pyrazol-3-yl)-benzoic acid. MS: 430.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:20]1[C:24]([CH:25]2[CH2:27][CH2:26]2)=[C:23]([CH:28]2[CH2:31][CH:30]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29]2)[O:22][N:21]=1)[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:11].C(O)(=O)C.Br.C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:20]1[C:24]([CH:25]2[CH2:26][CH2:27]2)=[C:23]([CH:28]2[CH2:29][CH:30]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:31]2)[O:22][N:21]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11]
Reactant: COC(=O)CCC(CC(=O)Nc1ccc(C)cc1Cl)c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(=O)CC(CCC(=O)O)c2noc(C3CC(CC(C)(C)C)C3)c2C2CC2)c(Cl)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Methyl 5-(2-chloro-4-methylphenylcarbamoyl)-4-{4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl}valerate (63.3 mg) and acetic acid (0.6 mL) were mixed. To the mixture was added 48 w/v % hydrobromic acid (0.3 mL) at 10° C. The mixture was stirred at RT, and further stirred at 50° C. To the reaction mixture were added sodium acetate (250 mg) and water at ice temperature. The mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform/acetic acid=1/20/0.1) to give the title compound (56.7 mg).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCCCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCCSc1nc2ccccc2n1CC(=O)O
Yield: 83 %

Procedure:
A solution of tert-butyl[2-(5-ethyloxycarbonyl-pentylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor E-01b, 44 mg, 0.11 mmol) in TFA/dichloromethane (1:1, 2 ml) is stirred at rt for 3 h. The solvents are removed under a stream of air. The solid residue is suspended in Et2O (2 ml) and sonicated. Filtration, rinsing with Et2O and drying under high vacuum yields the title compound (32 mg) as a white solid in 85% yield: tR=5.33 min (LC-1), ESI-MS (pos.): m/z 351.07 [M+H]+, ESI-MS (neg.): m/z 349.22 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H CH3), 1.44 (s, 9H, tBu), 1.32-1.44 (m, 2H), 1.52-1.70 (m, 4H), 2.24 (t, 2H, CH2C═O), 3.24 (t, 2H, SCH2), 4.10 (q, 2H, OCH2), 4.15 (br. s, 1H, CO2H), 4.86 (s, 2H, CH2CO2), 7.24 (s, 3Harom), 7.63 (m, 1Harom).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[N+:33]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)([O-:35])=[O:34]>CN(C=O)C>[CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:39][C:38]5[CH:41]=[CH:42][CH:43]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=5)=[CH:24][CH:25]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCO)cc4)C(=O)O3)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc([N+](=O)[O-])c5)cc4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one (1 g) in DMF (15 mL) was treated with sodium hydride (167 mg) under nitrogen and stirred for 15 min. To this was added 3-nitrobenzyl bromide (721 mg) and the reaction mixture was stirred for 20 h. The solution was then concentrated in vacuo and the residue was taken up in EtOAc, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 40 g) eluting with CH2Cl2-MeOH (500:1) and then CH2Cl2-MeOH (250:1) to give the title compound (1.22 g). LCMS RT=3.57 min.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5](=O)[C:6]([F:9])([F:8])[F:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCCl.C1(C)C(C)=CC=CC=1>[F:9][C:6]([F:7])([F:8])[C:5]1[CH:4]=[CH:3][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1
Reactant: CN(C)/C=C/C(=O)C(F)(F)F
Reactant: Nc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1C
Solvent: ClCCCl
Product: FC(F)(F)c1ccc2ccccc2n1

Procedure:
According to instructions in the literature (Baraznenok, I. L., Nenajdenko, V. G., Balenkova, E. S. Eur. J. Org. Chem. 1999, 937–941), 1.2 g (7.18 mmol) of (E)-4-(dimethylamino)-1,1,1-trifluoro-3-buten-2-one is reacted with 2.03 g (7.18 mmol) of trifluoroacetic acid anhydride and 1.30 ml (14.36 mmol) of aniline in 72 ml of 1,2-dichloroethane, then in 36 ml of xylene. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 1.01 g (71% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:15]([F:22])[CH:14]=1
Reactant: COC(=O)c1cnccc1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnccc1-c1ccc(Cl)cc1F
Yield: 46.1 %

