Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=C(\C#N)/C(NC(C2C=CC(OCCN(CC)CC)=CC=2)CCC)=O)[CH:5]=[CH:4][CH:3]=1.[C:33]([CH2:35][C:36]([NH:38][CH:39]([C:43]1[CH:72]=[CH:71][C:46]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[CH:45][CH:44]=1)[CH2:40][CH2:41][CH3:42])=[O:37])#[N:34]>>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:35](\[C:33]#[N:34])/[C:36]([NH:38][CH:39]([C:43]2[CH:72]=[CH:71][C:46]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][N:56]([C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])[C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])=[CH:45][CH:44]=2)[CH2:40][CH2:41][CH3:42])=[O:37])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that (2-(2-(2-(4-(1-(2-cyanoacetamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (46) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 7:3 hexanes/ethyl acetate, to give 47 (105 mg, 85%) as a clear oil: MS (ES+) m/z 731.2 (M+H)+.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.NC1[C:18]([Br:19])=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[Br:19][C:18]1[CH:17]=[N:16][N:15]2[C:5]([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CN(C)C=CC(=O)c1ccsc1
Solvent: CC(=O)O
Product: Brc1cnn2c(-c3ccsc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one and 0.01 mole of 3-amino-4-bromopyrazole in glacial acetic acid is heated at reflux temperature for 8 hours. The solvent is removed in vacuo to give the product of the example.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][NH:10][CH3:11])=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12.CCN(C(C)C)C(C)C>C(O)CC>[CH3:11][N:10]1[C:2]2=[C:3]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:4]3=[N:5][CH:6]=[C:7]2[CH2:8][CH2:9]1
Reactant: CNCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(cnc32)CCN4C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
2-(4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylethanamine (0.670 g, 1.84 mmol) in PrOH (20 mL) was heated to about 105° C. for about 44 h. DIEA (0.39 mL, 2.2 mmol) was added and heating was continued at about 105° C. for about 24 h. The mixture was cooled to rt and the solvent was evaporated under reduced pressure. The material was treated with saturated NaHCO3 (15 mL) and water (10 mL) then extracted with DCM (25 mL then 10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography on 10 g of silica with EtOAc as an eluent to give 1-methyl-6-tosyl-1,2,3,6-tetrahydrodipyrrolo[2,3-b:2′,3′-d]pyridine (0.308 g, 51%): LC/MS (Table 2, Method a) Rt=2.53 min; MS m/z 328 (M+H)+.
Reaction SMILES: C[O:2][P:3]([CH:7]([C:18]([O:20]C)=[O:19])[CH:8]([C:14]([O:16]C)=[O:15])[CH2:9][C:10]([O:12]C)=[O:11])(=[O:6])[O:4]C.Cl.CCl>CO>[C:18]([CH:7]([P:3]([OH:4])(=[O:2])[OH:6])[CH:8]([C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])([OH:20])=[O:19]
Reactant: COC(=O)CC(C(=O)OC)C(C(=O)OC)P(=O)(OC)OC
Agent: CCl
Agent: Cl
Solvent: CO
Product: O=C(O)CC(C(=O)O)C(C(=O)O)P(=O)(O)O

Procedure:
The ester thus obtained and 100 cc of concentrated hydrochloric acid were heated to boiling temperature (which increased from 75° to 105° C) while methyl chloride and methanol originating from the hydrolysis were distilled off. After the hydrolysis was complete, the reaction solution was evaporated under vacuum to dryness (maximum base temperature = 120° C) and diluted with water so as to obtain a solution of 50% strength.
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:11][C:12](=[O:29])[C@H:13]([CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)[NH:14][C:15](=[O:22])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[O:21]=[C:18]1[NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:40])=[O:8])[CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[O:29])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)OCc2ccccc2)N1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan benzyl ester (Ex. 1, 0.300 g, 0.555 mmol) and 5 percent palladium on carbon (0.060 g) in glacial acetic acid (30 ml) is stirred rapidly under an atmosphere of hydrogen for 16 hours at room temperature. The mixture is filtered through diatomaceous earth ("Celite") and the filtrate is concentrated under reduced pressure. The residue is dissolved in methanol (10 ml) and diethyl ether (100 ml) is slowly added with vigorous stirring. The precipitate is collected, dissolved in methanol (10 ml) and diethyl ether (100 ml) is slowly added. The precipitate is collected, dissolved in methanol, treated with charcoal (0.20 g) and filtered through diatomaceous earth ("Celite"). The filtrate is evaporated to yield the title compound as a hard white glass which is used as such in a subsequent step.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH:19][C:20](=O)[CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][N:19]=[C:20]([Cl:3])[CH2:21][Cl:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(CCl)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cl)c(NN=C(Cl)CCl)c(Cl)c1
Temperature: 70 °C
Yield: 90 %

