Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[O:27])[C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26][OH:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108 %

Procedure:
4-Benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-carbaldehyde (1.16 g) is dissolved in ethanol (15 ml) and thereto is added sodium borohydride (122 mg) and the mixture is stirred at room temperature for 10 minutes. Thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give (4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-yl)-methanol (1.26 g). MS (m/z): 345
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:19]([CH3:20])=[CH:18][N:17]([CH:21]([O:36][CH2:37][CH3:38])[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[NH:35])[NH:33]O)=[CH:28][CH:27]=2)=[O:23])[N:16]=1)C1C=CC=CC=1.C([OH:41])C>C(O)(=O)C.[Pd]>[C:37]([OH:41])(=[O:36])[CH3:38].[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[CH:21]([O:36][CH2:37][CH3:38])[N:17]2[CH:18]=[C:19]([CH3:20])[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])=[N:16]2)=[CH:31][CH:30]=1)(=[NH:33])[NH2:35]
Reactant: CCO
Reactant: CCOC(C(=O)NCc1ccc(C(=N)NO)cc1)n1cc(C)c(-c2ccccc2OCc2ccccc2)n1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)n1cc(C)c(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (RS)-2-[3-(2-benzyloxy-phenyl)-4-methyl-pyrazol-1-yl]-2-ethoxy-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-acetamide (90 mg) at r.t. in ethanol were added acetic acid (3 drops) and 10% Pd/C (9 mg). Stirring at r.t. under a hydrogen atmosphere was continued for 18 hrs. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, EtOAc/acetone/H2O/HOAc 6:2:1:1) to give (RS)-N-(4-carbamimidoyl-benzyl)-2-ethoxy-2-[3-(2-hydroxy-phenyl)-4-methyl-pyrazol-1-yl]-acetamide acetate (28 mg) as off-white solid. MS 408.5 ([M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CCO>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: [H][H]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 75 %

Procedure:
A stirred suspension of 59.5 g (102 mmol) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate and 6.0 g of 10% Pd(C) in 1.2 L of 2:1 THF/EtOH was saturated with hydrogen by bubbling hydrogen gas through for 10 minutes and then subjected to balloon hydrogenation at RT. After 6 hours LCMS indicated complete reaction. After 24 hours the mixture was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated to dryness at reduced pressure to give a light yellow solid. This material was recrystallized from hot EtOAc to afford 42.2 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a white solid. The filtrate was concentrated to dryness at reduced pressure to give an additional 13.0 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a light yellow foam determined to be 95% pure by LCMS. The two batches were combined for a total yield of 55.2 g (98%) of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.16 (s, 1H) 7.91-8.00 (m, 3H) 7.61 (dd, J=8.98, 2.73 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.15 (s, 1H) 6.76-6.86 (m, 3H) 3.79 (s, 3H) 3.28 (s, 3H) 2.83 (d, J=4.68 Hz, 3H) 2.25-2.38 (m, 1H) 0.82-1.10 (m, 3H) 0.42 (m, 1H). LCMS (ESI): 552 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:11](C#N)=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][CH2:8][CH2:9]2)=[CH:4][NH:3]1.Br.C(=O)(O)[O-].[Na+]>>[CH:4]1[NH:3][C:2](=[O:1])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:14])[CH2:7][CH2:8][CH2:9]2
Reactant: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCCc2cc(=O)[nH]cc21

Procedure:
A solution of 28.4 parts of 2,3,5,6,7,8hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile in 500 parts by volume of 48% hydrobromic acid is heated at the reflux temperature in the absence of light for about 7 hours, following which time the solvent is removed by distillation under reduced pressure. The resulting residue is partitioned between chloroform and aqueous sodium chloride and the layers are separated. The aqueous phase is extracted several times with chloroform, then combined with the original chloroform layer. That organic solution is washed with aqueous sodium chloride, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford the crude product. The original aqueous layer is neutralized by the addition of sodium bicarbonate, then is extracted with chloroform. Evaporation of that chloroform extract to dryness affords additional product. The combined crude product is purified by recrystallization from aqueous acetone, thus affording pure 2,3,5,6,7,8-hexahydro-3,8isoquinolinedione, melting at about 246°-248° with decomposition. Ultraviolet absorption maxima are observed in methanol at 279 and 221 mμ with molecular extinction coefficients of about 16,700 and 13,500, respectively. In deuteropyridine, nuclear magnetic resonance peaks are displayed at about 1.96, 2.57, 2.92, 5.50 and 8.71 parts per million.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9](O)=[O:10])[CH3:2].C(Cl)[Cl:16].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([Cl:16])=[O:10])[CH3:2]
Reactant: ClCCl
Reactant: CCOc1cccc(OCC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOc1cccc(OCC(=O)Cl)c1
Reaction time: 8 h

