Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:27]([O:29][CH3:30])=[O:28])=[CH:37][CH:36]=2)[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
18.9 g (86.2 mmol) of benzyl 4-hydroxypiperidine-1-carboxylate, 25.4 g (86.2 mmol) of methyl (2S)-2-(t-butoxycarbonylamino)-3-(4-hydroxyphenyl)propionate and 27.1 g (103.4 mmol) of triphenylphosphine were dissolved in 500 ml of tetrahydrofuran. 37.5 g (86.2 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred for 15 hours. After the isolation treatment with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]3[N:13]([CH2:20][CH2:21][N:22]=3)[C:14](=[O:19])[C:15]=2[NH:16][CH:17]=O)=[CH:4][CH:3]=1.[OH-].[Na+].C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:17]=[N:16][C:15]3[C:14](=[O:19])[N:13]4[CH2:20][CH2:21][N:22]=[C:12]4[N:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:10]2=3)=[CH:4][CH:3]=1
Reactant: CC(C)CN1C2=NCCN2C(=O)C(NC=O)=C1NCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CN1C2=NCCN2C(=O)c2ncn(Cc3ccc(Cl)cc3)c21

Procedure:
The formyl amino compound of Procedure 88 (0.08 mol) is dissolved with warming in a solution of sodium hydroxide (0.09 mol) in 100 ml. water. The solution is treated with activated charcoal, filtered, and the filtrate neutralized with acetic acid. The precipitate is collected.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1

Procedure:
The product was made by reducing ethyl 4-nitrocinnamate (110.6 g, 0.5 mol) with 10% palladium on Carbon (4.0 g) in 95% ethanol (2L) in the presence of ammonium formate (126 g) to afford ethyl 3-(4-aminophenyl)propionate which was sulfonated with methanesulfonyl chloride in CH2Cl2 in the presence of pyridine to produce 102 g (75.2%) of N-[4-(ethoxycarbonylethyl)phenyl]methanesulfonamide.
Reaction SMILES: [C:1]1([CH:7]2[S:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([N:17]1[CH2:16][CH2:15][C:14]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:20]2)[CH2:19][CH2:18]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: c1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12

Procedure:
A cold stirred solution of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4, and triethylamine in 50 ml of chloroform is treated dropwise with a solution of acetyl chloride in chloroform to provide 1'-acetyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:15]
Reactant: O=C(C[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NCCCNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCCNC(=O)C[C@H](N)CCCN
Yield: 100.1 %

Procedure:
In 18 ml of methanol were suspended 144 mg (0.238 mmol) of (R)-3,6-bis(benzyloxycarbonylamino)-N-(3-benzyloxycarbonylaminopropyl)hexanamide. To the resulting suspension was added a suspension of 81.0 mg of 10% palladium-carbon in 2 ml of water, followed by stirring. Hydrogen gas was passed through the resulting mixture at room temperature for 3 hours to effect the hydrogenolysis reaction. The palladium-carbon was filtered off from the reaction mixture obtained, and the filtrate was then concentrated to dryness. The residue obtained was dissolved in 1 ml of water and the resulting solution was subjected to chromatography on a column of "Amberlite CG-50" (trade name, NH4+ -form, 5 ml). After the column was washed with 25 ml of water, the column was eluted with aqueous ammonia at concentrations gradiently varying from 0.5% to 7.0% (0.5%-increased steps; 25 ml at each concentration). Fractions of the eluate as eluted with 4.0% to 6.0% aqueous ammonia were combined together and concentrated to dryness, to afford 48.2 mg of (R)-3,6-diamino-N-(3-aminopropyl)hexanamide as a colorless paste.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[CH3:9])[N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1C=CC=CC=1>[CH3:9][N:8]([CH3:10])[C:4]1[N:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cccc(N)n1
Solvent: c1ccccc1
Product: CC(=O)Nc1cccc(N(C)C)n1

Procedure:
Acetylation of 2-amino-6-dimethylaminopyridine from Part A with acetic anhydride in benzene for 2 hours at reflux gives a quantative yield of the title compound. Melting point is 118°-119°.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7](O)(=[O:10])[CH:8]=[CH2:9].S(=O)(=O)(O)O.C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])(=[O:10])[CH:8]=[CH2:9]
Reactant: OCCCCO
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCO

