Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:20][C:21]2[S:25][C:24]([Cl:26])=[N:23][C:22]=2[Cl:27])[CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][N:14]([CH2:20][C:21]1[S:25][C:24]([Cl:26])=[N:23][C:22]=1[Cl:27])[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(O)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Add 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-(2-hydroxy-2-methyl-propyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.4487 g, 1.02 mmol) to a stirred solution of dichloromethane (60 mL) and anisole (9.0 mL, 82.8 mmol). Cool the reaction to 0° C. Add the trifluoroacetic acid (6.0 mL, 72.9 mmol). Stir the reaction for 10 minutes at 0° C. and then for 2 hours at room temperature. The reaction is loaded directly onto a 10 g prepacked SCX-2 cartridge and washed with methanol (200 mL). The product is then eluted off with 2M ammonia in methanol (100 mL) and concentrated on a rotary evaporator to yield 0.3448 g (99%) of N-(2-hydroxy-2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=338.1 (M+1); 1H NMR (CDCl3): δ=3.97 (s, 2H), 3.18-3.15 (m, 2H), 2.59-2.53 (m, 5H), 1.80-1.70 (m, 4H), 1.49-1.39 (m, 2H), 1.22 (s, 6H).
Reaction SMILES: C12BC(CCC1)CCC2.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH2:28])[C:22]1=[O:29].[OH-:30].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][OH:30])[C:22]1=[O:29]
Reactant: C=Cc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With ice-cooling, 1.15 l (575 mmol) of a 0.5 molar solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran are added to 70.7 g (262 mmol) of the compound from Example 60A (alternative synthesis) such that the internal temperature does not exceed 10-15° C. The mixture is then warmed to RT and stirred at room temperature for 1.5 h. The mixture is then cooled and, at 0° C.-5° C., 653 ml (1.31 mol) of a 2-molar aqueous solution of sodium hydroxide are added. The mixture is stirred briefly, and 296 g (2.51 mol) of a 30% strength hydrogen peroxide solution are then added such that the temperature does not exceed 30° C. and does not fall below 25° C. After the addition has ended, the mixture is stirred for another 30 min. Water and ethyl acetate are added to the reaction mixture. After phase separation, the aqueous phase is once more extracted with ethyl acetate. The combined organic phases are washed with an aqueous sodium bisulphite solution. The organic phase is removed and evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane and purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:2, then ethyl acetate). This gives 66.5 g (88% of theory) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)(=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1

Procedure:
A mixture of 2.0 g of product from Example 4, 8.9 ml acetic anhydride, 0.0863 g 4-dimethylaminopyridine and 30 ml pyridine is heated at reflux temperature for 23 hours, cooled, poured into 150 ml of water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatogaphy (silica gel: 15-20% ethyl acetate/hexane) to give 1.4 g of the desired product as light yellow crystals.
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1[NH:4][CH:5]=[CH:6]N=1)=O.[C:13](O)(=[O:23])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.C(Cl)(=O)C1C=CC2OCOC=2C=1.N1CC=CCC1>>[O:19]1[C:20]2[CH:21]=[CH:22][C:14]([C:13]([N:4]3[CH2:5][CH:6]=[CH:8][CH2:1][CH2:3]3)=[O:23])=[CH:15][C:16]=2[O:17][CH2:18]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: C1=CCNCC1
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Product: O=C(c1ccc2c(c1)OCO2)N1CC=CCC1