Procedure:
A 250 mL flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with 3-ethoxyphenoxyacetic acid (13.0 g, 66.3 mmol) from above, CH2Cl2 (80 mL), and DMF (0.2 mL). To the resultant solution was added oxalyl chloride (2M in CH2Cl2, 41.4 mL, 82.8 mmol) over 30 min. The solution was stirred overnight then concentrated in vacuo to give 14.4 g of 47a as an oil/solid mix (100%). HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 95% with a retention time of 4.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]([N:12]3[CH:16]=[CH:15]N=C3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:19](N)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>>[Cl:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]([NH:12][CH2:16][CH2:15][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ncc(Cl)cc21
Reactant: CCCCCCCCN
Product: CCCCCCCCNC1=NS(=O)(=O)c2cc(Cl)cnc2N1

Procedure:
m.p. 170°-175° C.; from 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide and octylamine. (Compound 14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.ClCC(OC(=O)CCl)=O.[S:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>ClC(Cl)C>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[C:6]([C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:8]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: c1ccsc1
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1cc(C(=O)c2cccs2)cc(OC)c1OC
Temperature: 65 °C
Reaction time: 6 h
Yield: 41.5 %

Procedure:
In 50 ml of dichloroethane were dissolved 10.6 g (0.05 mole) of 3,4,5-trimethoxybenzoic acid and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 5.47 g (0.065 mole) of thiophene and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 65° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5.77 g of 2-(3,4,5-trimethoxybenzoyl)thiophene.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([CH2:4][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: C1CCNC1
Reactant: O=Cc1cccc(O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CN2CCCC2)c1Cl
Yield: 90.7 %

Procedure:
2-Chloro-3-hydroxybenzaldehyde (4.5 g, 0.03 mol) was added in portions for 30 min to a mixture of pyrrolidine (3. mL, 0.036 mol) and NaB(OAc)3H (7.6 g, 0.036 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 3 h and cooled with an ice bath. Water (50 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.76 g, 95%) as white crystals. LCMS-data: (M+H)+ 214.0 and 212.0 (calculated for C11H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.95 (br. s, 1H, ArOH), 7.07 (t, 1H, J1=7.8 Hz, J2=15.7, Ar—H), 6.90 (dd, 1H, J1=1.5 Hz, J2=7.6 Hz, Ar—H); 6.85 (dd, 1H, J1=1.5, J2=9.5, Ar—H), 3.63 (s, 2H, ArCH2), 2.43-2.50 (m, 4H, pyrrolidine (CH2)2N), 1.63-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[C:9]1([C:7]2[CH:6]=[CH:5][N:4]3[CH:15]=[N:2][N:1]=[C:3]3[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nccc(-c2ccccc2)n1
Product: c1ccc(-c2ccn3cnnc3n2)cc1

Procedure:
A mixture of 2.0 g. of 2-hydrazino-4-phenylpyrimidine and 25 ml. of triethyl orthoformate is refluxed for 6 hours. On cooling the desired compound is removed by filtration, m.p. 232°-234° C. [This compound is cited J. Chem. Soc. Japan, Ind. Chem. Sect. 58, 440 (1955) as having m.p. 192° C. No description or preparation procedures are given.]
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]2=[O:32])=[N:22][C:21]=1[CH3:33])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:27][C:26]2=[O:32])=[N:22][C:21]=1[CH3:33])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1nc(-n2ccc(OCc3ccccn3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 11 %

