Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 75.5 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.72 g) in anhydrous acetonitrile (7 ml), N,N-diisopropylethylamine (0.21 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.54 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was stirred overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=7/3), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.74 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:18][C:13]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])([CH3:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1cccc([N+](=O)[O-])c1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
2.00 g (13.06 mmol) of 2-methyl-3-nitrophenol were dissolved in 40 ml of DMF, and 3.55 g (19.59 mmol) of methyl 2-bromo-2-methylpropanoate and 4.68 g (14.37 mmol) of cesium carbonate were added. The reaction mixture was stirred at 100° C. for 2 d, and a further 1.77 g (9.80 mmol) of methyl 2-bromo-2-methylpropanoate were then added. The mixture was stirred at 100° C. for another 1 d, a further 1.77 g (9.80 mmol) of methyl 2-bromo-2-methylpropanoate were then added and the mixture was stirred at 100° C. for another 1 d. After cooling, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC. This gave 1.33 g (39% of theory) of the target compound.
Reaction SMILES: Cl([O-])=O.[Na+].OP([O-])(O)=O.[Na+].[CH2:11]([O:18][C:19]([NH:21][C:22]1[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([OH:35])[C:25]([C:36]2[CH:40]=[CH:39][O:38][C:37]=2[CH:41]=[O:42])=[CH:24][CH:23]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(=CC)C.[OH-:48].[Na+]>O.C(O)(C)(C)C.C(#N)C>[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:36]2[CH:40]=[CH:39][O:38][C:37]=2[C:41]([OH:48])=[O:42])=[C:26]([OH:35])[C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(-c2ccoc2C=O)c1O
Reactant: [OH-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(-c2ccoc2C(=O)O)c1O
Temperature: 25 °C

Procedure:
A solution of sodium chlorite (0.113 g) and sodium phosphate monobasic (0.168 g) in water (51 mL) was added to a suspension of tert-butyl 6-benzyloxycarbonylamino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (Intermediate 60, 0.438 g) and 2-methyl-2-butene (1.06 mL) in tert-butanol (25 mL) and acetonitrile (5 mL). The reaction mixture was stirred at room temperature. Further amounts of sodium chlorite (0.137 g) and sodium phosphate monobasic (0.180 g), in water (4 mL) were added and the reaction mixture was stirred at room temperature for 4.5 hours. The resultant mixture was basified to pH 10 with 1M sodium hydroxide solution and the mixture was concentrated in vacuo. Water (15 mL) was added and the mixture was extracted with ethyl acetate. The aqueous layer was acidified to pH 2 with 1M hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-15% to give 3-(4-benzyloxycarbonylamino-3-tert-butoxycarbonyl-2-hydroxyphenyl)-furan-2-carboxylic acid (0.385 g) as a yellow oil which solidified on standing.
Reaction SMILES: N[C@H](C(O)=O)CO.[OH:8][CH2:9][CH:10]([C:19]([OH:21])=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>>[OH:8][CH2:9][CH:10]([C:19]([NH:30][O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N[C@@H](CO)C(=O)O
Product: CC(C)(C)OC(=O)NC(CO)C(=O)NOCc1ccccc1

Procedure:
The 2,3-diaminopropionic acid esters, NH2—CH—[CH(R3)—NH2]—C(O)ester, are prepared as follows. t-Boc protected serine, HOCH2CH(NH-t-Boc)COOH, is coupled with O-benzylhydroxylamine at pH 4-5 with EDC HCl to provide the hydroxamate, HOCH2CH(NH-t-Boc)CONHOBn. The latter is cyclized in acetonitrile with triphenylphosphene-carbon tetrachloride in the presence of triethylamine to form the β-lactam, 1-benzyloxy-3-t-Boc-aminoazetidin-2-one. The β-lactam is then saponified with lithium hydroxide to provide, in 100% yield, the 2,3-diaminopropionic acid derivative, BnONHCH2CH(NH-t-Boc)COOH. In the above Bn is benzyl. The carboxylic acid group of the derivative obtained is esterified for use in the coupling reaction of Reaction scheme 3. The OBn protecting group is left intact during the coupling reaction while the t-Boc protecting group is removed to provide the free amino group involved in the coupling. Following amide formation the OBn group is removed via hydrogenation to provide the free amino amide ester for cyclization to the imidazoline. The above sequence of reactions is illustrated below.