Procedure:
Phosphoryl chloride (500 microlitres, 1.7 equivalents) was added in one portion to a stirred solution of N′-(2,6-dichloro-4-trifluoromethylphenyl)-chloroacetohydrazide (1.0 g, 3.11 mmol) in toluene (20 ml) and heated at 70° C. under an argon atmosphere for 20 hours. The cooled mixture was evaporated and the residue extracted with cyclohexane. The extracts were combined and evaporated to give the title compound (0.971 g) as an orange oil, NMR 4.4 (s, 2H), 7.55 (s, 2H), 7.7 (s, 1H). The yield was 90%.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].Cl.C(=O)([O-])O.[Na+]>CC(O)C.CO>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CC(C)O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Under ice-cooling, sodium borohydride (1.2 g) was dissolved in IPA (50 ml). After adding methanol (5 ml), a solution of the compound (5.0 g) obtained in Example 1 in IPA was dropped thereinto. Then the liquid reaction mixture was heated to 50° C. and stirred for 1 hour. Next, hydrochloric acid (1 mol/l) was added and the mixture was stirred for a while. Then a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to give 3.7 g (84%) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:9]1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>[OH-].[Na+]>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:9]1[C:21]([OH:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c(C)cn1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: Cc1cn(Cc2ccccc2)c(C(=O)O)c1-c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
Ethyl 1-benzyl-3-(4-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (5.0 g, 14.83 mmol) was added to a solution of 8M NaOH (30 mL) and catalytic amount of TBAF (0.5 mL) at 0° C. The resulting mixture was stirred at 110° C. for 24 h. The reaction mixture was cooled to 0° C., acidified (pH-2) with 6N HCl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated to afford the desired product (3.8 g, 84%) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>O1CCCC1.O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:25]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:32][CH2:33]2)=[O:12])[CH2:8]1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCN(c2ncccn2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was treated with 1.6 g (0.01 mole) of 1-(2-pyrimidyl)piperazine added dropwise. After stirring for 30 min, a few pieces of ice were added and stirring continued for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly crystallized. Recrystallization from isopropyl ether yielded 2.7 g (66.3%) of fine white crystals, m.p. 127°-128° C.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[C:9]([CH3:25])[CH:10]=[CH:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[O:6]=[C:5]1[CH:7]=[SH:1](=[C:9]([CH3:25])[CH:10]=[CH:11][C:12]2[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=2[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2](=[S:3])[NH:4]1
Reactant: O=C1CSC(=S)N1
Reactant: CCOC(=O)COc1ccccc1C=CC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccccc1C=CC(C)=[SH]1=CC(=O)NC1=S
Yield: 35.8 %

Procedure:
A mixture of 1.33 g (0.01 mol) of rhodanine, 2.48 g (0.01 mol) of ethyl 2-(3-oxo-1-butenyl]phenoxyacetate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 3 hours. After cooling, 100 ml of water were added to the reaction mixture which was extracted with ethyl acetate (3×100 ml). The ethyl acetate layer was washed twice with water and once with a saturated saline solution, dried and concentrated under reduced pressure to give orange crystals. The crystals were purified by silica gel column chromatography (eluent, chloroform : ethyl acetate) to obtain ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolinylidene)-1-butenyl]phenoxyacetate (35.8% yield) from the first eluate.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)CCO
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (20 mg, 20%), MS (ISP) m/z=399.3 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-hydroxy-propionic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3C(F)(F)F)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 2-(trifluoromethyl)phenylboronic acid (190 mg, 1.0 mmol) to afford after chromatographic purification the title compound (175 mg, 79%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (d, 1H, J=7.7 Hz), 7.50 (dd, 1H, J=7.3, 7.7 Hz), 7.40 (dd, 1H, J=7.7, 7.3 Hz), 7.31 (d, 1H, J=7.3 Hz), 6.89 (s, 1H), 6.85 (s, 1H), 3.82-4.30 (m, 2H), 3.66-3.71 (m, 1H), 2.88-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([NH:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])=[O:19])=[CH:3]1.CN([Si](C)(C)C)C(=O)C(F)(F)F.Cl[S:40]([NH:43][C:44]([N:46]1[CH2:49][C@H:48]([NH:50][C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[C:47]1=[O:61])=[O:45])(=[O:42])=[O:41]>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([NH:20][N:21]2[CH2:25][CH2:24][N:23]([S:40]([NH:43][C:44]([N:46]3[CH2:49][C@H:48]([NH:50][C:51](=[O:52])[O:53][CH2:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:47]3=[O:61])=[O:45])(=[O:41])=[O:42])[C:22]2=[O:26])=[O:19])=[CH:3]1
Reactant: O=C(C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1)NN1CCNC1=O
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Cl)C1=O)OCc1ccccc1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CCOC(C)=O
Product: O=C(C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1)NN1CCN(S(=O)(=O)NC(=O)N2C[C@H](NC(=O)OCc3ccccc3)C2=O)C1=O
Reaction time: 1 h