Procedure:
The product amide is made by the method employed for the preparation of Invention Compound V, which uses carbonyl diimidazole in order to activate piperonylic acid, or piperonyloyl chloride (available from Aldrich) can be combined with 1,2,3,6-tetrahydropyridine either in a suitable anhydrous solvent or without solvent. In either case, the isolation of product is performed in the same manner as done for Invention Compound V to give Invention Compound III as a white solid. EIMS m/z=231 (parent, 149 (base), and 121. 1H NMR δ 2.21 (br s, 2), 3.4-4.3 (br m, 4), 5.87 (m, 2), 6.00 (s, 2), 6.83 (d, 1, J=7.84 Hz), and 6.92-6.96 (dd and d, 2). 13C NMR δ 101.3 (—OCH2O—) and 169.9 ppm (carbonyl).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@H:6]([C:7]([O-:9])=[O:8])[N:5]2[C:10](=[O:17])[C@@H:11]([NH:12][Si](C)(C)C)[C@H:4]2[S:3]1.C1OC1C.ClC(Cl)C([O:27][N:28]=[C:29]([C:33]1[O:34][CH:35]=[CH:36][CH:37]=1)[C:30](Cl)=[O:31])=O.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:18])[C@H:6]([C:7]([OH:9])=[O:8])[N:5]2[C:10](=[O:17])[C@@H:11]([NH:12][C:30](=[O:31])[C:29](=[N:28][OH:27])[C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@H](N[Si](C)(C)C)C(=O)N2[C@H]1C(=O)[O-]
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccco1
Agent: CC1CO1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(=NO)c3ccco3)C(=O)N2[C@H]1C(=O)O

Procedure:
A solution of tirmethylsily 2,2-dimethyl-6β-trimethylsilylaminopenam-3α-carboxylate [prepared from the corresponding amino-acid (0.648 g.)] and propylene oxide (0.75 ml.) in dichloromethane (15 ml) was cooled to 0° and treated dropwise with a solution of 2-dichloroacetoxyimino(fur-2-yl)acetyl chloride [syn-isomer; prepared from the corresponding acid (0.579 g)] in dichloromethane (12 ml.). The resulting solution was maintained at 0° for 1 hour and was then evaporated to small volume and partitioned between ethylacetate and saturated sodium bicarbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 2N=hydrochloric acid and extracted with ethyl acetate. The dried organic solution was evaporated to a small bulk and added dropwise to stirred petroleum spirit (b.p. 40°-60°). The resulting precipitate was collected, washed and dried to give the title acid (0.56 g., 55% based on amine), [α]D + 243° (c 0.93, DMSO), λmax. (pH 6 buffer) 275 nm (ε 9,600) νmax. (Nujol), 1778 (β-lactam), 1740 and 2600 (CO2H), 1670 and 1528 cm.-1 (CONH), τ (d6 -DMSO) values include 0.44 (d, J 6 Hz; NH) 2.18 and 3.34 (multiplets; aromatic protons), 5.70 (s; C-3H), 8.36 and 8.46 (2s; CH3 groups).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:6][CH2:7][CH2:8][N:9]1[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:18].CCN(C(C)C)C(C)C.[S:33]1[C:37]2[CH:38]=[C:39]([S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:41][C:36]=2[N:35]=[CH:34]1>C(Cl)Cl>[S:33]1[C:37]2[CH:38]=[C:39]([S:42]([N:17]3[CH:15]4[CH2:14][CH2:13][CH2:12][CH:11]3[C:10](=[O:18])[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16]4)(=[O:43])=[O:44])[CH:40]=[CH:41][C:36]=2[N:35]=[CH:34]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: COc1ccc(OCCN2CC3CCCC(N3)C2=O)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCN2CC3CCCC(C2=O)N3S(=O)(=O)c2ccc3ncsc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxyl)ethyl)-3,9-diazabicyclo[3.3.1]nonan-2-one (32 mg, 0.1 mmol) in 3 ml DCM was treated with DIPEA (15 mg, 0.12 mmol) and stirring for 30 min at room temperature followed by addition of 1,3-benzothiazole-6-sulfonyl chloride (28 mg, 0.12 mmol). The reaction was stirred overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-TLC in 10% MeOH in CHCl3.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:28])[N:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:20]=1)[CH2:13][CH2:14][OH:15])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[N:20]=1)[CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)c1nc(-c2ccc(F)cc2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOS(C)(=O)=O)c1nc(-c2ccc(F)cc2)cs1
Reaction time: 4 h

