Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
To a solution of 8C (228 mg, 0.282 mmol) in acetonitrile (10 mL) and dichloromethane (5 mL) at 0° C., was added phosgene solution (20% in toluene) (0.178 mL, 0.339 mmol) dropwise. The mixture was stirred at 0° C. for 20 min, then at rt for 15 min. The extra phosgene was removed by bubbling Ar though the reaction mixture (15 min). The resulting solution was added dropwise via syringe pump into a stirred solution of TEA (0.315 mL, 2.258 mmol) in dichloromethane (80 ml) at rt over 3.0 h. The reaction was quenched by 0.5 N HCl and extracted with CH2Cl2. The organic layer was collected, washed with water and dried over sodium sulfate, then concentrated. The crude product was purified by flash chromatography to give a mixture of diastereoisomers (235 mg). The diastereomers (165 mg) were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 8D (54 mg, 0.065 mmol, 32.7% yield). MS (ESI) m/z: 883 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 1.26 (d, J=6.59 Hz, 3H) 1.28-1.37 (m, 21H) 1.42 (d, J=6.59 Hz, 3H) 2.09 (s, 3H) 3.27-3.42 (m, 5H) 3.90 (dd, J=10.77, 3.73 Hz, 1H) 4.30 (d, J=17.58 Hz, 1H) 4.63 (t, J=10.99 Hz, 1H) 5.43 (d, J=5.71 Hz, 1H) 5.68 (d, J=18.02 Hz, 1H) 6.36 (s, 1H) 6.55 (d, J=5.71 Hz, 1H) 6.75 (d, J=8.35 Hz, 1H) 6.86 (s, 1H) 7.01 (d, J=9.23 Hz, 1H) 7.04-7.12 (m, 2H) 7.45-7.54 (m, 2H) 7.61 (d, J=7.91 Hz, 1H) 7.77 (d, J=8.35 Hz, 1H) 8.03 (s, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −141.12 (br. s., 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:29])=[O:28]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(CCCCCCl)NCCCCO
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCCO
Yield: 93.2 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(4-hydroxybutyl)-5-chloropentanesulfonamide (515.6 mg, 2.00 mmol) prepared in Preparation Example 23 were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (947.0 mg) as a pale yellow oil (yield: 93.2%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][CH:54]=[C:48]([F:47])[CH:49]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1cccc(F)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoroaniline (Aldrich) to give the title product. LC-MS (ES+) 758 [(M+H)+].
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:27](C(C)C)CC)(C)C.[C:33]1([CH3:49])[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[N:41][C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=[CH:35][CH:34]=1>CN(C=O)C>[C:33]1([CH3:49])[CH:38]=[CH:37][C:36]([N:39]([CH:11]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:23])[C:40]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)=[NH:27])=[CH:35][CH:34]=1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=N)N(c2ccc(C)cc2)C(Cc2c[nH]c3ccccc23)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.0 mmol of tryptophan benzyl ester hydrochloride was dissolved in 20 ml of DMF and 1.1 mmol of diisopropylethylamine was added. After 10 min, 1.0 mmol of 1,3 di-p-tolylcarbodiimide was added to the stirred solution. The reaction mixture was stirred overnight in room temperature. The precipitated solid was filtered off and washed twice with 1 ml of DMF. To the collected filtrate, 50 ml of water was added. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate and 0.1 ml of conc. HCl was added. The pure product was precipitated from the solution with ethyl ether. Yield of pure compound=79%.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[OH:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]=1>C(OCC)(=O)C>[F:7][CH:2]([F:6])[O:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]=1
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)n1nc(OC(F)F)c2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Sodium chlorodifluoroacetate (4.75 g) and potassium carbonate (8.58 g) were added to a DMF (3 ml) solution containing ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (1.56 g), followed by stirring at 80° C. for 1 hour. The reaction solution was adjusted to room temperature and ethyl acetate was added to remove an insoluble precipitate. The organic layers were washed with a saturated ammonium chloride aqueous solution, water, and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A yellow solid of ethyl 3-(difluoromethoxy)-5-nitro-1H-indazol-1-carboxylate (1.14 g) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[CH:27]=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15].[Br:30]N1C(=O)CCC1=O>ClCCl>[Br:30][C:27]1[N:19]2[C:18]([CH2:17][N:16]([C:14]([C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]4)=[CH:7][C:2]=3[Cl:1])=[O:15])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20]2)=[CH:29][CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)n1
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(Br)n4Cc4ccccc43)c(Cl)c2)n1
Temperature: -40 °C
Yield: 76.4 %

