Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[C:16]([F:34])[CH:15]=2)[CH:9]1C(C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(F)c2)C1C(C)(C)C
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 112 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (2.21 g) in methanol (40 ml) was added ammonium formate (4.54 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (255 mg) was then added and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was then filtered through celite and the filtrate was poured into 1 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.42 g, 74%) as a white solid. MS (ISP): 319.2 ([M+Na]+), 297.3 ([M+H]+), 241.2 ([M+H—C4H8]+), 197.2 ([M+H—C4H8—CO2]+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH:28]([C:30]1[S:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[CH3:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH:28]([C:30]1[S:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[CH3:29]
Reactant: Cc1ccc(C(C)N)s1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)Nc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)s1
Yield: 49.7 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (96 mg, 0.227 mmol) with (±)-2-(1-aminoethyl)-5-methylthiophene (48 mg, 0.34 mmol) using palladium(II) acetate (10 mg, 0.0454 mmol), BINAP (60 mg, 0.0908 mmol) and cesium carbonate (148 mg, 0.454 mmol) in toluene (10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1) to give (±)-7-chloro-6-[1-(5-methylthiophen-2-yl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (47 mg, 50%). GC-MS m/z 416 (M+).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.BrC1C=CC(C(F)(F)F)=CC=1>>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC=C[C@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)CC1
Agent: FC(F)(F)c1ccc(Br)cc1
Product: COCC[C@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Hydrogenation of 1-methoxy-2-[trans-4-[p-trifluoromethylphenyl)cyclohexyl]ethene [obtainable from p-bromotrifluorotoluene by the above synthesis scheme] on Pd/C and customary work-up give trans-4-methoxyethyl-(p-trifluoromethylphenyl)cyclohexane.
Reaction SMILES: CN1CCCC1.CC(C)([O-])C.[K+].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].C([Li])CCC.[C:28](=[O:30])=[O:29]>O.C(N(CC)CC)C>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[C:28]([OH:30])=[O:29])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(CC)cc1
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: CN1CCCC1
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ccc(C(C)C(=O)O)cc1
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To a mixed solvent of dried 1-methylpyrrolidine (6.0 ml.) and triethylamine (10.0 ml.) were added potassium tertiary-butoxide (11.7 g., 104 mmoles), 4.15 ml. 1,4-diethylbenzene (3.60 g., 26.8 mmoles). The flask was flushed with nitrogen, and the reaction mixture was stirred in an ice-water bath for 15 minutes. n-Butyllithium (2.50 M.) (8.0 ml, 20.0 mmoles) was charged dropwise into the flask over a period of 10 minutes. A red suspension developed upon additions of n-butyllithium. The mixture was stirred for 5 hours under ice-water cooling. After completion of the reaction, the reaction mixture was carbonated with 200 ml. of dry-ice inside a dry-box under a nitrogen atmosphere. The resulting white solid mass was then hydrolyzed with water (3 ml.) on the next morning. After removal of all volatile components under vacuum, the solid paste was dissolved in water and washed with pentane. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. The combined ether extracts were dried over sodium sulfate, filtered and concentrated to afford 4-ethylphenylpropionic acid (2.76 g., 15.5 moles), corresponding to a yield of 77.5% based on n-butyllithium.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7].[NH2:14][CH:15]1[C:29](=[O:30])[N:17]2[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:13])[CH2:9][C:10]([NH:14][CH:15]1[C:29](=[O:30])[N:17]2[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]12)=[O:12])=[O:7]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(CC(=O)O)S(=O)c1cccs1
Product: CC(CC(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)S(=O)c1cccs1

