Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH:9]12[CH2:15][CH:12]([NH:13][CH2:14]1)[CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CN(C)C=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH:9]3[CH2:15][CH:12]2[CH2:11][N:10]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(I)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
A mixture of 1,4-diiodobenzene (9.98 g, 30.3 mmol), tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.0 g, 10.1 mmol), copper (I) iodide (434 mg, 3.03 mmol), 1,1′-bi-2-naphthol (867 mg, 3.03 mg), tripotassium phosphate (5.14 g, 24.2 mmol) and anhydrous N,N-dimethylformamide (50 ml) was stirred at 80° C. for 2 days. 1,4-Diiodobenzene (3.33 g, 10.1 mmol) was added, and the mixture was stirred at 90° C. overnight. After cooling to room temperature, the mixture was filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate and washing solution were combined, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane=80:20) to, give tert-butyl 5-(4-iodophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.34 g, yield 33%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[S:19][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N:26]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:23])[S:19][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylic acid (62.5 mg) in DMA (2 mL) were added EDCI hydrochloride (43.8 mg) and HOBt ammonium salt (34.7 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (55.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(N2CCN(CCCNC(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 105.5 %

Procedure:
A mixture of 5.9 g (30 mmol) of 1-(3-chlorophenyl)piperazine, 12.55 g (33 mmol) of 3-bromo-N-(triphenylmethyl)propanamine, 6.2 g (45 mmol) of potassium carbonate and 60 ml of dimethylformamide is stirred at 90° C. for 6.5 h under argon. The mixture is then poured into iced water and is extracted with ethyl acetate. The organic phase is separated off, is washed with water, is dried and the solvent is evaporated off. 15.7 g of oily residue are obtained and are purified by chromatography on a column of silica gel by eluting with a 99/1 dichloromethane/methanol mixture, which yields 11.8 g of light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24]3)[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC2CCC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
104 mg (0.27 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoic acid (racemate) and 57 mg (0.30 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 66 mg (purity 86%, 38% of theory)
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH3:5][CH:2]([NH2:1])[CH2:3][O:4][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Clc1ccncc1
Reactant: CC(N)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N)COc1ccncc1
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
6.2 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 4.0 g of 60% sodium hydride and 50 mL of N,N-dimethylformamide at 5° C.-10° C. After the reaction mixture was stirred for 30 minutes, 12.5 g of 4-chloropyridine hydrochloride in limited amounts was added to the reaction mixture. The mixture was stirred for 20 hours at room temperature. After completion of the reaction, the solids were filtered off. The solvent in the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 3.8 g of the desired product (yield: 30%). Refractive index: 1.5469.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[CH2:4][C:5]([NH2:7])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH2:7][CH2:5][CH2:4][CH:3]([OH:8])[C:2]([F:10])([F:9])[F:1]