Procedure:
Following the procedure as described in Example 6, making variations only as required to use 2-(bromomethyl)pyridine hydrobromide in place of 3-(bromomethyl)pyridine hydrobromide to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 11% yield: mp 202-205° C.; 1H NMR (300 MHz, CDCl3/CD3OD) δ 8.69 (m, 1H), 8.53 (m, 1H), 7.89-7.84 (m, 1H), 7.56-7.49 (m, 2H), 7.39-7.35 (m, 1H), 7.28-7.17 (m, 5H), 6.36-6.32 (m, 1H), 6.07 (d, J=2.7 Hz, 1H), 5.18 (s, 2H), 4.46 (s, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3/CD3OD) δ 170.1, 165.7, 164.9, 156.7, 156.3, 154.0, 150.6, 141.9, 140.9, 134.7, 131.1, 130.0, 129.8, 126.8, 126.0, 125.5, 106.6, 100.1, 72.6, 46.2, 19.4; MS (ES+) m/z 433.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:11])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 3-bromobenzoic acid (50 g, 248.73 mmol, 1.00 equiv.) in methanol (500 mL) and 98% sulfuric acid (5 mL) was heated at reflux for about 15 hours. After cooling to ambient temperature, the solution was concentrated in vacuo and water (300 mL) was added to the resulting residue. The pH of the solution was adjusted to about 9 by adding sodium carbonate. Standard extractive workup with dichloromethane (3×200 mL) gave a residue that was then dried in an oven to give the title product as an off-white solid (49.5 g; yield=92.5%). 1H NMR (300 MHz, CDCl3) δ: 8.20 (t, J=1.8 Hz, 1H), 7.97-8.01 (m, 1H), 7.69-7.73 (m, 1H), 7.32 (t, J=8.1 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: CC(OCC1C[S:14][C@@H:9]2[C@H:10](N)[C:11](=O)[N:8]2[C:7]=1[C:16](O)=O)=O.[S-]C#N.[K+].FC(F)(F)S(O)(=O)=O.[NH2:31][CH:32]1[C:46](=[O:47])[N:34]2[C:35]([C:43]([OH:45])=[O:44])=[C:36]([CH2:39]SC#N)[CH2:37][S:38][C@H:33]12.C(OC(C)C)(C)C>C(#N)C.C(O)(C)C.O.N1C=CC=CC=1>[S-:14][C:9]#[N:8].[NH2:31][CH:32]1[C:46](=[O:47])[N:34]2[C:35]([C:43]([OH:45])=[O:44])=[C:36]([CH2:39][N+:8]3[CH:7]=[CH:16][CH:9]=[CH:10][CH:11]=3)[CH2:37][S:38][C@H:33]12
Reactant: N#CSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N#C[S-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Reaction time: 0.5 h

Procedure:
To a mixture of 7-aminocephalosporanic acid (45.0 g) and potassium thiocyanate (14.55 g) in acetonitrile (225 ml) was added dropwise trifluoromethanesulfonic acid (67.5 g) below 18° C. under cooling in an ice-bath and stirring, which was continued for 30 minutes at 15° to 18° C. The reaction mixture containing 7-amino-3-cyanothiomethyl-3-cephem-4-carboxylic acid was added to a mixture of pyridine (118.5 g) and water (150 ml) at 30° to 33.5° C. under stirring. The resultant mixture was immediately poured into a cold mixture of isopropyl alcohol (900 ml) and diisopropyl ether (1.2 l) under cooling in an ice-bath and stirring. The resulting precipitate was filtered, washed with isopropyl alcohol and diisopropyl ether and then redissolved in water (1.0 l). An insoluble material was filtered off and the filtrate was passed through a column packed with acidic alumina (150 g). The eluate (1.38 l) was concentrated to about 60 g of weight under reduced pressure and stirred for 30 minutes under cooling in an ice-bath. The resulting precipitate was filtered, washed with methanol and diisopropyl ether and dried to give 7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate thiocyanate (12.56 g), mp. 175° to 180° C. (dec.).
Reaction SMILES: [NH2:1][C:2](=[O:18])[C@H:3]([NH:10]C(=O)OC(C)(C)C)[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:10][C@H:3]([CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:2]([NH2:1])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccs1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@H](N)Cc1cccs1
Yield: 32.5 %

