Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C.O.[Zn]>[CH2:28]([O:27][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1)=[O:13])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cn1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a stirred solution of 2-[(3,5-dibenzyloxybenzoyl)amino]-5-nitropyridine (910 mg) in DMF (6 ml) was added Zinc dust (1300 mg) and a solution of ferric chloride hexahydrate (1700 mg) in water (6 ml). The resulting mixture was stirred at 120° C. for three hours. Allowed to cool to ambient temperature. The mixture was extracted with ethyl acetate. The extract was washed with water (50 ml), brine (50 ml), dried over MgSO4, then volatile material was removed by evaporation to leave a solid, which was dried under high vacuum for 24 hours at 100° C. to give the title compound (518 mg) as a solid, 1H NMR δ (d6-DMSO): 5.17 (m, 6H), 6.80 (s, 1H), 7.00 (d, 1H), 7.26 to 7.46 (m, 12H), 7.71 (s, 1H), 7.78 (d, 1H), 10.28 (br s, 1H). MS ES+426.52 (M+H)+.
Reaction SMILES: [S:1]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([O:4][CH2:5][C@@:6]1([CH3:13])[CH2:10][O:9]C(C)(C)[O:7]1)(=[O:3])=[O:2].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[S:1]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)([O:4][CH2:5][C@@:6]([OH:7])([CH3:13])[CH2:10][OH:9])(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)COC(C)(C)O2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@](C)(O)CO)cc1

Procedure:
1.42 g (4.74 mmol) of {(R)-2,2,4-trimethyl-1,3-dioxolan-4-yl}methyl tosylate are evaporated twice from 100 ml of methanol in the presence of a catalytic amount of p-toluenesulfonic acid at 16 mbar/40° C. and the residue is finally purified by chromatography over silica gel 60 (0.040-0.063 mm, 20 g) using methylene chloride/diethyl ether (1:1) as the eluent. There are obtained 907 mg (3.49 mmol, 74% of the theoretical yield) of (R)-2,3-dihydroxy-2-methylpropyl tosylate, 99% pure by gas chromatography, [α]365 =-19.0° (1% in CHCl3).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccnc(-c3ccccc3)c2)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(O)cc(-c2nn(CC#N)cc2-c2ccnc(-c3ccccc3)c2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (45.6 mg, 0.12 mmol) prepared in Example 23 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (31 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:13][CH2:14]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1

Procedure:
A mixture of Example 213a (3.950 g, 11.23 mmol), 2-(tert-butoxycarbonylamino)acetic acid (2.165 g, 12.36 mmol), HOBT (1.892 g, 12.36 mmol), EDC (2.369 g, 12.36 mmol), and triethylamine (2.04 mL, 14.6 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 3 hours. The reaction was diluted with 50% brine and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was triturated with EtOAc/hexane (8:2) to give 2.756 g of the title compound. The filtrate was purified on an 80 g column using the ISCO Companion flash system eluting with EtOAc/hexane (7:3 to 8:2) to give the 1.091 g more title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:23])[C:9](=[O:22])[CH2:10][CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:23])[C:9](=[O:22])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C(=O)CCC(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 50 °C
Yield: 53.7 %

Procedure:
A mixture of diethyl 2-(3-(2-fluoro-4-biphenylyl)-2-oxobutyl)malonate (5.00 g, 12.5 mmoles), acetic acid (100 ml), and 30% sulfuric acid (100 ml) was heated under reflux for 4 hours. After cooling the reaction mixture was extracted with ether. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure The mixture of the residue, ethanol (100 ml) and concentrated sulfuric acid (1.0 g) was heated at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ether. The organic layer was washed successively with water, aqueous sodium bicarbonate and water, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by medium pressure silica gel column chromatography gave the desired 5-(2-fluoro-4-biphenylyl)-4-oxohexanoic acid (2.21 g, 6.71 mmoles, yield 54%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: COc1ccccc1S
Product: COc1ccccc1Sc1nc(C(=O)NCC(=O)O)c(O)c2ccccc12

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 2-methoxybenzenethiol under conditions analogous to Example D-110. The final product was crystallized from dichloromethane; MS (−) m/z 383.08 (M−1)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: Cc1ccc2c(Cl)c(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)sc2c1

