Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(CC(C#N)(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: CO
Product: N#CC(CC1CCCNC1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A mixture of α,α-bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-piperidinepropanenitrile (41.21 g, 0.0858 mole) and phenol (100 g, 1.06 mole) was heated at reflux for 2 hours. the reaction mixture was cooled to room temperature and made alkaline with ice and 50% sodium hydroxide. The aqueous layer was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide. The organic layer was then dried over sodium sulfate and filtered and solvent was removed to give a dark brown oil. This oil was subjected to flash chromatography on silica gel using methanol for elution. Fractions of similar purity were combined and solvent removed. The oil obtained was dried in vacuo overnight at 80° C., to give 18.83 g (67.2% yield) of brown oil.
Reaction SMILES: Cl[C:2]1[C:14]([F:15])=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]([F:12])[F:11])=[O:7])=[C:4]([F:16])[CH:3]=1.Cl.C[Si](C)(C)CCOC[N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([C:38]4([CH2:42][C:43]#[N:44])[CH2:41][NH:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:43]([CH2:42][C:38]1([N:36]2[CH:37]=[C:33]([C:32]3[C:27]4[CH:26]=[CH:25][NH:24][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:34]=[N:35]2)[CH2:41][N:40]([C:2]2[C:14]([F:15])=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]([F:12])[F:11])=[O:7])=[C:4]([F:16])[CH:3]=2)[CH2:39]1)#[N:44]
Reactant: O=C(NCC(F)F)c1cc(F)c(Cl)cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(c2cc(F)c(C(=O)NCC(F)F)cc2F)C1
Temperature: 105 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A solution of 4-chloro-N-(2,2-difluoroethyl)-2,5-difluorobenzamide (0.907 g, 3.55 mmol), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (1.57 g, 3.52 mmol), palladium acetate (55 mg, 0.24 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (285 mg, 0.493 mmol) and cesium carbonate (2.16 g, 6.63 mmol) in toluene (25 mL) was de-gassed and purged with N2 (g) several times prior to heating to 105° C. and stirring for 3 d. LCMS data indicated that ˜50% of the starting material was converted to the desired product. In an effort to drive the reaction to completion a second aliquot of 4-chloro-N-(2,2-difluoroethyl)-2,5-difluorobenzamide (353 mg), palladium acetate (58 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (274 mg), and cesium carbonate (550 mg) was added and stirring was continued overnight at 105° C. LCMS data indicated that there was no significant improvement. The crude reaction mixture was filtered through a pad of celite and the inorganics were washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-15%) to afford the desired product (0.789 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[ClH:11]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClC1C=CC=CC=1>[Cl:11][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Fc1ccc(CCCl)cc1

Procedure:
A mixture of 7 g of 2-(4-fluoro-phenyl)-ethanol, 25 mL of chlorobenzene, 42 mL of 37% HCl, and 0.9 g of Aliquat® 336 (tricaprylylmethyl ammonium chloride) was heated to reflux for 3 days, cooled and extracted into 3×100 mL of hexane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was a crude product of 1-(2-chloro-ethyl)-4-fluoro-benzene:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8]/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12]>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C=C/Oc1cccc(CCCO)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCOc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of methyl (2E)-3-[3-(3-hydroxypropyl)phenoxy]acrylate (300 mg) in MeOH (4.0 mL) was added 10% palladium on carbon (50 mg) at ambient temperature and the mixture was stirred at ambient temperature for 4 hours under hydrogen atmosphere (3 atms). The mixture was filtered through a bed of celite. The filtrate was evaporated in vacuo to afford methyl 3-[3-(3-hydroxypropyl)phenoxy]propanoate (275 mg) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([C:21]2[O:25][N:24]=[C:23]([CH2:26]Cl)[N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:26][C:23]1[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:29])([F:13])[F:28])[CH:16]=3)[O:25][N:24]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1

Procedure:
Synthesized as described in Example 4 using 5-nitro-1H-indazole and 5-[3(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole to afford a mixture of regioisomers. The following data are for the title regioisomer: 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=1.7 Hz, 1H), 8.34 (m, 2H), 8.27 (m, 2H), 7.84 (d, J=7.8 Hz, 1H), 7.65 (m, 2H), 5.83 (s, 2H); MS (ES) m/z 389 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30](O)(=[O:36])[CH2:31][NH:32][C:33]([NH2:35])=[O:34]>>[C:33]([NH:32][CH2:31][C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:36])(=[O:34])[NH2:35]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: NC(=O)NCC(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CNC(N)=O)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 200 mg, 0.51 mmol) and hydantoic acid (60 mg, 0.51 mmol).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH:13]([CH2:17]Br)[C:14]([NH2:16])=[O:15]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:17][CH:13]1[C:14]([NH2:16])=[O:15]
Reactant: CNCCNc1ccccc1
Reactant: NC(=O)C(Br)CBr
Product: CN1CCN(c2ccccc2)CC1C(N)=O