Procedure:
3-[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-N-(2-oxo-1-imidazolidinyl)-2-propenamide (3.55 g) was suspended in 100 ml of ethyl acetate and 6.3 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added. After stirring for 1 hour, a clear solution was obtained. The solution was then added within 10 minutes to a cooled solution (0° C.) of 3.3 g of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 50 ml of ethyl acetate. After stirring overnight, the solvent was evaporated and the oily residue was stirred for 1 hour with 50 ml of isopropanol. The resultant precipitate was isolated by filtration and washed with isopropanol and ether. Yield: 5.91 g.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:31])[C:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([O:19]CC)=O)=[C:12]([O:22][C:23]([O:25]CC)=O)[CH:11]=1)(=[O:3])[CH3:2].C[C:33]([CH3:38])([CH3:37])[C:34](Cl)=O>>[C:1]([O:4][CH2:5][O:6][C:7](=[O:31])[C@:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:19])[C:33]([CH3:38])([CH3:37])[CH3:34])=[C:12]([O:22][C:23](=[O:25])[C:8]([CH3:28])([CH3:9])[CH3:7])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(C)=O)cc1OC(=O)OCC
Reactant: CC(C)(C)C(=O)Cl
Product: CC(=O)OCOC(=O)[C@](C)(Cc1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1)NN

Procedure:
Following the procedure for preparation of compound 101, and substituting ethyl chloroformate with 2,2-dimethylpropionyl chloride, provided the title compound. 1H NMR (CD3OD, 400 MHz): δ 1.33 (s, 9H), 1.34 (s, 9H), 1.46 (s, 3H), 2.12 (s, 3H), 3.08 (dd, 2H), 5.83 (dd, 2H), 7.05–7.12 (m, 3H). MS (ESI) m/z 467.35 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=[O:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]([OH:28])[CH:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[OH:8])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
4-(tert-Butyldimethylsilyloxymethyl)-pyridine (T. F. Gallagher et al, Bioorganic and Medicinal Chemistry; 1997, 5, 49) (67 g, 0.3 mol) was dissolved in THF (250 ml) and cooled to −40° C. The solution was treated with a 2M solution of lithuim diisopropylamide in THF (200 ml, 0.4 mol) and stirred for 45 min maintaining a temperature of −40 to −20° C., before the dropwise addition of 3,4-dichlorobenzaldehyde (55.13 g, 0.32 mol) in THF (250 ml). The mixture was allowed to warm to room temperature then stirred for a further 18 hours. After re-cooling to 0° C. the reaction was quenched with saturated ammonium chloride solution (500 ml), and the resulting two phase mixture separated. The aqueous phase was extracted with ethyl acetate and the combined organics concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and concentrated under reduced pressure to an oil (129 g). The oil was dissolved in THF (300 ml) and a 1M solution of tetrabutylammonium fluoride (360 ml, 0.36 mol) added dropwise. The solution was stirred at room temperature for 45 min, then concentrated to an oil under reduced pressure. The oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and evaporated under reduced pressure. The oil was triturated with hexane and the resulting solid filtered and washed with hexane to afford the title compound (67.58 g 79%) as a tan solid; MS(AP+) m/e 284/286/288 [M+H]+.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.C(O)(C)(C)C>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in toluene (960 ml), and 35% conc. hydrochloric acid (30.0 g) was added. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in t-butanol (130 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (50.6 g, yield: 25.0%) and 2-keto-L-gulonic acid (146.8 g, residual ratio: 65.7%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:27])([F:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[BrH:28]>>[BrH:28].[NH2:11][C@@H:12]([CH2:17][C:18]([F:26])([F:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-methyl 2-(benzyloxycarbonylamino)-4,4-difluoro-5-phenylpentanoate (188 mg, 0.5 mmol) and hydrogen bromide (2 mL) was stirred at RT for two hr, after which the solvent was removed to give the title (S)-methyl 2-amino-4,4-difluoro-5-phenylpentanoate hydrobromide.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH2:10][C:9](=[O:18])[C:8]2=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:14]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:18])[C:8]=2[C:7]2[C:15]1=[CH:16][CH:17]=[C:5]([O:4][CH3:3])[CH:6]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2Cc2ccccc2)CCCC1=O
Temperature: 50 °C
Yield: 81.9 %

Procedure:
To a slurry of 60% sodium hydride (0.76 g, 19.6 mmol) in DMF (20 mL) is added 6-methoxy-1,2,3,9-tetrahydro-4H-carbazol-4-one (3.84 g, 17.8 mmol) over a period of 5 minutes and benzyl bromide (2.4 mL, 19.6 mmol). The mixture is heated to 50° C. for 1 hour then room temperature overnight. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer washed with water (200 mL) and concentrated. The residue is triturated in hexanes and filtered to give 4.45 g (80%) of the title compound; mp 174-175° C., IR (drift) 2939, 1633, 1484, 1467, 1448, 1349, 1276, 1242, 1159, 1130, 1099, 854, 791, 762, 710 cm−1. 1H NMR (DMSO-d6) δ2.1, 2., 2.93, 3.75, 5.44, 6.77, 7.09, 7.28, 7.39, 7.51; Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.45; H, 6.31; N, 4.58.