Reactant: NC(=O)CC(O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a cooled solution of 4,4,4-trifluoro-3-hydroxybutanamide (2.84 g, 18.1 mmol) in THF (60 mL) was added LiAlH4 (2.063 g, 54.3 mmol) in batches at 0° C. in an ice-water bath. The reaction mixture was then stirred at room temperature for 4 hours under nitrogen atmosphere. After the reaction was completed, 3.3 mL of water, 3.3 mL of 10% NaOH solution and 9.8 mL of water was added into the solution successively at 0° C. The resulting mixture was then filtered through celite, and the filtrate was concentrated in vacuo to afford 4-amino-1,1,1-trifluorobutan-2-ol (2.06 g, yield: 79.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:43][NH:44][NH:45][C:46](=[O:48])[CH3:47].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([N:44]([CH3:43])[NH:45][C:46](=[O:48])[CH3:47])=[O:13])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CNNC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
To a solution of (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionic acid (0.27 g, 0.96 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.13 g, 0.96 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.18 g, 0.96 mmol) and the mixture was cooled to 0° C. Then acetic acid N'-methylhydrazide (0.19 g, 0.96 mmol) and diisopropylethylamine (0.41 ml, 2.40 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.35 g (125%) of crude N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Cl:24][C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:25]([Cl:24])=[O:27])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCNc1ccc2nc(S)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(C(=O)Cl)c1ccc2nc(S)sc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 200.5 %

Procedure:
Into a 250 ml three-neck, round bottomed flask were added 6-(propylamino)-1,3-benzothiazole-2-thiol (500 mg, 2.23 mmol), chloroform (100 ml), and saturated aqueous NaHCO3 (75 ml). The solution was stirred (mechanical stirrer) for 10 min at 0° C. (ice-bath) for 10 min. Stirring was stopped, and a solution of triphosgene (235 mg 0.80 mmol) in CH2Cl2 (2 ml) was added to the lower (organic) phase. Stirring was resumed for 40 min, then the layers were separated, and the aqueous phase was extracted 2× with chloroform. The combined organic fractions were dried (MgSO4), filtered, and concentrated to afford 0.46 g (72%) of the carbamoyl chloride as a waxy solid. IR (neat) 1737 cm−1 (C═O).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(C(C)C)CC)(C)C.[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][N:43]([CH2:60][CH2:61][NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:44](=[O:59])[CH2:45][CH2:46][C@H:47]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:48](O)=[O:49])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:55]([O:54][C:52]([NH:51][C@H:47]([C:48](=[O:49])[NH:1][C@H:2]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])[CH2:46][CH2:45][C:44](=[O:59])[N:43]([CH2:42][CH2:41][NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:60][CH2:61][NH:62][C:63](=[O:64])[O:65][C:66]([CH3:69])([CH3:67])[CH3:68])=[O:53])([CH3:56])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a suspension of (R)-benzyl 2-amino-3-(4-(trifluoromethyl)phenyl)propanoate (CLXV) (3 g, 8.33 mmol) in DCM (25 mL) was added diisopropylethylamine (3.57 mL, 20.83 mmol). To this solution was added (S)-5-(bis(2-(tert-butoxycarbonylamino)ethyl)amino)-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (XVI) (4.88 g, 9.16 mmol) and TBTU (2.94 g, 9.16 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with DCM (50 mL) and washed with 2 N aqueous HCl, 1 N aqueous NaOH, brine, dried over MgSO4 and concentrated under vacuum to dryness. The residue was purified on a silica gel column using DCM:MeOH (100:1) to yield (12S,15R)-benzyl 12-(tert-butoxycarbonylamino)-8-(2-(tert-butoxycarbonylamino)ethyl)-2,2-dimethyl-4,9,13-trioxo-15-(4-(trifluoromethyl)benzyl)-3-oxa-5,8,14-triazahexadecan-16-oate (6.1 g, 7.28 mmol, 88% yield). 1H NMR (DMSO-d6) δ ppm 1.41 (s, 27H), 1.78-1.96 (m, 2H), 2.17 (brs, 1H), 2.59 (brs, 1H), 3.09-3.15 (m, 1H), 3.16-3.27 (m, 2H), 3.28-3.39 (m, 2H), 3.42-3.52 (m, 1H), 3.62 (brs, 1H), 4.06-4.14 (m, 1H), 4.83-4.91 (m, 1H), 5.08 (d, J=12 Hz, 1H), 5.17 (d, J=12 Hz, 1H), 5.76 (brs, 1H), 7.19 (d, J=8 Hz, 1H), 7.23-7.29 (m, 3H), 7.3-7.39 (m, 3H), 7.44 (d, J=8 Hz, 2H), 7.62 (brs, 1H); 19F NMR (DMSO-d6) δ ppm −61.84 (s, 3F); ESIMS found for C41H58F3N5O10 m/z 838.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCCC1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Yield: 29 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-butoxycyclohexane (2.28 g, 00 mmol) in the same manner as the example 20 to give the compound 34 (145 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:24]2[CH3:23])=[CH:15][CH:16]=1