Procedure:
In a manner similar to preparation 1, react N-methyl-N'-phenyl-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Cl[C:12]1[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.Cl>[Cu].[Cu]I.CN1CCCC1=O>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1cc(Cl)cc(OC)c1
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccccc2C(=O)O)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 22.8 %

Procedure:
A mixture of thiosalicylic acid (928.1 mg), 5-chloro-1,3-dimethoxybenzene (1.139 g), copper (powder) (222.4 mg), copper(I) iodide (666.6 mg) and N-methyl-2-pyrrolidone (5 ml) was stirred at 200° C. for 5 hours. After cooling, the reaction mixture was adjusted to pH 2 with 4 N hydrochloric acid, extracted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solvent; chloroform:methanol=97:3, 0.1% acetic acid) to give 397.6 mg (23%) of a compound of the indicated formula (10). The compound had a melting point of 182° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH2:30]>>[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Reactant: NCC(F)(F)C(F)(F)F
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NCC(F)(F)C(F)(F)F
Yield: 87 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.28 mmol) was converted, using 2,2,3,3,3-pentafluoropropylamine instead of 4-aminotetrahydropyran, to the title compound (115 mg, 87%) which was obtained as a brown oil. MS: m/e=477.0 [M−]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc2nc(Cl)c(C(=O)O)nc2cc1C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)c(C(=O)Nc3nnn[nH]3)nc2cc1C

Procedure:
3-Chloro-6,7-dimethyl-2quinoxalinecarboxylic acid (10.5 g) and N,N'-carbonyldiimidazole (7.35 g) in tetrahydrofuran (350 ml) were heated under reflux for 1 hour. 5-Amino-1H-tetrazole (4.3 g) in dimethylformamide (10 ml) was added and the mixture was heated under reflux for a further hour and cooled. The solid was collected and dissolved in aqueous dimethylaminoethanol. Dilute hydrochloric acid was added to the solution and the solid was collected and crystallised from dimethylformamide. The product decomposed at 360° (39%).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1)([CH2:9][CH3:10])[CH2:5][CH2:6][O:7]C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[Cl:20][C:17]1[N:16]=[CH:15][C:14]([N:13]2[CH2:12][CH2:11][C:4]3([CH2:9][CH2:10][O:7][CH2:6][CH2:5]3)[C:3]2=[O:21])=[CH:19][N:18]=1
Reactant: CCC(CCNc1cnc(Cl)nc1)(CCOC)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1N(c2cnc(Cl)nc2)CCC12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(2-chloro-pyrimidin-5-ylamino)-ethyl]-2-ethyl-4-methoxy-butyric acid methyl ester (0.083 g, 0.277 mmol) in THF (6 mL) was added a solution of potassium t-butoxide (1 M in THF) (0.5 mL), and the solution was allowed to stir at room temperature for 1 hour. An additional 0.5 mL of potassium t-butoxide (1 M in THF) was added and stirred for 2 hours. The reaction was still not complete, thus 0.75 mL of potassium t-butoxide (1 M in THF) was added and stirred for 4 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), quenched with water (3 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, and concentrated under vacuum to afford 0.07 (95%) of title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(O)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a mixture of 792 mg of 4-hydroxycoumarin and 809 mg of 1-phenyl- 1 -butanol of Preparation 12 in 25 mL of dioxane under an argon atmosphere is added 2.6 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed under reduced pressure and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether, acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 183 mg of the title product as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:21]#[N:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccccc2n1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
To a solution of {(S)-1-[1-(3-cyanophenyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (200 mg, 0.55 mmol) in DCM (2 mL) was added TFA (5 mL) and the mixture was stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-7% 2M NH3/MeOH in DCM) to afford the title compound (58 mg, 40%). 1H NMR (CDCl3, 400 MHz): δ 7.93-7.66 (6H, m), 7.39-7.21 (3H, m), 7.08 (1H, d, J=7.94 Hz), 4.16-4.05 (1H, m), 1.51 (3H, d, J=7.36 Hz)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[N:6]=1.[CH3:12][O-:13].[Na+:14]>CO>[CH3:12][O:13][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O-:10])=[O:9])[N:6]=1.[Na+:14]
Reactant: C[O-]
Reactant: COC(=O)Cc1csc(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(CC(=O)[O-])cs1