Procedure:
436 mg. of 3-(2-thienylsulfinyl)butyric acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 292 mg. of 7-[3-(2-thienylsulfinyl)butyramido]-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2Br)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:44][S:45]([C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][CH:53]=1)(=[O:47])=[O:46].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH:53]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (600 mg, 0.89 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (275 mg, 1.3 mmol), Pd2(dppf)Cl2 (65 mg, 0.095 mmol), and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction was heated to 90° C. for 2 h, then cooled to RT, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine, and dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/heptane) provides (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
In 150 ml of acetic acid, 20 g (96.9 millimole) of 2,4-di-tert-butylphenol was dissolved, and the solution was cooled on ice. Then, 5.0 ml (96.9 millimole) of bromine was added thereto drop by drop. After finishing dropwise addition, the temperature was elevated up to a room temperature, and the solution was stirred for 8 hours. Then, the reaction mixture was thrown into ice and water, and the aqueous layer was extracted with diethyl ether. The organic layer was dried on anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.96 g (yield: 72.0%) of 2-bromo-4, 6-di-tert-butylphenol.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[NH:26][CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:35](#[N:38])[CH:36]=[CH2:37]>C(O)C>[O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:37][CH2:36][C:35]#[N:38])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:7])([CH3:6])[CH3:8])([CH3:3])[CH3:4]
Reactant: C=CC#N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)NCC[C@]314
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCC#N)CC[C@]314
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
3,6-Bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan (0.26 g, 0.52 mmol) was dissolved in absolute ethanol (3 mL) and acrylonitrile (0.07 ml, 1.0 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure to give a white solid (0.26 g, 90% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][OH:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]=[O:14]
Reactant: Cn1cc(-c2ccccc2)nc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cc(-c2ccccc2)nc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (1-Methyl-4-phenyl-1H-imidazol-2-yl)-methanol 5 (50.0 mg, 0.266 mmol) in 1,2-dichloroethane (4.0 mL) under Ar was added Dess-Martin periodinane (124 mg, 0.292 mmol), and the mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 solution was added, the organic layer was separated and the aqueous layer was extracted with 1,2-dichloroethane. The combined organic layers were dried over Na2SO4, volatiles were evaporated and the residue was purified by silica gel chromatography on a FlashMaster system (gradient elution; 0-100% ethylacetate in heptane) to afford the title compound as a white solid (39.1 mg, 79%). 1H NMR (500 MHz, DMSO-d6): δ9.76 (s, 1H), 8.11 (s, 1H), 7.84 (d, J=7.7 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:25]([OH:26])=[CH:24][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:13][CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Br:27].[N+]([O-])(O)=[O:29]>C(O)(=O)C>[Br:1][C:2]1[C:25](=[O:26])[C:24](=[O:29])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:15][CH:16]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Br:27]
Reactant: O=C(c1ccc(OCc2nccs2)cc1)c1coc2c(Br)c(Br)c(O)cc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1C(=O)c2c(C(=O)c3ccc(OCc4nccs4)cc3)coc2C(Br)=C1Br
Temperature: 60 °C

Procedure:
To a suspension of (6,7-dibromo-5-hydroxybenzofuran-3-yl)(4-(thiazol-2-ylmethoxy)phenyl)methanone (70 mg, 0.137 mmol) in acetic acid (1 mL) was added nitric acid—69% (44.2 μl, 0.687 mmol) and the mixture heated at 60° C. for 1 hour. During this time the suspension turned bright red/orange and partially dissolved. After this time, the mixture was added to ice-water, then filtered to afford crude product as a red solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (234 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][O:27][CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][O:27][CH3:28])[C:22]([OH:24])=[O:23]
Reactant: COCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 50 °C
Yield: 32.1 %