Procedure:
98.7 mg (0.86 mmol) of methanesulfonyl chloride were added dropwise with cooling to 265 mg (0.78 mmol) of (4-(4-fluorophenyl)thiazol-2-yl)-(2-hydroxyethyl)-carbamic acid tert-butyl ester and 237.7 mg (2.35 mmol) of triethylamine in 25 ml of methylene chloride. After 4 h at room temperature, the mixture was extracted with water and the organic phase was concentrated. Yield: 241 mg (74%).
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:35])[C@H:5]([CH2:31][CH2:32][S:33][CH3:34])[NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[C@H:15]([CH2:17][C:18]2[N:22]=[CH:21][NH:20][CH:19]=2)[NH2:16])=[CH:10][C:9]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O[Li].O.Cl>C1COCC1.O>[ClH:1].[NH2:16][C@H:15]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:35])=[O:3])[CH2:31][CH2:32][S:33][CH3:34])=[O:30])=[C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:10]=1)=[O:23])[CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)[C@@H](N)Cc2c[nH]cn2)cc1-c1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)[C@@H](N)Cc2c[nH]cn2)cc1-c1ccccc1)C(=O)O
Reaction time: 6 h
Yield: 30.8 %

Procedure:
To a solution of [4-(L-histidyl)-2-phenylbenzoyl methionine methyl ester hydrochloride (98.9 mg, 0.200 mmol), prepared as in Example 184B, in THF/H2O (4:1, 20 mL) was added LiOH.H2O (68.5 mg, 1.60 mmol). The solution was stirred for 6 hours and then was treated with 1 M aqueous HCl (20 mL). The mixture was lyopholized to provide a white solid. Recrystallization from methanol afforded [4-(L-histidyl)-2-phenylbenzoyl]methionine hydrochloride (31 mg, 32%) as a white solid. 1H NMR (D2O) δ 1.68-1.82 (m, 1H), 1.88-1.99 (comp, 2H), 2.02 (s, 3H), 2.00-2.12 (m, 1H), 3.28-3.32 (m, 2H), 3.49 (d, 2H), 4.28-4.34 (m, 1H), 4.44 (t, 1H), 7.36-7.53 (comp, 8H), 7.57 (m, 1H), 8.67 (m, 1H); LRMS (CI): 482 (M+1)+, 701.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:20][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Br)ccc1Oc1ccccc1
Product: Cc1ccc2c(Nc3cc(Br)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 124b (412 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (206 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.73 (s, 3H) 6.69 (d, J=7.35 Hz, 2H) 6.96 (d, J=7.72 Hz, 2H) 7.05-7.15 (m, 3H) 7.24-7.36 (m, 2H) 7.68 (dd, J=8.82, 2.57 Hz, 1H) 7.75 (d, J=8.46 Hz, 1H) 7.82 (d, J=2.21 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 8.86 (d, J=8.82 Hz, 1H) 10.93 (s, 1H) 14.49 (s, 1H); MS (ESI+) m/z 408 (M+H−TFA)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1Cl
Temperature: 60 °C