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].Cl.Cl.[C:27]1([CH3:39])[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:36]3[CH2:37][CH2:38][N:33]([C:30]4[CH:31]=[CH:32][C:27]([CH3:39])=[CH:28][CH:29]=4)[CH2:34][CH2:35]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccc(C)cc4)CC3)c1)CC2(C)C
Temperature: 120 °C
Yield: 59.3 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (500 mg, 1.28 mmol), 1-p-tolyl-piperazine dihydrochloride (410 mg, 1.92 mmol), palladium (II) acetate (14.4 mg, 0.064 mmol), xantphos (44.4 mg, 0.077 mmol) and cesium carbonate (830 mg, 2.56 mmol) in toluene (10 mL) was heated for 3 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.37 g, 60%) as a white solid: MS (ESI) M+1=488.3.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.O>CS(C)=O>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:12]2([CH3:11])[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC1(NCc2ccc(F)cc2)COc2ccc3c(c2O1)CC(=O)N3
Temperature: 85 °C
Yield: 61.5 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.15 g, 3.07 mmole) and 4-fluorobenzylamine (1.56 ml, 13.6 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 as eluant. The free base of the title compound (0.62 g, 62%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.69 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 218°-220° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN1CCOCC1.[C:20](Cl)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(O)CCCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)C(O)CCCCNC(=O)OCc1ccccc1

Procedure:
To a well stirred mixture of 0.05 moles of ethyl 6-amino-2-hydroxyhexanoate and 100 ml of methylene chloride which has been cooled to 0° to 5° C is added 0.1 moles of N-methylmorpholine followed by 0.055 moles of carbobenzoxy chloride. The reaction mixture is stirred for 1 hour then washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel and elution with methanol/chloroform gives ethyl 6-(benzyloxycarbonylamino)-2-hydroxyhexanoate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.CN1CCCC1=O.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:27][O:26][C:22](/[CH:23]=[CH:24]/[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)=[O:25]
Reactant: O=C(O)C1CCc2cc(I)ccc2O1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/c1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 70 °C
Reaction time: 400 h

Procedure:
Palladium (II) acetate (0.15 g, 0.66 mmol) and the compound from Example 28 (2.00 g, 6.58 mmol) were put in a round bottom flask under an argon atmosphere. To the flask was added 1-methyl-2-pyrrolidinone (20 mL), methyl acrylate (0.74 mL, 8.22 mmol), and triethylamine (2.29 mL, 16.5 mmol). The mixture was heated to 70° C. and stirred for 400 h. The reaction was cooled to RT and poured into water (70 mL). The mixture was extracted with ethyl acetate (1×). The aqueous layer was then acidified with 1.0 N aqueous HCl to generate a cloudy mixture. The mixture was extracted with ethyl acetate (3×). The combined organics from the second extraction were dried (MgSO4) and concentrated to a tan solid (1.75 g, 100%). 1H NMR (300 MHz, acetone-d6) δ 11.28 (s, 1H), 7.57 (d, J=16.18 Hz, 1H), 7.43 (m, 1H), 7.40 (m, 1H), 6.86 (m, 1H), 6.37 (d, J=16.18 Hz, 1H), 4.88 (m, 1H), 3.70 (s, 3H), 2.85 (m, 2H), 2.24 (m, 2H); MS (ES) m/z 263 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@H:21]1[C@H:28]2[C@H:24]([O:25]C(C)(C)[O:27]2)[C@@H:23]([CH2:31][F:32])[CH2:22]1)[CH2:9][CH3:10].Cl.O>C1COCC1.O(C(C)C)C(C)C.CCCCC>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:21]1[CH2:22][C@H:23]([CH2:31][F:32])[C@@H:24]([OH:25])[C@H:28]1[OH:27])[CH2:9][CH3:10]