Procedure:
Following the 2a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 2b white powder; (179.63 mg, 96.1%). [α]D25: +23.9 (c=0.29, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.76-7.72 (m, 3H), 7.39-7.22 (m, 6H), 5.04-4.98 (m, 1H), 3.44-3.26 (m, 2H), 2.48 (s, 3H); 13C NMR (300 MHz, acetone-d6): δ 171.81, 159.86, 138.26, 138.03, 136.71, 134.63, 131.56, 129.53, 128.38, 127.49, 126.86, 122.53, 122.49, 118.80, 54.13, 36.88, 20.75; HRMS (ESI): calcd for: C19H16ClNO3S [M−H]−=372.0467, obsd [M−H]−=472.0475.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][OH:16].[OH-].[K+]>CN(C)C=O.O>[OH:16][CH2:15][CH2:14][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1ccc2cc(Br)ccc2c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-2-naphthol (15.1 g, 67.7 mmol), 2-bromoethanol (10.11 g, 80.9 mmol) in N,N-dimethylformamide (60 ml) was added a solution of KOH (5.41 g, 81.9 mmol) and KI (0.37 g, 2.20 mmol) in water (10 ml). Upon stirring at 85° C. for 4 hours, the reaction mixture was filtered. The filtrate was shaken with diethyl ether (400 ml) and water (400 ml). The organic layer was washed with 2% KOH (100 ml water). The solvent was evaporated off to obtain crude product. Recrystallization from a mixed solvent of methanol (20 ml) and water (200 ml) yielded (h) in 10.0 g (55%). Proton-NMR spectral data (CDCl3), δ(ppm): 2.16 (t, HOCH2, 1H), 4.10 (m, HOCH2CH2, 2H), 4.22 (t, ArOCH2CH2,2H), 7.10-7.95 (m, aromatic, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCOC(=O)N1CCN(C(=O)CCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)N1CCN(C(=O)CI)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.3 %

Procedure:
A mixture of ethyl 4-(2-chloroacetyl)piperazine-1-carboxylate (2.36 g, 10.06 mmol) and sodium iodide (3 g, 20.11 mmol) in acetone (45 mL) was stirred at room temperature for 24 h to give a suspension containing white solids. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with CH2Cl2 and H2O. The organic layer then dried over MgSO4, filtered and concentrated to give ethyl 4-(2-iodoacetyl)piperazine-1-carboxylate (2.47 g, 75% yield). C9H151N2O3; brown oil; IR vmax (neat) 2981, 2927, 2864, 1697, 1642, 1464, 1434, 1385, 1286, 1232, 1133, 1073, 1030, 989, 767 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.14 (2H, q, J=7.0 Hz), 3.75 (2H, s), 3.58 (4H, m), 3.43 (4H, m), 1.26 (3H, t, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 166.6, 155.1, 61.8, 47.0, 43.1 (2×), 42.0 (2×), 14.7; ESI-HRMS calcd for C9H161N2O3: 327.0206. found: m/z 327.0215 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:11](I)=[N:10]2)=[N:3]1.B(O)(O)O.F[C:27]([K])=[C:28](F)F.C(N(CC)CC)C>C1COCC1.CC(O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:27]=[CH2:28])=[N:10]2)=[N:3]1
Reactant: Cc1cc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)nn1C
Reactant: FC(F)=C(F)[K]
Agent: OB(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C=Cc1nn(Cc2cc(C)n(C)n2)c2cccc([N+](=O)[O-])c12
Temperature: 80 °C
Yield: 82 %

