Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:18]([N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccccc3)C2=O)cc1

Procedure:
The title compound 28i was prepared from compound 2 (75 mg, 0.30 mmol), benzyl bromide (39 μL, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in a manner similar to that described for 28d in 99.6% (101 mg) yield as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:21][C:22]=2[CH:27]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2cc(-c3nc4cc(Cl)ccc4o3)ccc2n1C1CCOCC1
Yield: 15.3 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-4-chlorophenol (0.15 g, 1.05 mmol), anhydrous DMF (10 mL) and WSC (0.22 g, 1.14 mmol) were stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.32 g, 1.68 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (54 mg, 15.3% yield) as a light brown solid.
Reaction SMILES: C[Al](C)C.Cl.[CH2:6]([NH2:8])[CH3:7].[C:9]1([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18](OC)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1(C)C=CC=CC=1>[CH2:6]([NH:8][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=1)[CH3:7]
Reactant: CCN
Reactant: COC(=O)c1cccc(-c2ccccc2)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 62 %

Procedure:
Trimethylaluminum (920 μL of 2M solution in toluene, 1.84 mmol) was added drop wise to a suspension of ethylamine hydrochloride (151 mg, 1.84 mmol) in 2.76 mL of dry toluene at 0° C. The reaction was then warmed to room temperature and stirred until no gas evolution was observed. The clear solution was then canulated onto a solution of Methyl 3-phenylbenzoate in 6 mL of toluene. The reaction was then heated to 80° C. and stirred for 18 hours. The reaction mixture was then carefully treated with 5% HCl at 0° C. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The oil obtained was purified by flash chromatography using SiO2 with CH2Cl2/MeOH 99:1 to give a pale yellow oil (129 mg, 62%). NMR 1H (ppm, CDCl3): 8.0 (s, 1H), 7.72 (d, J3=8.1 Hz, 2H), 7.61 (d, J3=5.4 Hz, 2H), 7.52-7.35 (m, 4H), 6.14 (br. s., 1H), 3.58-3.49 (m, 2H), 1.28 (t, J3=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[NH:26][N:27]=[C:28]([C:35]2C=CC=CC=2)[C:29]2C=CC=[CH:31][CH:30]=2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41]C(=O)CC(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH2:25][CH3:41])=[O:23])[CH:19]=[CH:18][C:17]=2[N:26]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:35])=[N:27]2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1ccc(NN=C(c2ccccc2)c2ccccc2)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2nc(C)cc2C)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 120 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
Put 600 mg (1.08 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate, 378 mg (3.78 mmol) of 2,4-pentanedione, 186 mg (1.08 mmol) of paratoluenesulphonic acid and 5 mL of ethanol in a screw-top bottle. Heat the mixture at 120° C. while stirring for 48 h, then cool, and concentrate under reduced pressure. Then distribute the residue in 50 mL of EtOAc and 50 mL of a saturated aqueous solution of NaHCO3. Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 235 mg of ethyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[CH:9]=1)[C:3](=[O:6])[CH:4]=[CH2:5].CN(CC1SC2C=CC=CC=2C=1C)C(=O)C=C.Br[C:36]1[CH:37]=[C:38]([CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[C:39]([NH2:42])=[N:40][CH:41]=1.BrC1C=NC2NC(=O)C(C)(C)NCC=2C=1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[O:6])=[CH:37][C:38]=1[CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: Nc1ncc(Br)cc1CN1CCOCC1
Reactant: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Agent: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Agent: CC1(C)NCc2cc(Br)cnc2NC1=O
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc(N)c(CN2CCOCC2)c1
Yield: 38 %

Procedure:
According to the procedure of Example 2(a), except substituting N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide for the N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide, and substituting 5-bromo-3-morpholin-4-ylmethyl-pyridin-2-ylamine for the 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one, the title compound (510 mg, 38%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H),7.78 (s, 1H), 7.63-6.91 (m, 7H), 6.51 (s, 2H), 4.89-4.72 (m, 2H), 3.76 (s, 3H), 3.57 (br s, 4H), 3.42-3.34 (m, 2H), 3.02-2.90 (m, 3H), 2.33 (br s, 4H); MS (ESI) m/e 420 (M+H)+.