Reactant: CN
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CC(=O)CC(c3ccc(OC)cc3)N2C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
1,5-Bis(4-methoxyphenyl)-1, 4-pentadien-3-one (20e, 0.40 g, 1.4 mmol) was dissolved in dimethyl formamide (10 ml). Methylamine (51, 0.75 ml, 8.7 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.30 g (68%) of a white solid: mp 141-143° C. [expected mp 129-130° C.]; 1H NMR δ 1.77, (s, 3H), 2.45 (d, 2H, J=14.5 Hz), 2.78 (t, 2H, J=12.9 Hz), 3.33 (d, 2H, J=11.9 Hz), 3.79 (s, 6H), 6.88 (d, 4H, J=8.5 Hz), 7.32 (d, 4H, J=8.5 Hz); 13C NMR: δ 40.6, 50.9, 55.3, 69.5, 114.1, 128.0, 135.3, 158.9, 207.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[NH:25])[C:10]([C:23]#[N:24])=[C:11]([SH:22])[NH:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.BrBr.O>C(#N)C>[C:16]1([O:15][C:13](=[O:14])[NH:12][C:11]2[S:22][N:25]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CC(C(=N)OCc1ccccc1)=C(S)NC(=O)Oc1ccccc1
Agent: BrBr
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: N#Cc1c(OCc2ccccc2)nsc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. suspension of the adduct, 2-cyano-3-mercapto-3-phenoxycarbonylaminoacrylimidic acid benzyl ester (282 g, 798 mmol) in acetonitrile (2 L) was added pyridine (129 mL, 1.60 mol). Next was added a solution of bromine (41.1 mL, 798 mmol) in acetonitrile (200 mL) over 15 minutes. The reaction was stirred at 0° C. for an additional 1 hour and then at ambient temperature for 2 hour. The mixture was placed in the refrigerator and held at 5° C. overnight. The solid product was filtered and washed with 0° C. ether (1 L), dried in the same funnel by drawing air through the solid for 4 hours. The solid was added to water (1 L), stirred vigorously for 1 hour, filtered and dried in the same funnel by drawing air through the solid overnight to afford a white solid (320 g pure though still containing some water) that was used, as is, in the next step. 1H NMR (400 MHz, DMSO) δ5.35 (s, 2H), 7.25-7.45 (m, 10H), 13.20 (broad s, 1H) ppm; MS (APCI, m/z): 350 [M−H]−.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](Br)=[CH:9][CH:10]=1)=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1.[F-].[Cs+].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][CH:9]=2)=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1-c1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 17 h
Yield: 73.9 %

Procedure:
Combine 6-bromopyridine-3-carboxylic acid methyl ester (387 mg, 1.79 mmol), 4-fluoro-2-methylphenylboronic acid (338 mg, 2.19 mmol), Pd(OAc)2 (40 mg, 0.18 mmol), cesium fluoride (27 mg, 0.18 mmol) and sodium carbonate (570 mg, 5.38 mmol) in DMF (6 mL) and water (6 mL) with stirring. Purge the reaction mixture with N2, add triphenylphosphine (47 mg, 0.18 mmol), and purge again with N2. Place the sealed reaction in an oil bath maintained at 80° C. and allow to stir for 17 hours. Cool the reaction to room temperature and pass through a short plug of silica gel. Wash the column with dichloromethane (100 mL) followed by aqueous methanol (100 mL, 3 methanol/1 water). Reduce the combined fractions in vacuo and suspend the residual solid in water (10 mL). Filter to remove a black solid and acidify with 1N hydrochloric acid solution to pH 4. A white precipitate forms which is collected by filtration and dried to give 306 mg (74%) of the title compound. MS (ES): m/z 231.9 