Procedure:
To 1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-3-iodo-4-nitro-1H-indazole (8.35 g, 21.0 mmol) in THF/IPA (10 mL/30 mL) was added trifluorovinylpotassium borate (5.63 g, 42.0 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.858 g, 1.05 mmol) and triethylamine (8.79 mL, 63.1 mmol). The reaction mixture was heated to 80° C. for 16 hours. The mixture was diluted with EtOAc (100 mL), washed with H2O and brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hexane/EtOAc 5:1) to provide the product (5.12 g).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Cl:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])O.[Na+].Cl>[N+](C)([O-])=O>[Cl:9][C:10]1[NH:11][CH:12]=[C:13]([N+:7]([O-:8])=[O:6])[N:14]=1
Reactant: Clc1ncc[nH]1
Reactant: O=[N+]=O
Agent: Cl
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: C[N+](=O)[O-]
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Nitronium tetrafluoroborate (398 mg) was dissolved in nitromethane (5 ml), next 2-chloroimidazole (205 mg) was added, the reaction mixture was stirred at a room temperature for 1 hour. The reaction mixture was neutralized with an aqueous solution of sodium hydrogencarbonate, then was turned back to acidic by adding hydrochloric acid, the separated 2-chloro-4-nitroimidazole (137 mg) was collected by filtration. The filtrate was extracted with ethyl acetate-methanol, the solid matter obtained from the organic layer was triturated with diethyl ether, 2-chloro-4-nitroimidazole (103 mg) was obtained. The sum of 240 mg (yield: 81.3%) of 2-chloro-4-nitroimidazole was obtained as colorless solid product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17](C(=O)C)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)n1cc(CC2C(C)CCN2C(=O)OC(C)(C)C)c2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCN(C(=O)OC(C)(C)C)C1Cc1c[nH]c2cc(F)ccc12
Reaction time: 0.5 h

Procedure:
To a solution containing 65 (2.2 g, 0.006 mol) in MeOH (15 mL) was added 1M NaOH (6 mL, 0.006 mol) at 0° C. After 30 min, TLC analysis revealed complete consumption of 65 [EtOAc/hexanes 1:1, Rf(65) 0.6; Rf(66)=0.5]. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with 1M HCl, water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 2.11 g (quant.) of crude 66 which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ9.0 (s, 1H, major rotamer), 8.85 (s, minor rotamer), 7.62-7.5 (m, 1H), 7.1-6.72 (m, 3H), 3.8-2.7 (m, 5H), 2.15-1.3 (m, 3H), 1.55 (s, 9H), 0.85 (d, J=7 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[N:13]([CH2:21][CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)nn(CC=Cc2ccccc2)c1=O
Yield: 59.3 %

Procedure:
Using 6-(3-chloro-4-fluorophenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one and cinnamyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 59.3%.
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>CCO.[Pd]>[OH:8][N:9]([CH2:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14]1)[CH:10]=[O:11]
Reactant: O=CN(CC1CCc2ccccc2NC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=CN(O)CC1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of N-benzyloxy-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl)-formamide (0.052 mmol) and Pd/C (10%) (3 mg) in EtOH is degassed and filled with hydrogen. After the mixture is stirred at room temperature for 14 hours, Pd/C is removed by filtration. The filtrate is concentrated and purified by preparative thin layer chromatography (10% EtOH/CH2Cl2) to provide the title compound N-hydroxy-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl)-formamide. Yield: 58%. 1H NMR (400 MHz, MeOD): δ 8.13 (s, 1H), 7.87 (s, 1H), 7.17 (m, 2H), 7.06 (t, 1H, J=8.0 Hz), 6.92 (d, 1H, J=8.0 Hz), 3.88 (dd, 1H, J=8.0 Hz, J=14.4 Hz), 3.24 (dd, 1H, J=4.8 Hz, J=14.4 Hz), 2.77 (m, 2H), 2.62 (m, 1H), 2.11 (m, 1H), 1.84 (m, 1H). MS: (ES+): 235.2 [M+1].
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1B(O)O>>[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OB(O)c1nccs1
Reactant: O=Cc1ccc(Br)cc1
Product: O=Cc1ccc(-c2nccs2)cc1
Yield: 82 %