Reaction SMILES: Cl.C(OCC)C.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH2:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=4)[S:25][C:19]=3[N:18]([CH2:45][C:46]3[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=3[F:53])[C:17]2=[O:54])=[CH:12][CH:11]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C.[Pd]>[NH2:7][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH2:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=4)[S:25][C:19]=3[N:18]([CH2:45][C:46]3[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=3[F:53])[C:17]2=[O:54])=[CH:14][CH:15]=1
Reactant: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCOC)c(=O)n(-c2ccc([N+](=O)[O-])cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOCC
Product: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCOC)c(=O)n(-c2ccc(N)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
2 N-hydrochloride/diethyl ether solution (20 ml) and 50% hydrous-10% palladium/carbon (1.00 g) were added to a solution of the compound of Example 96 (1.00 g) in ethanol (200 ml) and the mixture was stirred thoroughly under hydrogen atmosphere for 1 hour. The filtrate except a catalyst was neutralized with aqueous sodium bicarbonate, and then the solvent was distilled off. The obtained residue was partitioned between ethyl acetate and water, and then the organic layer was washed with saturated brine and dried over anhydride magnesium sulfate. The residue obtained by distilling off the solvent under the reduced pressure, was subject to NH-silica gel (manufactured by Fuji Silysia Chemical Ltd.) chromatography, and was recrystallized from methanol to give the title compound (0.80 g, 62%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:20][C:21]([Br:24])=[CH:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([CH2:43][CH2:42][C:39]2[CH:38]=[CH:37][C:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=3)=[CH:41][CH:40]=2)[CH2:45][CH2:46]1
Reactant: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=O)CC3)cc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=C(Br)Br)CC3)cc2)cc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A solution of 6.7 g of triphenylphosphine in 60 ml of methylene chloride was placed at -20° C. under argon gasification in a sulphonation flask equipped with a thermometer, dropping funnel and solid substance addition tube and treated within 5 minutes with 4.3 g of tetrabromomethane. The clear orange solution was stirred at -15° C. for a further 10 minutes and then a solution of 2.33 g of trans-4-[2-(4'-pentyl-4-biphenylyl)ethyl]cyclohexanecarboxaldehyde in 40 ml of methylene chloride was added dropwise at -5° C. within 10 minutes. The mixture was stirred at -5° C. for a further 10 minutes, then poured into 700 ml of hexane and freed from precipitated triphenylphosphine oxide by filtration. The concentrated filtrate was digested with 300 ml of hexane, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.5 g) on silica gel with 1% ethyl acetate/petroleum ether gave 2.87 g (87%) of 4-[2-[trans-4-(2,2-dibromovinyl)cyclohexyl]ethyl]-4'-pentylbiphenyl as colourless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinamide (0.097 g, 0.4 mmol) in 5 mL of methanol with benzylamine (0.4 mmol), and 1 g of 3 Å molecular sieves. Stir for 18 h. Add sodium borohydride (0.076 g, 2 mmol), and stir for 18 h. Flush the reactions down through a 5 g SCX column, first wash with 1:1 chloroform/methanol, then collect washes with 1:1 chloroform/2 M ammonia in methanol. Adsorb the collected material on silica, then purify via a ISCO® Combiflash 16x system (use a 10 g silica cartridge, and elute with 98:2:2 chloroform/ethanol/ammonium hydroxide, gradient to 90:10:1 chloroform/ethanol/ammonium hydroxide). 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (m, 1H), 8.0 (s, 1H), 7.46 (s, 1H), 7.27-7.38 (m, 6H), 7.20 (m, 1H), 7.02-7.08 (m, 3H), 3.67-3.68 (d, 4H). TLC Rf (90:10:1 chloroform/ethanol/ammonium hydroxide): 0.31.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]([OH:11])=[O:10].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]([OH:11])=[O:10])(=[O:20])[CH3:19]
Reactant: C[C@@H]1CC[C@@H](C(=O)O)[C@@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a solution of (1R,2S,4R)-2-Hydroxy-4-methyl-cyclohexanecarboxylic acid (162 mg, 1.02 mmol) in dichloromethane (5 ml) was added pyridine (495 ul, 6.12 mmol) followed by acetic anhydride (385 ul, 4.08 mmol). The reaction mixture was stirred for 20 h at room temperature. Then, the solvents were removed and 10 ml of 3N HCl solution was added. This mixture was stirred for 30 minutes and then a saturated solution of NaHCO3 was slowly added until PH=9-10. This solution was then extracted with ethyl acetate (2×5 ml). The aqueous phase was then acidified with a 10% HCl solution and extracted with ethyl acetate (3×5 ml). The following ethyl acetate layers were combined, dried (Na2SO4) and concentrated to obtain 109 mg (53%) of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid.