Procedure:
3-(3-Chloro-4-hydroxy-phenyl)-propionic acid benzyl ester (step 1) (5.9 g, 20.3 mmol) in DMF (60 ml) was treated with potassium carbonate (5.61 g, 40.6 mmol) followed by t-butyl bromoacetate (4.49 ml, 30.4 mmol) and the mixture was heated at 60° C. overnight. The reaction mixture was diluted with water (500 ml), and the product extracted into EtOAc (450 ml). The organic portion was washed with water (200 ml), brine (200 ml), dried over MgSO4 and the solvent removed in vacuo to yield a yellow oil. Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 7.11 (1H, d), 6.89 (1H, d), 5.07 (2H, s), 4.74 (2H, s), 2.81 (2H, t), 2.68 (2H, t), 1.42 (9H,s). LC-MS Rt 1.64 mins; 427.3 [M+Na]+, Method 2minLC_v002.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18]
Reactant: OCc1cccs1
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1cccs1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles), thiophenemethanol (0.08 ml, 0.6 mmoles), and triphenylphosphine (197 mg, 0.75 mmoles) was added dropwise diisopropylazodicarboxylate (0.15 ml, 0.75 mmoles) under an atmosphere of nitrogen at 21° C. The reaction mixture was stirred overnight and concentrated under vacuum to give an oil. The oil was chromatographed with silica gel (eluting with 1:4 ethyl acetate/hexane) to give (after crystallization from methanol) 98 mg (56% yield) of the desired 6-(2-thienylmethyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid: mp 141.5°-145.0° C; 1H NMR (CDCl3, 300 MHz) δ5.41 (s, 2H), 6.97-7.56 (m, 9H), 8.78 (dd, 1H, J=8.1, 1.9), 8.93 (dd, 1H, J=4.5, 1.9); 13C NMR (75 MHz, CDCl3) δ161.56, 154.34, 151.68, 137.91, 136.93, 136.79, 134.14, 133.70, 130.04, 129.54, 128.26, 127.81, 127.77, 127.09, 126.65, 122.13, 121.91, 120.05, 46.85; IR (KBr) vmax 1643, 1612, 1591, 1564, 1552, 1483, 1441, 1429, 1415, 1377, 1358, 1302, 1207, 1174, 792, 763, 734, 715, 696, 601 cm-1 ; mass spectrum (EI), m/e 352. Anal. (C19H13ClN2OS) Calcd.: C, 64.68; H, 3.71; N, 7.94. Found: C, 64.45; H, 3.69; N, 8.00.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:8]([C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: Cc1cccc(CC(=O)c2ccccc2)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(C)c2)cc([N+](=O)[O-])c1O
Yield: 2.6 %

Procedure:
To a solution of 1-phenyl-2-m-tolylethanone (Intermediate 4) (460 mg, 2.18 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (460 mg, 2.18 mmol) and urea (300 mg, 6.54 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (38-68% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) and thin layer chromatography (PE:EtOAc=1:2) to give Compound 17 (25 mg, yield 2.6%). 1H NMR (CD3OD 400 MHz): δ 7.62 (s, 1H), 7.27 (s, 5H), 7.18 (d, J=1.6 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.74 (s, 1H), 6.67 (d, J=7.6 Hz, 1H), 5.36 (s, 1H), 4.07 (m, 2H), 2.10 (s, 3H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 446.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[CH3:14][O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:46]=[CH:45][CH:44]=[CH:43][C:21]=1[C:22]([NH:24][CH2:25][C@H:26]([CH:40]([CH3:42])[CH3:41])[CH2:27][C@H:28]([NH:32][C:33](=[O:39])[O:34]C(C)(C)C)[C@@H:29]1[CH2:31]O1)=[O:23]>CS(C)=O>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:46]=[CH:45][CH:44]=[CH:43][C:21]=1[C:22]([NH:24][CH2:25][C@@H:26]([CH2:27][C@H:28]1[C@H:29]([CH2:31][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[O:39][C:33](=[O:34])[NH:32]1)[CH:40]([CH3:42])[CH3:41])=[O:23]
Reactant: O=C1CCCCN1
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H]1NC(=O)O[C@H]1CN1CCCCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.115 g of piperidin-2-one, 0.136 g of potassium tert-butoxide in 3 ml of dimethyl sulphoxide is stirred at room temperature over 30 minutes, admixed with 0.26 g of tert-butyl (3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methyl-1(S)—(R)-oxiranylpentyl)-carbamate (Example 1b) and subsequently stirred further at room temperature overnight. The reaction mixture is poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])[C:3]([O-:5])=[O:4].C(CC[NH2:21])CCC(O)=O.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=O.C([C@H]([NH3+:37])C([O-])=O)C=O>N[C@H](C(O)=O)CCCCN>[NH2:21][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])[C:3]([O-:5])=[O:4].[O:1]=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])[C:3]([O-:5])=[O:4].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:37]
Reactant: NCCCCCC(=O)O
Reactant: NCCCCCC=O
Reactant: [NH3+][C@@H](CC=O)C(=O)[O-]
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=C([O-])CCCCC(=O)C(=O)[O-]
Product: NC(CCCCC(=O)[O-])C(=O)[O-]
Product: NCCCCCCN