Procedure:
A solution of (R)-tert-butyl 1-amino-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (454 mg, 1.68 mmol) in TFA (4 mL) and CH2Cl2 (6 mL) was stirred at room temperature for 3 h. It was then concentrated in vacuo. The residue was partitioned between EtOAc and aq. 5% NaHCO3. The EtOAc phase was separated, washed with water, concentrated in vacuo to give (R)-2-amino-3-(thiophen-2-yl)propanamide (93 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C=O)C>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: COCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc3ccccc3[nH]2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Yield: 96.8 %

Procedure:
(R)-tert-Butyl 3-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (7B) (9.95 mmol, 3.0 g) was added to a 200 mL round-bottomed flask equipped for stirring under nitrogen. DMF (50 mL) was added and the resultant solution was cooled to 0° C. with an ice bath. NaH (60% in mineral oil, 11.95 mmol, 0.478 g) was then added and the subsequent solution was allowed to stir under nitrogen for 0.5 hr. At this time 1-bromo-3-methoxypropane (12.44 mmol, 1.90 g) was added, the ice bath was removed and the reaction solution was allowed to warm to room temperature and stir fort hr. The reaction solution was then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording a brown oil. This material was then purified by chromatography on silica gel (3-10% CH3OH in CH2Cl2) to afford (R)-tert-butyl 3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (7C) as a brown oil (9.63 mmol, 3.6 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (br.s., 1H) 1.79-1.88 (br.s., 1H) 2.04-2.13 (m, 4H) 2.74-2.88 (br.s., 1H) 2.98-3.38 (m, 7H) 4.21-4.39 (m, 3H) 7.22-7.28 (m, 2H) 7.34-7.40 (dd, 1H, 6.57 Hz, 2.02 Hz) 7.72-7.77 (dd, 1H, 6.57 Hz, 2.02 Hz). ESI-MS: m/z 374.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH:8]=O)OCCO1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[NH:17][NH2:18]>C(O)C>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[N:17]1[C:2]([CH3:1])=[CH:7][CH:8]=[N:18]1
Reactant: NNc1c(Br)cncc1[N+](=O)[O-]
Reactant: CC1(CC=O)OCCO1
Solvent: CCO
Product: Cc1ccnn1-c1c(Br)cncc1[N+](=O)[O-]

Procedure:
2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde (320 mg, 2.459 mmol) and (3-bromo-5-nitro-4-pyridyl)hydrazine (286.4 mg, 1.229 mmol) were heated under reflux in ethanol (2.864 mL) overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and a saturated aqueous sodium hydrogen carbonate solution. Combined organic extract was dried over MgSO4 and concentrated in vacuo to leave 3-bromo-4-(5-methyl-1H-pyrazol-1-yl)-5-nitropyridine as a yellow oil. (200 mg, 85%). MS (ES+) 284.9.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C(N1C=CN=C1)([N:21]1C=CN=C1)=O>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:21])=[O:15])[CH2:6][CH2:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Reaction time: 1 h

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1 equiv.) was dissolved to 0.2 M THF and the stirred pale yellow solution treated with carbonyldiimidazole (CDI) (1.1 equiv.). The reaction was let stir for one hour and a solution of amine (1.1 equiv 0.2 M in THF) was added over one hour and the reaction stirred overnight. The solution was concentrated, dissolved to 0.04 M in CH2Cl2 and washed sequentially with half-volumes of 0.5 M HCl, 1.0 M NaHCO3, saturated NaCl, the organic layer dried over Na2SO4 and concentrated. Flash chromatography yielded the desired 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide derivative.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:38]1[CH2:44][CH2:43][CH2:42][C@H:39]1[CH2:40][OH:41]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([N:38]1[CH2:44][CH2:43][CH2:42][C@H:39]1[CH:40]=[O:41])=[O:14])[CH2:10][OH:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 20.5 g of t-butyloxycarbonylserine. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from chloroform to obtain a white solid substance which was then dissolved in 450 ml of THF. To this solution was added 18.0 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 330 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 36.9 g of WSCD.HCl and 150 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 6.5 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 300 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 250 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 2.1 g (7.3%).