Reaction SMILES: [CH2:1]1[C@@H:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[C@H:8]([CH2:25]O)[C@H:3]2[CH2:4][C:5]([O:7][C@@H:2]12)=[O:6].[Na+].[Br-].C([O-])(O)=O.[Na+].CC(O)C.[O-]Cl.[Na+].[C:41]([C:45]1[CH:46]=[C:47]([O:51][CH2:52][C:53]([CH2:55]P(OC)(OC)=O)=[O:54])[CH:48]=[CH:49][CH:50]=1)([F:44])([F:43])[F:42].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[O:54]=[C:53]([CH2:52][O:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([C:41]([F:42])([F:43])[F:44])[CH:46]=1)/[CH:55]=[CH:25]/[C@@H:8]1[C@@H:3]2[C@@H:2]([O:7][C:5](=[O:6])[CH2:4]2)[CH2:1][C@H:9]1[O:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Reactant: COP(=O)(CC(=O)COc1cccc(C(F)(F)F)c1)OC
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)COc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of (−)-Corey lactone 5-(4-phenylbenzoate) (17.6 g, 50.0 mmol) and TEMPO (0.16 g, 1.0 mmol) in CH2Cl2 (100 mL) was added to a mixture of NaBr (0.5 g, 5.0 mmol), NaHCO3 (12.6 g, 150.0 mmol) and IPA (6.0 g, 100.0 mmol) in water (100 mL). 5% aq. NaOCl (about 150 mL) was added dropwise to the stirred mixture at −5 to 0° C. until disappearance of Corey lactone (TLC monitoring). The obtained mixture was stirred for 0.5 h at the same temperature. The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layer was added dropwise over 1 hour to a stirred mixture of a solution of m-CF3C6H4OCH2COCH2PO(OMe)2 (19.6 g, 60.0 mmol) in CH2Cl2 (20 mL) and 30% NaOH (8.0 g, 60.0 mmol) at 0 to −5° C. The mixture was stirred 1 h at the same temperature and treated with 10% aq. citric acid (100 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layer was dried over Na2SO4, filtered through short silica gel column and concentrated in vacuo. The oily residue (26.96 g) was dissolved in refluxed MeOH (150 mL) and cooled in ice bath. The precipitate was filtered off, washed with cold MeOH and dried in vacuo to give 22.1 g (80%) of (3aR,4R,5R,6aS)-4-[3-oxo-4-[3-(trifluoromethyl)phenoxy]-1E-butenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one with 99.1% purity by HPLC: mp 115–116° C.; [α]D20 −118.4° (c 1.0, CHCl3). 1H NMR (CDCl3) δ: 8.02 (d, J=8 Hz, 2H), 7.58 (m, 4H), 7.40 (m, 4H), 7.22 (d, J=8 Hz, 1H), 7.10 (s, 1H), 6.94 (m, 2H), 6.57 (d, J=15.7 Hz, 1H), 5.35 (q, J=5.5 Hz, 1H), 5.09 (t, J=5.5 Hz, 1H), 4.71 (s, 2H), 2.92 (m, 3H), 2.56 (m, 3H).