Procedure:
Two mols of 1,4-butanediol, 2 mols of acrylic acid, 0.1 ml of sulfuric acid and 0.001 mol of hydroquinone were dissolved in 100 mol of toluene, and the solution was refluxed for 4 hours while removing water generated. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified through silica gel column chromatography using acetone as an eluent to obtain 4-hydroxybutyl acrylate. One mol of 4-hydroxybutyl acrylate obtained, 1 mol of catechol and 1 mol of borane were reacted in dichloromethane at room temperature, and 1 mol of LiBr was further added and dissolved to obtain a desired compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.[Na]>ClC(Cl)C>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)cc1
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: [Na]
Solvent: CC(Cl)Cl
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNCc2ccc(OC)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 79 mg (0.184 mmol) of (SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (racemate of Example 19, Step A) and 4-methoxybenzylamine (35.7 μL, 0.275 mmol) in 1.8 mL of dichloroethane was added sodium triacetoxyborohydrate (117 mg, 0.551 mmol)at 0° C. in several portions. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM) and the combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (0% to 3% MeOH/DCM with 1% aq. NH4OH) provided the title compound as a yellow film.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N+:27]([O-])=O)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.[H][H]>C(O)C.[Pd]>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2N)cc1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 0.475 g (1.23 mmol) of 7-methyl-3-[(2'-nitrobiphen-4-yl)methyl]-2-propyl-3H-imidazo[4,5-b]pyridine in 15 mL of absolute ethanol was added 50 mg of 10% palladium on carbon catalyst and the mixture was hydrogenated at 40 psig of hydrogen on a Parr apparatus. Reduction was complete after 1 hour and the reaction mixture was filtered and evaporated in vacuo to afford a tan solid (0.416 g, 95%) which was used in the subsequent step without further purification.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([OH:9])=O.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:5]1[N:4]=[N:3][NH:2][N:1]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1nn[nH]n1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3nn[nH]n3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (2H-tetrazol-5-yl)-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.50 min, [M+1]+ 450. Potency class B.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.Cl>O1CCCC1>[CH:19]1([CH:7]([C:6]2[CH:5]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:14]=3)[S:3][C:2]=2[CH3:1])[OH:8])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde (2.33 g) synthesized above in tetrahydrofuran (50 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (12.9 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane), and then purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (1.98 g, 65%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=4)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:35][CH3:36])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:36][O:35][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine (compound 442) (475 mg) was dissolved in trifluoroacetic acid (4.7 ml) to prepare a solution. Methanesulfonic acid (0.47 ml) was added to the solution, and the mixture was stirred at 70° C. for one hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (433 mg, yield 100%).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[N:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[CH:17]1([Mg]Cl)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>CCOCC>[Cl:6][C:7]1[C:8]([C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:11])=[CH:12][CH:13]=[C:14]([CH3:16])[N:15]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(=O)C2CCCCC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
A tetrahydrofuran (30 ml) solution of 2-chloro-6-methylnicotinic acid (3.43 g, 20 mmol) was cooled to -40° C., mixed with ether (30 ml) solution of 2.0 M cyclohexyl magnesium chloride and stirred overnight at room temperature. The reaction solution was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-3-cyclohexylcarbonyl-6-methylpyridine (650 mg, 14%) as a brown oily material.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:11][CH:12]=O.C(=O)(O)[O-].[Na+]>C(O)C>[OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:11]=[CH:12][N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncccc1CO
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCc1cccn2ccnc12
Yield: 129.1 %

Procedure:
A mixture of 2.92 g (23 mmole) of 3-hydroxymethyl-2-pyridinamine, 6.15 g (35 mmole) of chloroacetaldehyde, and 2.0 g (35 mmole) of sodium bicarbonate in 100 ml of ethanol was heated at reflux for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to a solid. Recrystallization from diethyl ether yielded 4.4 g of 8-hydroxymethylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra. A mixture of 683 mg (3.8 mmole) of 2-mercapto-5-methoxybenzimidazole and 700 mg (3.8 mmole) of 8-hydroxymethylimidazo[1,2-a]pyridine was dissolved in 3 ml of 30% hydrogen bromide in acetic acid and heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield the title compound as an oil. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]I.[CH3:17][O:18][CH2:19][CH2:20][NH:21][CH3:22].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH3:22]
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: CNCCOC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCN(C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 70 °C
Reaction time: 16 h
Yield: 492.8 %