Procedure:
To a solution of methyl 2-[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate (0.124 g; 0.31 mmol) in methanol (3.1 mL) was added a solution of sodium hydroxide 10 N (0.31 ml) and the mixture was heated to 50° C. for 18 h. After cooling, the reaction mixture was carefully acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.038 g (32%) of the title compound as a beige powder.
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N+:15]([O-])=[C:14]([CH3:20])[C:13]=3[CH3:21])[CH2:6][O:5]2)[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:24])C.[OH-].[Na+]>CO>[CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:20][OH:24])[C:13]=3[CH3:21])[CH2:6][O:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC2(CCC2)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(CO)c(C)c1OCC1COC2(CCC2)OC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
The 4-(5,9-dioxaspiro[3.5]non-7-ylmethoxy)-2,3,5-trimethylpyridine 1-oxide (1.97 g, 6.72 mmol) obtained in the step (13b) was mixed with acetic anhydride (20 ml, 212 mmol). The mixture was stirred at 85° C. for 1.5 hours. After cooled to room temperature, the reaction mixture was concentrated. To the residue, methanol (20 ml) and a 5N aqueous sodium hydroxide solution (20 ml, 100 mmol) were added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with a 2N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (1.69 g, yield: 85.7%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:40]O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH3:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:23]=2[C:22]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(Br)(Br)(Br)[Br:68]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:40][Br:68])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH3:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:23]=2[C:22]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CO)NC(=O)OCc3ccccc3)[nH]c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CBr)NC(=O)OCc3ccccc3)[nH]c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Methyl 5-{2-[((2R)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxypropyl)oxy]phenyl}-6-cyclohexyl-3-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate and triphenylphosphine (2.27 eq.) were dissolved in DCM (0.02M) and K2CO3 (4.31 eq.) was added. To the stirred mixture CBr4 (2.22 eq.) was added and the yellowish reaction mixture was left stirring at RT for 3 h. All volatiles were evaporated i. vac. and the residual material was subjected to chromatography (PE:EtOAc, 8.5:1.5). The product was obtained as a yellowish sticky solid (86%). MS (ES+) m/z 639, 641 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1F.C[O-].[Na+].CO.C(O)(=O)C[C:16](CC(O)=O)(C(O)=O)[OH:17]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:17][CH3:16]
Reactant: Fc1ccncc1Br
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccncc1Br
Reaction time: 72 h
Yield: 40 %

Procedure:
3-Bromo-4-fluoropyridine (253 mg, 1.44 mmol) was suspended in a solution of sodium methoxide in methanol (3.0 mL, 4.6 M, 14 mmol) at ambient temperature, the mixture stirred for 3 days, and then poured into aqueous citric acid (1M) and extracted twice into dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil (108 mg, 40%) that was used without further purification. LCMS: M+H+=188 & 190.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[C:27]([C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cccc(C#N)c2CC1

Procedure:
1,1-dimethylethyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 13) (5 g), zinc (II) cyanide (1.5 g) and tetrakis(triphenylphoshine)palladium(0) (1.5 g) were heated in dry DMF at 150° C. for 18 hours. The cooled reaction mixture was diluted with EtOAc (200 ml) and filtered. The filtrate was washed with saturated sodium bicarbonate, (200 ml), water (200 ml) and brine (200 ml). The crude reaction mixture was dried in the usual manner and evaporated. Purification by chromatography (eluting with DCM) yielded the title compound (3.4 g). δH (400 MHz, CDCl3) 7.50 (1H, d), 7.35 (1H, d), 7.27-7.21 (1H), m), 3.62-3.56 (4H, m), 3.22-3.20 (2H, m), 2.97-2.94 (2H, m), 1.47 (9H, s); MS (ES) C16H20N2O2 requires 272; found 217 [M+H−56]+, 273 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3].Cl.[C:23]([NH:31][CH2:32][C@@H:33]([C:35]([O:37][CH3:38])=[O:36])[NH2:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32][NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 69.6 %

Procedure:
A solution of 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (4.64 g, 15.0 mmol), 3-(benzoyl)amino-L-alanine, methyl ester hydrochloride (4.00 g, 15.5 mmol), and triethylamine (4.00 g, 39.5 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 h. The solvent was evaporated, and 1 M HCl (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (50-75% ethyl acetate/hexanes) to give N-[4-(azidomethyl)-2-chlorobenzoyl]-3-(benzoyl)amino-L-alanine, methyl ester (4.34 g, 69%) as a colorless oil that solidified on standing, mp 112-114° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2ncn(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
To a stirred solution of ethyl 3-benzyl-3H-benzo[d]imidazole-5-carboxylate (0.12 g, 0.43 mmol) in ethanol (10 mL) was added NaOH (0.12 g in 2 mL of H2O) and then the solution was stirred for 24 hr at room temperature. The reaction solution was then concentrated, diluted with water (10 mL) and then the pH was adjusted to using 1N HCl. The aqueous layer was then saturated with NaCl and extracted with ethyl acetate (2×50 mL). Then organic layer was dried (MgSO4), filtered and then concentrated to provide 0.1 g (93%) of 3-benzyl-3H-benzo[d]imidazole-5-carboxylic acid as an off-white solid.