Reaction SMILES: C([N:4]1[C@@H:9]([C:10]([O:12]CC)=[O:11])[C@H:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:22]=[C:23](Br)[S:24][C:6]=2[C:5]1=[O:26])C=C.[CH3:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>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:21][C:18]1[CH:17]=[CH:16][C:15]([C@H:8]2[C@H:9]([C:10]([OH:12])=[O:11])[NH:4][C:5](=[O:26])[C:6]3[S:24][C:23]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=4)=[CH:22][C:7]2=3)=[CH:20][CH:19]=1
Reactant: C=CCN1C(=O)c2sc(Br)cc2[C@@H](c2ccc(Cl)cc2)[C@@H]1C(=O)OCC
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: Cc1cc(-c2cc3c(s2)C(=O)N[C@@H](C(=O)O)[C@@H]3c2ccc(Cl)cc2)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of ethyl rel-(4R,5R)-6-allyl-2-bromo-4-(4-chlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (505.0 mg, 1.11 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (486 mg, 2.22 mmol) in 1,4-dioxane (14.6 mL, 187 mmol) and water (1.9 mL, 110 mmol) were added tetrakis(triphenylphosphine)palladium(0) (64.2 mg, 0.055 mmol) and cesium carbonate (1.08 g, 3.33 mmol). The mixture was stirred at 80° C. for 16 hr. After the reaction was completed, the solvent was evaporated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% [(60/20/20/20) EA/ACN/MeOH/water)]/EA to give the title compound as a yellow solid (428.7 mg, 73% yield). LCMS: (AA) ES+ , 399/401. 1H NMR (400 MHz, DMSO) δ 8.72 (d, J=6.1 Hz, 1H), 8.45 (d, J=6.6 Hz, 1H), 8.30 (d, J=4.4 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.43 (t, J=10.0 Hz, 2H), 7.21 (dd, J=24.7, 7.7 Hz, 3H), 4.98-4.59 (m, 1H), 4.32 (d, J=2.9 Hz, 1H), 2.69 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([O:7]C(C)(C)C)=[O:6])[CH2:2]1.[NH:12]1[CH2:15][CH:14]([C:16](O)=O)[CH2:13]1.C1N=CN(C(N2C=NC=C2)=O)C=1.NO>C(O)(C)(C)C>[NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[CH:5]([C:3]1[CH:2]=[CH:16][C:14]([C:13]#[N:12])=[CH:15][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: NO
Agent: O=C(O)C1CNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C=O)cc1

Procedure:
tert-Butyl azetidine-3-carboxylate (3.6.1) may be prepared from azetidine-3-carboxylic acid (3.5) via protection of the amine (for example with the CBZ group) followed by esterification of the acid with tert-butyl alcohol in the presence of a coupling reagent (for example CDI) and then removal of the amine protecting group. (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (2.1.1) is available from the reaction of tert-butyl azetidine-3-carboxylate (3.6.1) with 4-formylbenzonitrile (4.2) under reducing conditions to give 4.3, which is then reacted with hydroxylamine. Alternatively, compound 4.3 may be prepared by esterification of 4.5, which is obtained from the reaction of azetidine-3-carboxylic acid (3.5) with 4-formylbenzonitrile (4.2) under reducing conditions.
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([OH:26])=O)[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[CH:48]=1>C(Cl)Cl>[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:56])([F:57])[F:58])[CH:48]=4)=[O:26])[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Nc1ccc(CO)c(C(F)(F)F)c1
Reactant: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)O)[C@@H]1c1ccc(NC2CCCC2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
Step b) Methanesulfonyl chloride (378 mg, 3.3 mmol) was added to a solution of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid prepared above (1.4 g, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) in dry CH2Cl2 (25 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred for an additional 15 minutes, then [4-amino-2-(trifluoromethyl)phenyl]methanol (631 mg, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) were added sequentially. The reaction mixture was allowed to attain room temperature over a period of 30 minutes. When TLC and LCMS indicated completion of the reaction, excess solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in dichloromethane) to get the desired compound (1.2 g) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 9.50 (bs, 0.6H), 9.38 (bs, 0.4H), 7.75-7.70 (m, 1H), 7.50-7.33 (m, 3H), 7.24-7.19 (m, 2H), 7.06-6.90 (m, 2H), 6.67-6.55 (m, 3H), 4.77-4.76 (m, 2H), 3.78-3.66 (m, 1H), 3.32-3.00 (m, 3H), 2.44-1.45 (m, 17H). MS: (ES) m/z 598 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([N:10]([C:16]([CH3:23])([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:17])[C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].ClC1C=CC=C(Cl)C=1C(N1C2C=CN=CC=2C=C1)=O>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27]([N:1]1[C:9]2[CH:8]=[C:7]([N:10]([C:16]([CH3:23])([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:17])[C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:28]
Reactant: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2[nH]ccc2cn1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(c1c(Cl)cccc1Cl)n1ccc2cnccc21
Product: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2c(ccn2C(=O)c2c(Cl)cccc2Cl)cn1

Procedure:
The compound was prepared from N-(1H-pyrrolo[3,2-c]pyridin-6-yl)-N-(2,4,4-trimethylpentan-2-yl)cyclopropanecarboxamide and 2,6-dichlorobenzoyl chloride following the procedure same as that of (2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([C:8]([C:7]3[CH:11]=[C:3]([CH:4]=[CH:5][C:6]=3[O:12][CH:13]([CH3:15])[CH3:14])[C:1]#[N:2])=[O:10])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: Cl
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CC=C(c2ccc(Cl)cc2)CC1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 5-cyano-2-isopropoxy-benzoic acid (CAS: 845616-14-0) and 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (commercial). MS (m/e): 381.1 (MH+, 100%).