Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][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][CH2:30][CH3:31])[CH2:8][NH2:9])[N:5]=[N:4][N:3]=1.[Cl:33][CH2:34][CH2:35][CH2:36][S:37](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:9][CH2:8][CH:7]([N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][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][CH2:30][CH3:31])(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)n1nnnc1C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)n1nnnc1C

Procedure:
2-(5-Methyl-1H-tetrazol-1-yl)-3-octadecylcarbamoyloxypropylamine IVi2 is allowed to react and worked up by the same procedure as described in (4). m.p. 74°-77° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH:49]1([CH2:54][CH:55]=[O:56])[CH2:53][CH2:52][CH2:51][CH2:50]1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:55]([OH:56])[CH2:54][CH:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: O=CCC1CCCC1
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)c1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 1, 2.6 g, 8.3 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (6.7 mL, 10.7 mmol) to a solution of diisopropylamine (1.6 mL, 11.3 mmol) in dry tetrahydrofuran (15 mL) at 0° C.] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with cyclopentyl acetaldehyde (1.2 g, 10.7 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and then quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 15% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-(2-cyclopentyl-1-hydroxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester as a colorless oil (730 mg, 21%): 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (m, 2H), 1.53-1.68 (m, 4H), 1.73-2.16 (m, 5H, H), 3.50 (br, 1 H), 3.89 (s, 3H), 5.41 (dd, J=5.0 Hz, 8.1 Hz, 1H), 6.67 (s, 1H), 7.42 (brt, 2H), 7.53 (brt, 1H), 8.14 (br. d., 2H), 8.33 (m, 1H), 8.96 (m, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18].ClC1C=CC(OC[C:26]#[N:27])=CC=1>CN(C=O)C>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([CH2:1][N+:27]#[C-:26])=[CH:10][C:9]=1[O:17][CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc([N+](=O)[O-])cc1F
Reactant: N#CCOc1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]Cc1cc(OC)c(F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Potassium t-butoxide (15.74 g, 140 mmol) in DMF (50 mL) was added to a solution of 2-fluoro-1-methoxy-4-nitrobenzene (12 g, 70.1 mmol) and 2-(4-chlorophenoxy)acetonitrile (11.75 g, 70.1 mmol) in DMF (100 mL) at −20° C. The reaction mixture was stirred for 1 h and then quenched with water. The aqueous layer was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 3% ethyl acetate in hexane to afford title compound (3.6 g, 23.21%) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J=10.84 Hz, 1H), 7.27-7.23 (m, 1H), 4.28 (s, 2H), 4.05 (s, 3H); ESI-MS m/z=209 (M−H)−; LCMS Purity: 95%
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:28]([NH:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1NC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Pyridine (43 μL, 0.54 mmol) was added to a stirred solution of aniline 21 (50 mg, 0.18 mmol) in DCM (0.9 mL) at room temperature under nitrogen atmosphere. After 5 min, benzoylchloride 3 (22.5 μL, 0.198 mmol) was added and the reaction was stirred for 2 h before being diluted with DCM and washed with HCl (3×, aq, 1M), NaHCO3 (aq, sat), and brine. The organic phase was dried over Na2SO4, concentrated and purified by column chromatography (toluene:acetone 100:0→98:2) to give benzamide 23a in 62% yield (36 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([N:16]=2)=[CH:14][N:13]=[N:12][CH:11]=3)=[C:4]([O:17][CH3:18])[CH:3]=1.[CH2:19](I)[CH3:20]>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([S:1][CH2:19][CH3:20])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][N:13]=[N:12][CH:11]=2
Reactant: COc1cc(S)ccc1-c1nc2cnncc2[nH]1
Reactant: CCI
Product: CCSc1ccc(-c2nc3cnncc3[nH]2)c(OC)c1