Reactant: CC[C@H](Cc1sccc1Cl)Nc1ncnc2c1ncn2[C@@H]1C[C@H](CF)[C@H]2OC(C)(C)O[C@H]21
Agent: Cl
Solvent: CCCCC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC[C@H](Cc1sccc1Cl)Nc1ncnc2c1ncn2[C@@H]1C[C@H](CF)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(R)-1-(3-chloro-thiophen-2-ylmethyl)-propyl]-[9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl-tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purin-6-yl]-amine (1.23 g, 2.56 mmoles) prepared as described above was put in solution in THF (31 ml) and the resulting solution was treated with 12 N HCl in water (2.56 ml, 30.7 mmoles), and stirred for 2 h at room temperature. The solvent was then evaporated to dryness and the residue partitioned between water and AcOEt and neutralized with a saturated bicarbonate solution, the aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The filtrate was concentrated under reduced pressure to give a residue which was taken up in iPr2O and the resulting solution is diluted with pentane, the solid was filtrated, washed with pentane 3 times and dried to yield (1R,2S,3R,5S)-3-{6-[(R)-1-(3-chloro-thiophen-2-ylmethyl) -propylamino]-purin-9-yl}-5-fluoromethyl-cyclopentane-1,2-diol. 1H NMR (300 MHz, (CD3)2SO d6, δ in ppm): 0.92 (t, J=7,5 Hz: 3H); 1.68 (mt: 2H); 1.84 (mt: 1H); 2.31 (mt:2H); 3.13 (mt:2H); 3.92 (mt: 1H); 4.40 (mt: 1H); 4.51 (mf: 1H); 4.55 (dmt, JHF=48 Hz: 2H); 4.75 (mt: 1H); 4.94 (d, J=3,5 Hz: 1H); 5.10 (d, J=6 Hz: 1H); 6.98 (d, J=5 Hz: 1H); 7.43 (d, J=5 Hz: 1H); 7.72 (broad d, J=8 Hz: 1H); 8.18 (mf: 1H); 8.23 (s:1H). m.p.=143°.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14](OCC)=[O:15]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:13]([CH:19]([CH3:21])[CH3:20])[C:14](=[O:15])[N:11]=1
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: NC(=S)NC1CC2CCC1C2
Product: CC(C)C1SC(NC2CC3CCC2C3)=NC1=O

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and ethyl 2-bromoisovalerate according to Method C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11])([O-])=O.[CH3:12]OC(OC)N(C)C.N1CCCC1.O>CN(C=O)C.C(OCC)(=O)C.[Pd]>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[CH:11]=[CH:12][NH:1]2
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: COC(OC)N(C)C
Agent: [Pd]
Solvent: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2[nH]ccc12
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A mixture of 3-nitro-o-xylene (13.4 mL, 0.1 mol), dimethylformamide dimethyl acetal (40 mL, 0.3 mol) and pyrrolidine (10 mL, 0.12 mol) in 200 mL of dry DMF was heated at 120°-130° C. (oil-bath temperature) under Ar for 21 h. The cooled mixture was poured into cold water (400 mL) and extracted with ether (4×200 mL). The ethereal solution was washed (H2O, 4×100 mL), dried (Na2SO4) and evaporated to give a dark red viscous oil. This oil was taken up in 150 mL of ethyl acetate, 1.5 g of 10% palladium-on-charcoal was added and the mixture was hydrogenated at 50 psi on a Parr shaker for 1 h. The reaction mixture was then filtered, the catalyst was washed with additional ethyl acetate and the filtrate was evaporated to give a dark purple oil. Flash chromatography (SiO2 /dichloromethane-petroleum ether, 1:1) of this oil gave pure 4-methylindole (8.85 g, 68%) as a light yellow-brown oil: 1H NMR (DMSO-d6, 200 MHz) δ 11.04 (br s, 1H), 7.29(t, J=2.7 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.75 (dt, J=6.9, 0.8 Hz, 1H), 6.43 (m, 1H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.[OH-].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C-]#N.[Na+].CC1(C)[C@H]2[C@@H]1[CH2:25][NH:26][C@H]2S([O-])(=O)=O>>[CH3:1][C:2]1([CH3:8])[C@H:7]2[C@@H:3]1[CH2:4][NH:5][C@@H:6]2[C:25]#[N:26]