Procedure:
Ex-5A: 4-Thiazol-2-yl-benzaldehyde was prepared from 4-bromobenzaldehyde and thiazole-2-boronic acid in a similar manner as described in Ex-3A, 82% yield. 1H-NMR (CDCl3) δ 10.07 (s, 1H), 8.15 (d, J=8 Hz, 2H), 7.95–7.98 (m, 3H), 7.45 (d, J=3 Hz, 1H). HMRS (EI) calcd. for C10H7NOS: 189.0248; found: 189.0242.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:5]([N+]([O-])=O)[C:6]=1[Cl:7].Br[C:20]1[NH:21]C(C2C=CC(Cl)=C(Cl)C=2)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:5]([C:20]#[N:21])[C:6]=1[Cl:7]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Br)c1Cl
Reactant: O=[N+]([O-])c1cc(Br)[nH]c1-c1ccc(Cl)c(Cl)c1
Product: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Br)c1Cl

Procedure:
In a similiar fashion one can prepare 2-bromo-3-chloro-5-(3,4-dichlorophenyl)-4-nitropyrrole by starting with 2-bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Na+].S(O[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][OH:59])(C1C=CC(C)=CC=1)(=O)=O>COCCOC>[CH2:58]([OH:59])[CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCCCSCCOCCOCCOCCOCCOCCOCCOCCOCCO
Temperature: 85 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a heated (40° C.) solution of 20.1 g (0.97 mole) of n-octadecanethiol in 200 ml of dried 1.2-dimethoxyethane was slowly added under argon 0.07 mole (3.4 g., 50%) of sodium hydride (rinsed with hexane to remove the mineral oil) slurried in 1,2-dimethoxyethane. The reaction mixture was then heated at reflux (85° C.) with stirring for 2 hrs. A solution of 40 g. (0.07 mole) of the nonaethylene glycol monotosylate in 200 ml. 1,2-dimethoxyethane was added dropwise and the reaction mixture allowed to reflux with stirring for 16 hours. The mixture was cooled, insoluble salts were filtered, and the solvent was evaporated to yield a near quantitative yield (0.07 mole) of the thioether.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[N:9])[CH2:3][CH2:2]1.[OH-].[K+].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:15][C:14]=1[CH:35]=O>CS(C)=O.O.[Cl-].[NH4+]>[NH2:9][C:8]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:35][C:14]2[C:13](=[CH:18][CH:17]=[C:16]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH:15]=2)[N:12]=1
Reactant: Cc1cccc(N(C)C(=O)CC(C)(C)C)c1-c1ccc(N)c(C=O)c1
Reactant: N#CCN1CCOCC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(N(C)C(=O)CC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 80 °C

Procedure:
A solution of 2-morpholinoacetonitrile (37.7 mg, 0.299 mmol) in DMSO (0.5 mL) was treated with concentrated aqueous KOH (11M; 8.08 μL, 0.095 mmol). The reaction mixture was heated to 80° C. and a solution of N-(4′-amino-3′-formyl-6-methylbiphenyl-2-yl)-N,3,3-trimethylbutanamide (64 mg, 0.189 mmol) in DMSO (1 mL) was added dropwise. After 10 min the reaction mixture was diluted with water and aqueous saturated ammonium chloride solution. The aqueous mixture was extracted with DCM. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The titled compound was isolated as a light-yellow foam. MS (ESI, pos. ion) m/z: 447 (M+1).
Reaction SMILES: N[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N([O-])=O.[Na+].CCOCC.CCCCCC.[ClH:25]>O>[Cl:25][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-3,5-dichloropyridine (21.0 g.) is dissolved in conc. HCl (200 ml.), then cooled with ice. To this solution, NaNO2 (48 g.) in water (60 ml.) is added slowly over 30 minutes. The reaction mixture is stirred at 0° for 1 hour and then 50° for 1 hour. The mixture is then poured into ice-water and extracted with ether. The combined extracts are washed, dried and evaporated to dryness to give yellow solid. The solid is stirred with 25% ether/hexane and filtered. The filtrate is concentrated and washed again with 25% ether/hexane to give 2,3,5-trichloropyridine (12 g.).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>O1CCCC1.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)ON
Reactant: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[3-(dimethylamino)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 76) (200 mg, 0.51 mmol) and N-methylmorpholine (112 μl, 1.00 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0° C., treated with isobutyl chloroformate (79 μl, 0.69 mmol) and stirred under a nitrogen atmosphere for 2 hours. O-(Trimethylsilyl)hydroxylamine (85 μl, 0.61 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (2×25 ml) and brine (25 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a foam (180 mg).