Procedure:
To a stirred solution of methyl 4-chloronicotinate (7 g, 40.8 mmol), (4-chloro-2-fluorophenyl)boronic acid (7.11 g, 40.8 mmol) and cesium carbonate (26.6 g, 82 mmol) in a mixture of dioxane (60 mL) and water (8 mL) purged with nitrogen gas for 5 min, was added Pd(PPh3)4 (2.83 g, 2.448 mmol) and the resultant mixture was heated at 85° C. for 15 h. Water (30 mL) was added and the mixture was extracted with EtOAc (1×50 mL). The organic layer was washed with water (1×30 mL) and brine (1×30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column (30% EtOAc in hexane) to give methyl 4-(4-chloro-2-fluorophenyl)nicotinate (5 g, 18.82 mmol, 40% yield). LCMS (ESI) m/e 266.7 [(M+H)+, calcd for C13H10ClFNO2 266.0]; LCMS retention time (Method C): tR=1.73 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:14][C:15]1[C:20]([O:13][CH2:12][C@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: Cc1ncccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: Cc1ncccc1OC[C@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 55.4 %

Procedure:
An ice cooled solution of the compound from step 41a (0.151 g,0.81 mmol) was allowed to react with 2-methyl-3-hydroxypyridine (0.092 g, 0.85 mmol) under the conditions of Example 2a, except that DEAD was replaced by di-t-butyl azodicarbonate, to yield the title compound (0.125 g, 55%). MS (DCI/NH3) m/e: 279 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.11 (dd, J=4.6, 1.3 Hz, 1H), 7.20-7.10 (m, 2H), 4.54-4.53 (m, 1H), 4.36-435 (m, 1H), 4.09 (dd, J=10.0, 2.6 Hz, 1H), 3.95-3.88 (m, 2H), 2.55 (s, 3H), 2.42-2.30 (m, 2H), 1.40 (s, 9H).
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(C)(C)[Si](C)(C)OCc1cccc(N2CCC(C3CCNCC3)CC2)c1F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
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: [C:1]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:25]>C(O)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:25]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCC(=O)OCC(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 110 °C
Yield: 31.3 %

Procedure:
A mixture of 2-(4-chlorophenyl)-2-oxoethyl ethyl succinate (7.6 g), ammonium acetate (9.8 g) and acetic acid (80 ml) was stirred for an hour at 110° C. and refluxed for 2 hours. The solvent was distilled off. The residue was diluted with water, made basic by addition of aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over MgSO4. After removal of the solvent, the oily residue was subjected to a silica gel column chromatography. Crystals of ethyl 4-(4-chlorophenyl)-2-oxazolepropionate (2.23 g, 31%) were obtained from the fraction eluted with ethyl acetate-hexane (1:3, V/V). Recrystallization from ethyl acetate-hexane gave colorless plate crystals of mp 65°-66° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:34][CH3:35])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[N:5]([C:19]([NH:21][C@H:22]([CH2:30][CH:31]=[CH2:32])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:20])[C:4]1=[O:33])[CH3:2].[Br-].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:57]([NH:59][CH2:60][CH3:61])[CH3:58]>>[CH2:34]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:59]([CH2:60][CH3:61])[CH2:57][CH3:58])[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[N:5]([C:19]([NH:21][C@H:22]([CH2:30][CH:31]=[CH2:32])[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:20])[C:4]1=[O:33])[CH3:35]
Reactant: CCNCC
Reactant: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(O)COC)cc1)c1ccc(C)cc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(COC)N(CC)CC)cc1)c1ccc(C)cc1

Procedure:
According to the procedure given in Example 21, Step D, 86 mg (0.18 mmol) of 3,3-diethyl-1-[(R)-α-(allyl)-4-(methyl)benzylaminocarbonyl]-4-(S)-[4-(1-(RS)-(hydroxy)-2-methoxyethyl) phenoxy]azetidin-2-one, 98 mg (0.23 mmol) of triphenylphosphine dibromide and ca. 0.3 mL of diethylamine gave after purification on 15 gm of silica eluting with 500 mL of 98:2 methylene chloride: methanol then 200 mL of 97.5:2.5 methylene chloride: methanol 44 mg (46%) of an oil.