Reactant: CC1(C)C2CNCC21
Reactant: CC1(C)[C@@H]2[C@H](S(=O)(=O)[O-])NC[C@@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [C-]#N
Agent: [K+]
Product: CC1(C)[C@@H]2[C@@H](C#N)NC[C@@H]21
Temperature: 21 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a 100-mL flask was added 40 mL of dH2O and 1.8 mL of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane to provide a homogeneous solution with a pH of approximately 11.4. To this solution was added 2.7 g of Na2S2O5 to provide a homogeneous solution and the pH was adjusted to about 7.5 with approximately 1 mL of 8 N NaOH. To this solution was added 60 μL of Antifoam-204 (Sigma catalog number A-6226), 120 μL of A. niger catalase suspension (Sigma Aldrich; catalog number C-3515) and 300 mg of monoamine oxidase powder of the polypeptide of SEQ ID NO 8 (prepared by the method of Example 2) in 10 mL of 100 mM pH 8.0 potassium phosphate buffer. Air was sparged into the reaction mixture through fritted glass at a rate of ˜10 mL/min and the resulting pale yellow solution was stirred under air for 24 hours at room temperature (about 21° C.) for 24 hours. Throughout, the pH was maintained at 7.4 via feedback controlled addition of 2.5 N NaOH in 1 μL portions. After 24 hours, 1.0 g (1.3 equiv) of NaCN was added to the reaction mixture then comprising (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-sulfonate. After stirring at room temperature (about 21° C.) for an additional 15 minutes, the mixture was extracted with MTBE. (2-Me-THF can also be used for the extraction.) Following phase separation and solvent removal, 1.78 g (90% yield) of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile was isolated a pale yellow solid. Analysis by 1H-NMR in CDCl3 confirmed preparation of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile (1H-NMR (300 MHz, CDCl3) spectrum: δ 3.92 (d, J=1.2, 1H, NC(H)(CN)), 3.25 (m, 1H), 2.96 (dd, J=2.1, 17.0), 1.48 (dd; J=1.2, 12.2; 1H), 1.42 (m, 1H), 1.13 (s, 3H), 1.11 (S, 3H)).
Reaction SMILES: C1(C=CC=C(O)C=1)O.ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.[OH-].[Na+].[N+]([C:30]1[CH:31]=[C:32]([C:38]#[N:39])[C:33](=[CH:36][CH:37]=1)[C:34]#[N:35])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:38](#[N:39])[C:32]1[C:33](=[CH:36][CH:37]=[CH:30][CH:31]=1)[C:34]#[N:35]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Oc1cccc(O)c1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 90 %

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added resorcinol (26.0 g, 0.236 mol), 4,4′-dichlorobenzophenone (22.8 g, 0.0907 mol), sodium hydroxide (20.8 g, 0.520 mol), toluene (25 mL), and dimethylsulfoxide (DMSO) (500 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 135-145° C. under a nitrogen atmosphere for 6 h or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (52.7 g, 0.304 mol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile and the resorcinol phthalonitrile composition (70.6 g, 90% yield). IR [cm−1]: ν 3072 (C═CH), 2234 (CN), 1586 (C═C), 1478 (aromatic), 1307 (aromatic), 1308 (C—O), 1245 (CH3), 1162 (C—O), 930 (C—O), 847 (aromatic).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6]2.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6]2
Reactant: COc1ccc2c(c1)CNC2=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1NCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A mixture of 5-methoxy-2,3-dihydro-isoindol-1-one (3.7 g, 23 mmol) and boron tri-bromide (1 M in CH2Cl2, 15.2 mL, 88 mmol) in CH2Cl2 (30 mL) at −78° C. was stirred for 16 h at RT. The mixture was then cooled to −78° C. and MeOH (25 mL) was added. After 1 h at −78° C. the mixture was evaporated and the residue purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 98:2 to 90:10) to afford the title product (2.5 g, 72%) as an off-white solid. MS m/e=148.0 (M−H+).