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)([OH:33])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH3:40][C:37]1[CH:36]=[CH:35][C:34]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)([OH:33])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[OH:19])[CH2:11][CH2:10]2)=[CH:39][CH:38]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccc(C)cc3)c3ccc(C)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccc(C)cc3)c3ccc(C)cc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a −10° C. solution of 6.8 g (0.013 mol) of methyl 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate in 150 mL of methanol in a 500 mL round bottom flask equipped with a mechanical stirrer was slowly added 0.86 g (0.023 mol) of sodium borohydride, and the reaction was stirred for 2 hr. The methanol was removed in vacuo, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried with sodium sulfate, and the ethyl acetate was removed in vacuo to provide crude product. The resultant material was purified by column chromatography (Davisil grade 633 silica gel, packed in methylene chloride, material applied in chloroform, and eluted with a gradient of 2% methanol to methylene chloride to 5% methanol to methylene chloride) to afford methyl 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:11])[C:7](=[O:10])[CH2:8][CH3:9])[C:3]#[N:4].[BH4-].[Na+]>C(O)(C)C>[CH3:1][CH:2]([CH2:5][CH:6]([CH3:11])[CH:7]([OH:10])[CH2:8][CH3:9])[C:3]#[N:4]
Reactant: CCC(=O)C(C)CC(C)C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCC(O)C(C)CC(C)C#N
Temperature: 25 °C
Reaction time: 40 h
Yield: 87.8 %

Procedure:
To a stirred solution of 2,4-dimethyl-5-oxoheptanenitrile (IIb, 239 g, 1.56 moles) in isopropanol (2.5L) at 5° C. under a nitrogen atmosphere, was added sodium borohydride (60 g, 1.59 moles) over a 15 minute period. The mixture was stirred for 40 hours at room temperature, after which GC analysis indicated complete reaction. The reaction mixture was cooled to -5° C. and carefully quenched with water (1L) followed by saturated aqueous ammonium chloride (200 ml). After the gas evolution had subsided, the isopropanol was removed under reduced pressure (30 mm). The residue was extracted with diethyl ether (1×750 ml, 2×350 ml) and the combined organic layers washed with water (2×200 ml) and saturated aqueous sodium chloride (200 ml). After drying (MgSO4), the solvent was removed at reduced pressure (30 mm) and the crude product distilled at 75-80° C. and 0.20-0.10 mm to give a 88% yield of 2,4-dimethyl-5-hydroxyheptanenitrile (212 g, 1.37 moles).
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH3:13]O>>[O:1]([CH3:13])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CO
Product: COC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 68 h
Yield: 56.3 %

Procedure:
α-D-glucose (500 g, 2.78 mol) and a strongly acidic cation exchange resin (100 g Amberlyst 15, BDH Chemicals) was suspended in methanol (1500 ml, 37.1 mol). The mixture was stirred at 65° C. for 68 hours. The progress of the reaction was followed by HPLC. 1H NMR analysis of the reaction mixture showed a 1:1 ratio of the α-and β-anomers. The ion exchange resin was removed by filtration and the solution was cooled to 4° C. The crystalline methyl α-D-glucopyranoside was removed by filtration (230 g, 43%) and the mother liquor was evaporated in vacuo to give a crude methyl D-glucopyranoside (304 g, 57%) as a thick syrup (1H NMR showed a ratio between α- and β-anomers of 2/3).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][C@H:7]([F:9])[CH2:6][N:5]1C(OC(C)(C)C)=O)=[O:3].[ClH:17]>O1CCOCC1>[ClH:17].[F:9][C@@H:7]1[CH2:6][NH:5][C@H:4]([C:2]([NH2:1])=[O:3])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1C[C@H](F)CN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl (2S,4S)-2-aminocarbonyl-4-fluoro-1-pyrrolidinecarboxylate obtained in Example 7-8 (46 g) was dissolved in 4N HCl in dioxane (200 mL) and the resulting mixture was stirred for 10 minutes at room temperature. After removal of the solvent, the resulting residue was triturated with ethyl acetate to give the target compound as a white powder (34 g).