Procedure:
In a manner similar to that of Example 12, conversion of 2-(4-mercapto-2-methoxyphenyl)-1,3,5,6-tetraazaindene into the Na salt and subsequent reaction with ethyl iodide gives 2-(2-methoxy-4-ethylthiophenyl)-1,3,5,6-tetraazaindene, m.p. 248°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[C-:11]#[N:12].[K+]>O1CCOCC1.O.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][C:11]#[N:12])[CH:9]=1
Reactant: Fc1ccc(Br)cc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: N#CCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
5-Bromo-2-fluorobenzyl bromide (8.0 g, 0.03 mole) was dissolved in 1,4-Dioxane (60 mL) and added to a solution of KCN (2.04 g, 0.031 mole) in H2O (20 mL) and ethanol (20 mL). The resulting mixture was heated under reflux for 5 h. After cooling to rt, the product was extracted with ether (200 mL), washed with brine, dried over MgSO4, concentrated, and crystallized from ether/hexane to give 5-bromo-2-fluorophenylacetonitrile as a white crystalline material (5.6 g, 88%): mp 55-58° C.; 1H NMR (DMSO-d6) δ 4.07 (s, 2H), 7.29 (t, 1H, J=9.23 Hz), 7.60-7.69 (m, 2H); MS(EI) M+. m/z 213; Anal. Calc. For C8H5Br2FN: C, 44.89; H, 2.35; N, 6.54. Found: C, 44.90; H, 2.24; N, 6.43.
Reaction SMILES: C[Mg]I.C([O:6][CH2:7][CH3:8])C.[CH2:9](OCC)C.[Br:14][C:15]1[N:20]=[C:19]([C:21](C)([CH3:27])[C:22](OCC)=O)[CH:18]=[CH:17][CH:16]=1.P(=O)(O)(O)O>O>[Br:14][C:15]1[N:20]=[C:19]([C:21]([CH3:22])([CH3:27])[C:7]([CH3:8])([OH:6])[CH3:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: CCOC(=O)C(C)(C)c1cccc(Br)n1
Agent: C[Mg]I
Agent: O=P(O)(O)O
Solvent: O
Product: CC(C)(O)C(C)(C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 13 mL of 2 M methylmagnesium iodide/diethyl ether solution was added to diethyl ether (20 mL) solution of 2.72 g of ethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate with cooling in an ice bath. The reaction liquid was stirred at room temperature for 3 hours, and then water and aqueous 10% phosphoric acid solution were added thereto, extracted with diethyl ether, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and then dried with anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 8/1) to obtain 1.47 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][OH:25].O>CO.CN(C=O)C>[Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11](=[NH:12])[O:25][CH3:24])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2
Reactant: N#Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=N)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
2,5,6-Trichloro-3-cyano-1-(β-D-ribofuranosyl)indole (4.4, 107 mg, 0.28 mmol) was dissolved in dry MeOH (10 mL) which was cooled to 0 C in an ice bath. Hydrogen chloride gas was slowly bubbled through the solution for 2 h, then the reaction vessel was tightly capped, and the resulting solution was stirred at room temperature for 24 h. The acidic solution was diluted with Et2O (20 mL) and evaporated to dryness. The residual solid was suspended in 10% aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL, with vigorous shaking). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid which was dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield 64 mg (58%) of 4.34 as a white crystalline solid: mp 248-249 C; Rf0.6 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.43 (s, 1H, D2O exch.), 7.96 (s, 1H), 5.98 (d, 1H), 5.39 (d, 1H, D2O exch.), 5.37 (t, 1H, D2O exch.), 5.24 (d, 1H, D2O exch.), 4.41 (q, 1H), 4.14 (s, 1H), 3.98 (d, 1H), 3.85 (s, 3H), 3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 161.40, 132.01, 128.23, 125.67, 124.82, 124.50, 121.32, 115.19, 106.29, 88.73, 86.08, 71.40, 69.50, 60.99, 52.45. HRMS (EI) m/z calcd. for C15H15Cl3N2O5 408.0047, found 408.0043. Anal calcd for C15H15Cl3N2O5: C, 43.98; H, 3.69; N, 6.84. Found: C, 43.97; H, 3.81; N, 6.75.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:14])=O>>[ClH:14].[CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccnc1CO
Reactant: O=S(Cl)Cl
Product: CCCCn1ccnc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 1-butyl-2-hydroxymethylimidazole (3.0 g) was added thionyl chloride (30 ml), and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature, the solvent was distilled off under reduced pressure, and the obtained solid was washed with ethyl acetate, to give 1-butyl-2-chloromethylimidazole hydrochloride (3.5 g) as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11]>[Cl-].[Zn+2].[Cl-]>[C:10]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:9]
Reactant: C=C(C)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(c1ccccc1)c1ccc(N)cc1
Yield: 78 %