Procedure:
To a stirred pre-cooled solution of [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.61 g) in dichloromethane (25 ml) was added solid N-bromosuccinimide (0.712 g) over 10 minutes at −78° C. The reaction was allowed to warm to −40° C. over thirty minutes. The mixture was diluted with dichloromethane, and extracted sequentially with saturated aqueous sodium bicarbonate (2×100 ml) and water (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered through a plug of silica gel, and evaporated in vacuo to a residue. Crystallization from diethyl ether yielded 1.47 g of the title compound as a colorless solid, m.p. 148-149° C. (dec); MS (EI), m/z: 480 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][NH:29][CH3:30])[CH:9]=1
Reactant: CNC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1j (60 mg, 0.11 mmol) was dissolved in 8 mL of dichloromethane, followed by addition of 2 mL of trifluoracetic acid, and then the reaction solution was stirred for 1 h. 20 mL of saturated sodium bicarbonate solution was added, and the reaction solution was extracted with dichloromethane (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide 1 (15 mg, a yellow oil), and the yield of the three steps was 16%.
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([C:20](OC)=[O:21])[CH2:5]1)[CH2:2][CH3:3].[BH4-].[Na+]>CO.O>[CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([CH2:20][OH:21])[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1C[C@H](C(=O)OC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCN1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 82.4 %

Procedure:
10 grams of 6-n-propyl-8β-methoxycarbonylergoline were added to a mixture of 10 g of sodium borohydride in 125 ml of methanol. The reaction mixture was refluxed for about 2 hrs; then a second 5 g batch of sodium borohydride was added. The reaction mixture was cooled after 5 hrs, diluted with water, and the precipitate was filtered to give 7.5 g of 6-n-propyl-8β-hydroxymethylergoline melting at about 166°-168° C. A solution of 15 g of 4-toluenesulfonyl chloride in 100 ml of pyridine was added slowly to a cooled solution of 7.5 g of 6-n-propyl-8β-hydroxymethylergoline in 300 ml of pyridine. The mixture was stirred for 7 hrs whereafter it was poured over iced water and the precipitate was filtered to give 9 g of 6-n-propyl-8β-toxyloxymethylergoline melting at 147°-150° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:6].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1.O>CCO>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:6])[CH3:23])=[CH:18][CH:17]=1
Reactant: CN(C)CCC(=O)c1ccccc1F
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: O
Solvent: CCO
Product: C[C@H](NCCC(=O)c1ccccc1F)c1ccc(Br)cc1
Yield: 3.3 %

Procedure:
A solution of 3-dimethylamino-1-(2-fluoro-phenyl)-propan-1-one (17 g, 0.087 mol) and (S)-1-(4-bromophenyl)ethanamine (17 g, 0.087 mol) in EtOH (50 mL)/H2O (50 mL) was refluxed at 80° C. over night. The solvent was removed under vacuum. The residue was purified by column chromatography to afford (S)-3-(1-(4-bromophenyl)ethylamino)-1-(2-fluorophenyl)propan-1-one (1 g, 3%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH3:10])=[N:4]1)[CH3:2].CCCCCCCCCCCCCCCC(OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=O.[I:39]I>[OH-].[Na+]>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([I:39])[C:5]([CH2:9][CH3:10])=[N:4]1)[CH3:2]
Reactant: CCc1cc(C)n(CC)n1
Reactant: II
Agent: CCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Product: CCc1nn(CC)c(C)c1I

Procedure:
A mixture of 13.2 g (95.7 mmol) of 1,3-diethyl-4-5-methylpyrazole (from Step C) and 1.50 g (3.7 mmol) of sorbitan monopalmitate in 200 mL of 2.5 N NaOH was treated with 44 g (0.17 mol) of iodine. Additional portions of sorbitan monopalmitate and iodine were added after 30 min and 60 min. The mixture was partitioned between 1 L of ether and 500 mL of water and the layers were separated. The organic layer was washed with 500 mL of 5% Na2S2O3, dried over MgSO4 and concentrated. Chromatography on a Biotage 75L using 9:1 heptane/EtOAc as the eluant afforded the title compound. 1H-NMR (400 MHz) δ 1.22 (t, J=7.6, 3H), 1.36 (t, J=7.2, 3H), 2.27 (s, 3H), 2.58 (q, J=7.6, 2H), 4.10 (q, J=7.2, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+]>CO>[NH2:36][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13]
Reactant: [BH3-]C#N
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (1.86 g, 4.44 mmol) in MeOH (20 mL) was added ammonium acetate (3.42 g, 44 mmol) and sodium cyanoborohydride (0.195 g, 3.1 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched with concentrated hydrochloric acid and concentrated in vacuo. The residue was dissolved in water and basified with aqueous 3N NaOH (pH>10). The product was extracted with dichloromethane (2×) and ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.29 g, 69% yield)
Reaction SMILES: [B]=O.[CH:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=O>N1CCCCC1.C1C=CC=CC=1>[CH:13](=[C:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:11]1=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1Cc2ccccc2C1=O
Agent: [B]=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
(8) (Chem. Pharm. Bull. 1974, 22(2), 448-451). Boron oxide (720 mg, 10.26 mmol) and benzaldehyde (800 mg, 7.53 mmol) were added to a stirred solution of the indandione (1.00 g, 6.84 mmol) and piperidine (3 drops) in 10.2 ml of benzene. The solution was refluxed with stirring for 30 minutes. After filtration of the solution, the filtrate was concentrated under reduced pressure. The resulting crystalline solid was recrystallized from ethanol to afford 1.00 g (62.4%) of yellowish-green platelets: mp 149.5-150.0° C. (lit. mp 150° C., Okukawa, et al., Chem. Pharm. Bull., 1974, 22(2), 448-451). 1H NMR (250 MHz) δ 8.47-8.45 (m, 2H), 8.06-7.99 (m, 2H), 7.90 (s, 1H), 7.84-7.79 (m, 2H), 7.58-7.50 (m, 3H); 13C NMR (62.7 MHz) 190.5, 189.2, 147.2, 142.7, 140.2, 135.6, 135.4, 134.3, 133.4, 133.2, 129.3, 129.0, 123.5, 123.5 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]=1[C:27]([O:29]CC)=[O:28])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([C:22]([OH:24])=[O:23])[C:5]=1[C:27]([OH:29])=[O:28])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCc2ccccc2)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCc2ccccc2)c2ccccc12
Yield: 96.4 %