Procedure:
A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[C:15]([CH3:16])=[N:14][NH:13][C:12]=3[NH2:17])=[N:8][C:7]=2[CH:18]=1.BrB(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:17][C:12]1[NH:13][N:14]=[C:15]([CH3:16])[C:11]=1[C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:18][C:7]=2[N:8]=1
Reactant: COc1ccc2sc(-c3c(C)n[nH]c3N)nc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1n[nH]c(N)c1-c1nc2cc(O)ccc2s1
Temperature: 4 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a suspension of 4-(5-methoxy-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine (60 mg, 0.23 mmol) in CH2Cl2 (5 mL) at 4° C. was slowly added tribromoborane (2.3 mL of a 1M solution in dichloromethane, 2.3 mmol). The reaction temperature was maintained at 4° C. and the solution was stirred overnight. The mixture was then neutralized with sodium carbonate solution. The resulting solids were isolated by filtration and were purified by flash chromatography eluting with CHCl3:MeOH=9:1 to yield 10 mg (19%) of the title compound as a cream coloured solid. MS (m/z, ES+): 247.1 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:32]=[C:31]([O:33][C@H:34]([CH3:38])[CH2:35][O:36][CH3:37])[C:30]([C:39]#[N:40])=[CH:29][N:28]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:39]([C:30]1[C:31]([O:33][C@H:34]([CH3:38])[CH2:35][O:36][CH3:37])=[CH:32][C:27]([NH:26][C:25]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH:14]=[O:15])=[C:4]([CH:3]([O:2][CH3:1])[O:16][CH3:17])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:24])=[N:28][CH:29]=1)#[N:40]
Reactant: COC[C@@H](C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(C=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 90 °C

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 156 mg, 0.660 mmol), (R)-phenyl(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)carbamate (intermediate 145, 281 mg, 0.858 mmol) and DMAP (121 mg, 0.990 mmol) in DMF (3 ml) was heated for 1 h at 90° C. The cooled reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, extracted 2× with EtOAc, the organic layers dried over Na2SO4 and evaporated. The residue was applied to a 40 g RediSep® column and purified by normal phase chromatography, eluting with hetane and then a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound. (UPLC-MS 6) tR 1.20; ESI-MS 470.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([O:16]C)=[O:15].CCO.O>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([OH:16])=[O:15]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2o1)OC
Solvent: CCO
Solvent: O
Product: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a stirred solution of methyl (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoate (1.0 g, 3.87 mmol) in EtOH/water 1/1 (80 ml) potassium hydroxide (0.43 g, 7.66 mmol) was added. The solution was refluxed for 1 hour, then it was cooled to RT and poured into water (200 ml). After acidification to pH 2 (1N HCl) the resulting suspension was extracted with EtOAc (3×50 ml). The organic phase was washed with water (2×30 ml), dried (MgSO4) and concentrated to give a yellow solid. This was repeatedly washed with CH2Cl2 and dried to give the pure title compound (0.80 g, 3.28 mmoles, yield 84.6%) as yellow crystals, m.p.=206°.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:40]1[C:44]2[CH:45]=[CH:46][C:47]([NH2:49])=[CH:48][C:43]=2[N:42]=[N:41]1.CN1CCOCC1>C(#N)C>[NH:40]1[C:44]2[CH:45]=[CH:46][C:47]([NH:49][C:15]([C@@H:14]3[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[N:10]3[C:8](=[O:9])[C@@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:16])=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc3[nH]nnc3c2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 72 h
Yield: 69.3 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (103.1 mg, 0.192 mmol), 1H-1,2,3-benzotriazol-5-amine (56.6 mg, 0.422 mmol), and N-methylmorpholine (46.4 μl, 0.422 mmol) in acetonitrile (1.87 ml) was added DMTMM tetrafluoroborate (69.2 mg, 0.211 mmol). The solution was stirred for 3 days, and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), and washed with 1 N aq. HCl (50 mL), followed by 5% aq. NaHCO3. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC (20% to 90% MeCN in water, 8 min gradient), and the desired fractions were combined, and concentrated in vacuo. The residue was azeotroped with MeOH (2×30 mL) to give phenylmethyl (3S)-3-[(1H-1,2,3-benzotriazol-5-ylamino)carbonyl]-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-pyrazolidinecarboxylate (87.2 mg, 0.133 mmol, 69.6% yield) as a light yellow oil. LC/MS: (M+H)+: 654.5. Reference for DMTMM tetrafluoroborate: Raw, S. A. Tetrahedron Lett. 2009, 50, 946.