Procedure:
The first engineered pathway as shown in FIGS. 2 and 3 includes first decarboxylation of 2-ketopimelate to amino caproic acid as described above in the amino caproic engineered pathway (enzymatic steps I followed by enzymatic step 4 or enzymatic step II followed by enzymatic step 8). In some embodiments, an aldehyde dehydrogenase enzyme is expressed and catalyzes the conversion of the amino caproic acid to a 6-aminohexanal intermediate (enzymatic step 5) and a 1-amintransferase enzyme is expressed and catalyzes the conversion of the 6-aminohexanal to HMD (enzymatic step 6). Alternatively, the engineered pathway comprises a phosphorylation step (using a kinase) before the dehydrogenation and the amino transfer enzymatic reactions described above. One should appreciate that the phosphorylation step and the dehydrogenation steps are analogous to the phosphorylation step (catalyzed by an aspartokinase EC 2.7.2.4) and the dehydrogenation step (catalyzed by EC 1.2.1.11 enzyme) involved in the synthesis of aspartate semialdehyde in the Lysine pathway. According to the second engineered pathway, the conversion of 2-aminopimelate produced from α-ketopimelate (enzymatic step II, FIG. 3) to hexamethylenediamine consists of enzymatic steps 9, 10 or 11, and 12 which combine enzymes or homologous enzymes characterized in the Lysine biosynthetic IV pathway. The pathway includes the following substrate to product conversions:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][N:10]=1)=[O:4].[CH3:13][O:14][C:15]([C:17]1[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N+:18]=1[O-])=[O:16].P(Cl)(Cl)([Cl:27])=O.CN(C=O)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:27][C:8]1[N:7]=[C:6]([CH3:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:10][CH:9]=1.[Cl:27][C:19]1[N:18]=[C:17]([C:15]([O:14][CH3:13])=[O:16])[C:22]([CH3:23])=[N:21][CH:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ncc[n+]([O-])c1C
Reactant: COC(=O)c1c(C)ncc[n+]1[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(Cl)cnc1C
Product: COC(=O)c1ncc(Cl)nc1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 106 %
Yield: 48.1 %

Procedure:
A solution of mixture of 2-(methoxycarbonyl)-3-methylpyrazine 1-oxide compound with 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (1:1) (5.1 g, 15.17 mmol) in toluene (50 mL) was cooled to 0° C. To the mixture was added phosphorus oxychloride (2.78 ml, 30.3 mmol) under nitrogen followed by n,n′-dimethylformamide (0.117 ml, 1.517 mmol). The reaction mixture was stirred at room temperature for 4 h and then was heated to 65° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc and washed with saturated NaHCO3 solution. The aqueous layer was back-extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The mixture was purified with ISCO (0% to 50% EtOAc/Hexanes) to afford both isomers: methyl 5-chloro-3-methylpyrazine-2-carboxylate (0.68 g, 48.1% yield) and methyl 6-chloro-3-methylpyrazine-2-carboxylate (1.5 g, 106% yield).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]([CH3:23])=[C:10]2[CH2:24][C:25]([NH2:27])=[O:26])C.[OH-].[Na+].Cl>CCO.C1COCC1>[NH2:27][C:25](=[O:26])[CH2:24][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH2:5][C:4]([OH:28])=[O:3])[CH:8]=2)[N:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[CH3:23]
Reactant: CCOC(=O)COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CC(N)=O)c2cc(OCC(=O)O)ccc2n1Cc1ccccc1
Yield: 88 %

Procedure:
A solution of 190 mg (0.5 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]acetic acid ethyl ester and 2 mL of 5N NaOH in 30 mL of EtOH and 10 mL of THF was stirred for approximately 15 hours, the mixture made acidic with 5N HCl and extracted with EtOAc. The EtOAc solution was washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was washed with ether to give 155 mg (90% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]acetic acid, mp, 196°-198° C.