Procedure:
18.6 Parts of aniline, 20.4 parts of 36% w/w hydrochloric acid containing 13.6 parts of zinc chloride are stirred and refluxed for 24 hours with 23.6 parts of α-methylstyrene. The work-up follows Example 3 and gives on distillation 32.9 parts of 4-cumylaniline mb4 175°-80° C. (78% yield based on a 93% purity by G.L.C.).
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:5]=2[O:4]1)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([Cl:21])=[O:18])=[CH:15][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@H]1Oc2cc(C(=O)O)ccc2N(CC)C1=O
Reactant: O=S(Cl)Cl
Product: CC[C@H]1Oc2cc(C(=O)Cl)ccc2N(CC)C1=O

Procedure:
A mixture of (R)-2,4-diethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (1.0 g) in thionyl chloride (10 ml) was stirred under reflux for 2 hours. Thionyl chloride was distilled off under reduced pressure to give (R)-2,4-diethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbonyl chloride (1.14 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26](ON=C(C(OCC)=O)C(OCC)=O)=[O:27])=[CH:22][CH:21]=1>O.C(O)(C)(C)C>[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=NOC(=O)OCc1ccc(OC)cc1)C(=O)OCC
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
L-Phenylalanine (330 mg.) and sodium bicarbonate (202 mg.) were dissolved in water (10 ml.) under heating and allowed to stand. A solution of diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0 g.) in tert-butyl alcohol (10 ml.) was added to the solution with stirring at room temperature and water (10 ml.) was added thereto, the mixture was then stirred for 2 hours at room temperature. The reaction mixture was brought to pH 9 by adding water (20 ml.) and saturated sodium bicarbonate aqueous solution (10 ml.), and water (10 ml.) was added thereto. The resulting mixture was then washed twice with ethyl acetate (20 ml.). The aqueous layer was adjusted to pH 7 with a 10% citric acid aqueous solution, washed twice with ethyl acetate (30 ml.), adjusted to pH 3.5 with a 10% citric acid aqueous solution and extracted three times with ethyl acetate (30 ml.). The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give N-(4-methoxybenzyloxycarbonyl)-L-phenylalanine (410 mg.), oil.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[N:7]([CH2:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][C:31]=3[CH3:40])[C:8](=[O:28])[C@@H:9]([NH:20]C(=O)OC(C)(C)C)[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[NH2:20][C@@H:9]1[C:8](=[O:28])[N:7]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][C:31]=2[CH3:40])[C:6]2[CH:41]=[CH:42][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@H:10]1[CH3:19]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Yield: 90 %

Procedure:
A rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (510 mg, 863 μmol) in 4 M HCl in dioxane (4.32 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (410 mg, 90%) as a white solid. MS m/z 491 (MH)+.
Reaction SMILES: [Br:1]Br.[N+:3]([CH:6]=[C:7]1[NH:12][CH2:11][CH2:10][CH2:9][S:8]1)([O-:5])=[O:4]>C(Cl)Cl.O>[Br:1][C:6]([N+:3]([O-:5])=[O:4])=[C:7]1[NH:12][CH2:11][CH2:10][CH2:9][S:8]1
Reactant: BrBr
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])C(Br)=C1NCCCS1