Procedure:
A mixture of diethyl 1-(ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylate (3.05 g, 7.23 mmol), ethanol (30 ml), and 2N aqueous sodium hydroxide solution (35 ml) was refluxed for 3 hours. The reaction mixture was cooled and evaporated. This was acidified with HCl (2N) and extracted with ethyl acetate twice. Combined organics were dried over magnesium sulphate and the solvent evaporated to give the title compound as a white solid (2.55 g, 6.97 mmol). LC/MS: Rt=2.76, [MH]− 365.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([CH3:18])[N:9]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([CH3:18])[N:9]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(C)nc(N2CC[C@H](N)[C@H](OC)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)cc(C)n3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-6-methylpyridine-4-carboxylate obtained in Example (166b) (23.9 mg, 0.44 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (14 mg, 0.08 mmol), WSC hydrochloride (46.8 mg, 0.24 mmol) and HOBt (11 mg, 0.08 mmol), to obtain 30.4 mg of the title compound as a pale yellow oily substance (86%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[C:10]1([N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of Compound 5 (2.58 g, 7.93 mmol) in DCM (50 mL) was slowly added BBr3 (8.5 mL, 8.5 mmol) at about −78° C. The resulting mixture was stirred overnight under argon while slowly warming up to room temperature. Methanol (60 mL) was added into the flask, and the mixture was stirred for about 3 hours. After concentration to 20 mL, the mixture was poured into DCM (200 mL), then washed with water, brine, and dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes/ethyl acetate 8:1 to 3:1). The desired fraction was concentrated to give a white solid (Compound 6) (1.84 g, in 77% yield).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[N:2]1.C([Li])CCC.C[CH2:23][O:24]CC>CCCCCC>[O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:23]=[O:24])=[N:2]1
Reactant: CCOCC
Reactant: Brc1ccccc1-c1noc2c1CCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=Cc1ccccc1-c1noc2c1CCCC2
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.1 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-bromobenzene in 100 ml of ether at a temperature of 40° C. was added 11 ml of a 1.5M solution of butyllithium in hexane with magnetic stirring. The reaction was warmed to −20° C. and held at this temperature for 5 minutes. The lithio species was quenched by the addition of 1.3 ml of N,N-dimethylformamide. To the reaction was added 100 ml of saturated ammonium chloride and the solution was extracted with two 200 ml portions of ether. The combined organic layers were dried over sodium sulfate and evaporated to yield 3.5 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-benzaldehyde, GC-M.S. (E.I.) (M/Z): 226 [M−H]+.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH:7]1[N:8]=[C:9]([NH2:50])[C:10]2[N:15]=[CH:14][N:13]([C@@H:16]3[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]4[O:36][C@@H:35]([N:37]5[CH:42]=[C:41]([C:43]([NH2:45])=[O:44])[CH2:40][CH:39]=[CH:38]5)[C@H:34]([OH:46])[C@@H:33]4[OH:47])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:48])[C@H:17]3[OH:49])[C:11]=2[N:12]=1>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH:7]1[N:8]=[C:9]([NH2:50])[C:10]2[N:15]=[CH:14][N:13]([C@@H:16]3[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]4[O:36][C@@H:35]([N:37]5[CH:42]=[C:41]([C:43]([NH2:45])=[O:44])[CH2:40][CH:39]=[CH:38]5)[C@H:34]([OH:46])[C@@H:33]4[OH:47])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:48])[C@H:17]3[OH:49])[C:11]=2[N:12]=1
Reactant: CC(=O)C(=O)[O-]
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC(O)C(=O)[O-]

Procedure:
the pyruvate is reacted with the NADH in the presence of the LDH to give lactate and NAD; and