Procedure:
A solution of methyl 2-(2-bromothiazol-4-yl)acetate (80 mg, 0.34 mmol), and sodium methanolate (300 mg) in MeOH was stirred at 85° C. overnight. Then the reaction mixture was concentrated to give the desired product. 1H NMR (METHANOL-d4) δ: 4.04 (s, 3H), 3.47 (d, J=1.1 Hz, 2H), 3.37 (s, 1H). LC-MS: m/z (M+H)=174.2
Reaction SMILES: [CH:1]([C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4])=[O:2].CC(=CC)C.Cl([O-])=[O:48].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C>[C:1]([C:3]([C@H:5]1[N:8]([CH:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4])([OH:48])=[O:2]
Reactant: C=C(C=O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C=C(C(=O)O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-4-(1-Formylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (4.5 g) was dissolved in t-butanol (380 ml). After addition of 2-methyl-2-butene (42.5 ml) thereto, there was dropwise added an aqueous solution (72.3 ml) of sodium chlorite (7.15 g) and disodium hydrogenphosphate (7.15 g). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo at 40° C. or lower. The concentrate was diluted with ethyl acetate (150 ml) and water (75 ml), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (80 ml), and the combined ethyl acetate layer was washed with brine (150 ml) and extracted with a saturated sodium bicarbonate solution (150 ml). The alkaline layer was acidified with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extracts were washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-carboxyethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [N:1]1[N:2]2[CH2:11][CH2:10][CH2:9][C:3]2=[CH:4][C:5]=1[C:6]([O-])=[O:7].[K+].CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].N1C=CC=CC=1>ClCCl.O>[CH3:28][O:27][N:26]([CH3:25])[C:6]([C:5]1[CH:4]=[C:3]2[CH2:9][CH2:10][CH2:11][N:2]2[N:1]=1)=[O:7]
Reactant: CNOC
Reactant: O=C([O-])c1cc2n(n1)CCC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2n(n1)CCC2
Temperature: 5.5 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a cooled (5-6° C.), stirred suspension of crude potassium 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (0.82 g, 4.3 mmol) in dichloromethane (15 mL), containing N,N-dimethylformamide (0.1 mL, 1.3 mmol), is added, dropwise, oxalyl chloride (0.6 mL, 6.9 mmol). The reaction is exothermic with gas evolution. After the addition, the ice-bath is removed to allow the reaction mixture to stir at room temperature. After 3 hours, the solution is added to a stirred, cooled (10-12° C.) suspension of N,O-dimethylhydroxylamine hydrochloride (0.67 g, 6.9 mmol) in dichloromethane (7 mL) containing pyridine (1.7 mL, 21 mmol). After 40 minutes at room temperature, dichloromethane (35 mL) and water (25 mL) are added. The two layers are separated. The organic layer is extracted with water (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under diminished pressure to give 0.75 g (89% yield) of N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide as a brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1.[CH3:32][C:33]1([CH3:40])[CH2:37][C:36](=[O:38])[O:35][C:34]1=[O:39].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH3:32][C:33]([CH3:40])([CH2:37][C:36](=[O:38])[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1)[C:34]([OH:39])=[O:35]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: O=C(Nc1ccc(OC2CCCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N1CCCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1)C(=O)O
Yield: 68.5 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl]-amide (52.3 mg, 0.121 mmol), 3,3-dimethyl-dihydro-furan-2,5-dione (17 mg, 0.133 mmol) and triethylamine (34 uL, 0.242 mmol) in 1 mL DMSO were stirred at room temperature for 30 minutes and then diluted with 30 ml ethyl acetate. The organic phase was washed with 2.5% KHSO4 (5 mL) and saturated sodium chloride (2×5 mL), dried over MgSO4, filtered and evaporated to dryness under vacuum. The crude product was purified by flash chromatography to yield 2,2-dimethyl-4-oxo-4-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-butyric acid as a white solid (46.4 mg, 68%). ES-MS calcd for C28H28F3N3O6 (m/e) 559.55, obsd 560 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9](OCC)=[O:10]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH:9]=[O:10]
Reactant: NCCCCCCO
Reactant: CCOC=O
Product: O=CNCCCCCCO
Yield: 72 %

Procedure:
The reaction was carried out in similar procedure to Example 71a using 1.50 g (12.8 mmol) of 6-amino-1-hexanol and 3 mL of ethyl formate to obtain 1.34 g (yield: 72%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7]=1[C:8]([O:10]C)=[O:9].C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 25.6 %

Procedure:
The product from Step 1 (2.32 g, 7.9 mmol, 1.00 equiv) was dissolved in MeOH (32 mL). THF (10 mL) was added, followed by 2.5N NaOH (10 mL). The reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl. The aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were washed with satd. NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexane. The resulting solid was triturated with 50% CH2Cl2/hexanes to afford 570 mg of the acid as an off-white solid. MS (ES+) m/e 282 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][O:11][CH:12]3[CH:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])=[CH:20][CH:19]=4)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:49][CH2:50][CH2:51][O:52][CH3:53]>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:13][CH:12]2[O:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][N:1]3[CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:23][CH:22]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3[nH]ccc23)cc1
Reactant: COCCCCl
Product: COCCCn1ccc2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21

Procedure:
Analogously to Example 10a, 0.148 g of benzyl 3-(1H-indol-4-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10b2) and 0.110 ml of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=27.24 min (II).