Procedure:
A solution of 3.2 g of bromine in 10 ml of methylene chloride was added dropwise to a solution of 3.2 g of 1A in 50 ml of water, the temperature being held at 5°-10°. The mixture was then stirred for 45 minutes when 200 ml of methylene chloride was added to dissolve the solid material. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated under reduced pressure to give a yellow solid. This was washed with ether to give 2A as a yellow solid, m.p. 122° (with decomposition).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[CH:18]([NH:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:17][CH2:16]2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[OH:40].OO.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][C:10]1[NH:23][C:22](=[O:40])[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][CH2:17][CH:18]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[C:19]=3[CH:20]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc(NC(=O)COCc4ccccc4)c(C#N)cc32)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(COCc5ccccc5)[nH]c(=O)c4cc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, ice-bath cooled mixture of tert-butyl 4-[N-(5-(2-benzyloxy-ethanoylamino)-6-cyanoindan-1-yl)amino]benzoate (3.77 g, 7.59 mmol), EtOH (70 ml), and H2O (11 ml) was added 30% H2O2 (8.05 ml) followed by granulated NaOH pellets (0.640 g, 16.0 mmol). The reaction mixture was stirred at 0° C. for 10 min, then placed in an oil-bath preheated to 55° C. and stirred at this temperature for 1 hour. The solvents were then removed in vacuo; the residue was treated with H2O (80 ml) and the pH was adjusted to ˜5 with 1N HCl. The pale yellow solid was collected by filtration, washed with H2O and dried in vacuo over P2O5 (3.56 g, 95%); mp 194-195° C.; 1H-NMR (250 MHz, DMSO-d6, TMS) 1.52 (s, 9H, C(CH3)3), 1.90 (m), 2.62 (m) (1H each, 7-CH), 2.90-3.17 (m, 2H, 8-CH2), 4.43, 4.60 (2×s, 2H each, PhCH2 and OCH2CO), 5.18 (q, J=7.43 Hz, 1H, 6-CH), 6.79 (d, J=8.8 Hz, 2H, 3′,5′-ArH), 6.87 (d, J=8.0 Hz, 1H, N10—H), 7.34 (m, 5H, PhCH2), 7.54, 7.92 (2×s, 1H each, 5-H and 9-H), 7.68 (d, J=8.9 Hz, 2H, 2′,6′-ArH), 12.20 (s, 1H, CONH); MS (ESI, m/z) 520 {(M+Na)+, 90%,}, 498 {(M+H)+, 100%}; Found: C, 72.13; H, 6.25; N, 8.38; C30H31N3O4 requires C, 72.41; H, 6.28; N, 8.44%.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:64][C:58]1[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:57]=1[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 55 %

Procedure:
DIPEA (186 mg, 1.44 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (119 mg, 0.37 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was added and the precipitate formed was collected to afford the residue. The residue was purified by preparative HPLC to afford 80 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457.14, 96.27%. 1H NMR (300 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.14 (s, 1H), 8.1 (t, 2H), 7.8 (d, 2H), 7.6-7.4 (m, 4H), 7.32 (d, 1H), 6.9 (t, 1H), 4.9 (bs, 1H), 4.2 (d, 2H), 3.8 (b, 2H), 3.55 (b, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](CO)COCc1ccccc1
Reactant: O=P(Br)(Br)Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](CBr)COCc1ccccc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Dissolve (R)-2-(benzyloxy-methyl)-3-methyl butanol (15.6 g, 75 mmol) in N,N-dimethyl formamide (246 ml), add phosphorus oxybromide (22.58 g, 78.75 mmol) in droplets slowly and control the temperature below 50° C. in that process, and then let them to react at 50° C. for 3 hours. Cool down to room temperature, and pour the reactant liquid into water (246 ml) slowly, extract with normal hexane for three cycles, combine the normal hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 18.1 g of oily matter. Treat the oil matter by reduced pressure distillation to obtain 16.6 g of colorless transparent liquid; the yield is 81.1%, and the chiral purity is ≧99.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH2:47])=[N+:34]=[N-:35]>C(Cl)(Cl)Cl.C(Cl)Cl>[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)(=[O:22])=[O:21])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 8 h

Procedure:
To a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (600 mg, 1.41 mmol) in chloroform (2.82 mL) was added DIEA (545.7 mg, 4.24 mmol) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (616.3 mg, 2.82 mmol). The reaction was stirred overnight at which point the mixture was diluted with 50 mL DCM and washed with NaHCO3 (50 mL). The aqueous layer was extracted with DCM (2×50 mL) and the combined organic fractions washed with water (200 mL), brine (200 mL), and dried over Na2SO4. Removing the solvent gave the title compound as an oil which was used without further purification.