Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Mg]Br>CCOCC>[OH:18][CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[CH3:19]
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of N-(benzyloxycarbonyl)-4-formyl-piperidine (1 g, 3.92 mmol) in Et2O (40 mL) at −78° C. was treated with methylmagnesium bromide (3M in Et2O, 3.2 mL, 9.60 mmol). The reaction mixture was stirred at −78° C. for 2 h, quenched with saturated aqueous NH4Cl and extracted with Et2O. The combined organic extract was washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a colorless oil. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 70% EtOAc/hexanes to give 0.64 g (62%) of (±)-phenylmethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.25 (m, 5H), 5.11 (s, 2H), 4.30-4.15 (m, 2H), 3.65-3.55 (m, 1H), 2.80-2.65 (m, 2H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.70-1.55 (m, 1H), 1.30-1.10 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23]C)=[C:6]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]=[C:15](C#N)[CH:14]=[CH:13][C:12]2=3)[CH:7]=1.[C:25](=[O:28])(O)[O-:26].[Na+]>Br.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]=[C:15]([C:25]([OH:26])=[O:28])[CH:14]=[CH:13][C:12]2=3)[CH:7]=1
Reactant: COc1ccc(F)cc1CCNC1CCCc2nc(C#N)ccc21
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
72.8 g (223.73 mmol) of rac-5-{[2-(5-fluoro-2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile were taken up in 360 ml of hydrobromic acid (48% in water) and initially stirred at boiling point for 12 h, then cooled to room temperature and allowed to stand at this temperature overnight. The reaction solution was then diluted with 400 ml of water and adjusted to pH 6 using saturated sodium bicarbonate solution. The crystals formed were filtered off with suction, washed with water and dried under reduced pressure at 50° C. This gave 59 g (178.59 mmol, 80% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([C:10]1([C:13](OCC)=[O:14])[CH2:12][CH2:11]1)#[N:9]>COC1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:8]#[N:9])[C:13]2=[O:14])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)C1(C#N)CC1
Solvent: CCOC(C)=O
Solvent: COC1CCCC1
Product: Cn1ccc(N2CCC(C#N)C2=O)n1
Temperature: 120 °C
Reaction time: 30 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (223 mg) in cyclopentyl methyl ether (5.0 mL) was added ethyl 1-cyanocyclopropanecarboxylate (0.90 ml). The reaction mixture was stirred at 120° C. for 30 hr, and diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (237 mg).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[N+:16]([C:12]1[CH:11]=[C:10]([C:9]2[S:21][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(Nc1cnccc1O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2nc3cnccc3s2)c1
Temperature: 140 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
A mixture of N-(4-hydroxypyridin-3-yl)-3-nitrobenzamide (1.33 g, 5.2 mmol) and P2S5 (2.40 g, 10.4 mmol) in pyridine (6.0 mL) and p-xylene (24 mL) was stirred at 140° C. for 18 h. The solvent was removed under vacuo while hot and the residue was purified by recrystallization from EtOH to afford 2-(3-nitrophenyl)thiazolo[4,5-c]pyridine as a yellow solid (1.08 g, yield: 81%). MS (ESI) calcd. for C12H7N3O2S (m/z): 257. found: 258 [M+1]+.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[C:13]([O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O[Li].O>C1COCC1>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[C:13]([O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OC(=O)[C@@H]2CCCC[C@@H]2c2ccccc2)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)[C@@H]2CCCC[C@@H]2c2ccccc2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(cis-2-phenyl- 1-cyclohexanoyloxy)-2-methoxybenzoate (230 mg, 0.64 mmol) in THF:H2O (5 mL:1 mL) was added LiOH.H2O (113.5 mg, 2.7 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 90:10 CH2Cl2 :MeOH(NH3) and eluted with same. The solvent was removed under reduced pressure to afford 4-(cis-2-phenyl-1-cyclohexanoyloxy)-2-methoxy-benzoic acid as a foam.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[H][H].[CH2:12](O)[CH2:13][CH2:14][CH2:15][OH:16]>[Pd]>[NH2:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH:9][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:1]=1.[NH2:3][C:2]1[N:4]=[C:5]([NH:6][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:7]=[C:8]([NH:9][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:1]=1
Reactant: Nc1nc(N)nc(N)n1
Reactant: [H][H]
Reactant: OCCCCO
Agent: [Pd]
Product: Nc1nc(N)nc(NCCCCO)n1
Product: Nc1nc(NCCCCO)nc(NCCCCO)n1
Reaction time: 2 h

Procedure:
In a stainless steel autoclave of an inner volume of 100 ml, 3.78 g (30 mmol) of melamine, 250 mg of 5% Pd—C catalyst (50% hydrated preparation), and 30 ml of 1,4-butanediol were charged. After the inside of the reaction system was sufficiently substituted with nitrogen gas, 10 kg/cm2 of hydrogen gas was introduced under pressure at normal temperature. Then, the temperature was elevated while stirring and after the temperature reached 240° C., the reaction was carried out at the same temperature for further 2 hours. After cooling, the reaction mixture was taken out and quantitative analysis of the reaction product was performed under the above analytical conditions. As a result, the reaction conversion rate of the starting material melamine was 26.4% and it was confirmed that there were produced 2,4-diamino-6-(4-hydroxybutylamino)-1,3,5-triazine in a yield of 6.2% and 2-amino-4,6-bis(4-hydroxybutylamino)-1,3,5-triazine in a yield of 0.4%, respectively, and an obvious decrease in activity as compared with the reactions using mixed catalyst systems was confirmed.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OC(C)C)(=O)C>[Cl:25][C:26]1[C:31]([NH:32][CH:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[CH2:19][CH2:20]2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC(Nc2cccnc2Cl)CC1

Procedure:
560 mL (7.25 mol) TFA were added dropwise to 930 g (3.99 mol) N-benzyloxycarbonyl-4-piperidone and 466 g (3.63 mol) 2-chloro-3-aminopyridine in 9.5 L isopropyl acetate at approx. 15° C. 922 g (4.35 mol) sodium triacetoxyborohydride were added batchwise. The mixture was stirred until the reaction was complete. At RT the reaction mixture was combined with 860 mL sodium hydroxide solution (2 mol/L). The organic phase was separated off, washed with 5 L water and evaporated down.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.[OH:29][C:30]1[C:38]2[N:37]=NNC=2C=[CH:32][CH:31]=1.C(N(CC)CC)C.NCC(O)CC>C(Cl)Cl.O>[CH2:10]([O:9][C:7](=[O:8])[NH:1][CH2:2][CH2:3][C:4](=[O:6])[NH:37][CH2:38][CH:30]([OH:29])[CH2:31][CH3:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(O)CNC(=O)CCNC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A mixture comprising Z-Beta-Ala-OH (9.0 g, 40.3 mmol), EDCI.HCl (10.0 g, 52.4 mmol), hyrdoxybenzotriazole (5.45 g, 40.3 mmol), triethylamine (7.3 ml, 52.4 mmol) in DCM (150 ml) is stirred at 0° C. for 30 minutes. 1-Amino-2-butanol (4.2 ml, 44.3 mmol) is added in one portion and stirring is continued for 1 hour. The reaction mixture is diluted with water (150 ml) and extracted with dichloromethane (2×150 ml) The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo to yield a crude white solid. The product is purified by chromatography on silica eluting with ethanol-ethyl acetate (1:10) to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH:16]([OH:21])[CH:15]=[CH:14][CH:13]([CH3:22])[CH:12](/[C:23](/[CH3:50])=[CH:24]/[CH:25]=[CH:26]/[C:27]([O:44][CH:45]([O:47][CH2:48][CH3:49])[CH3:46])([CH3:43])[CH2:28][CH:29]2[O:42][CH:30]2[CH:31]([CH3:41])[CH:32]([O:35][CH:36]([O:38][CH2:39][CH3:40])[CH3:37])[CH2:33][CH3:34])[O:11][C:9](=[O:10])[CH2:8]1)[CH3:5])[CH3:2].C(N(CC)CC)C.ClC(O[C:62]1[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=1)=O.[C:71]([O:74]CC)(=[O:73])C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH:16]([O:21][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=2)[CH:15]=[CH:14][CH:13]([CH3:22])[CH:12](/[C:23](/[CH3:50])=[CH:24]/[CH:25]=[CH:26]/[C:27]([O:44][CH:45]([O:47][CH2:48][CH3:49])[CH3:46])([CH3:43])[CH2:28][CH:29]2[O:42][CH:30]2[CH:31]([CH3:41])[CH:32]([O:35][CH:36]([O:38][CH2:39][CH3:40])[CH3:37])[CH2:33][CH3:34])[O:11][C:9](=[O:10])[CH:8]1[C:71]([OH:74])=[O:73])[CH3:5])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Reactant: CCOC(C)OC1CCC(C)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)C(Oc2ccc([N+](=O)[O-])cc2)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)OC1CCC(C)C(Oc2ccc([N+](=O)[O-])cc2)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(8E,12E,14E)-3,16,21-tris(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (129 mg, 182 μmol) was dissolved in methylene chloride (1 mL). Triethylamine (127 μL, 911 μmol) and 4-dimethylaminopyridine (67.0 mg, 548 μmol) were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 30 minutes. A solution of 4-nitrophenyl chloroformate (112 mg, 556 μmol) in methylene chloride (1 mL) was added dropwise to this reaction mixture and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and purified water (10 mL) twice, and with brine (10 mL). The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting concentrate was purified by silica gel column chromatography (Merck Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=5:1->4:1) to obtain the title compound (137 mg, 156 μmol, 85.8%) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(#N)C>[OH:34][C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:23]2[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:21]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[CH:22]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(=O)O)CC3)c2)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a suspension of trans-4-aminocyclohexanecarboxylic acid (0.199 g, 1.392 mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265 mmol). The reaction was stirred at 75° C. After 48 hours, the reaction mixture was concentrated, diluted with water (10 mL) and extracted with DCM and EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid (0.524 g, 1.249 mmol, 99% yield) as an orange powder.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[Cl:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH2:12][C:11](=[O:20])[C:10]=2[CH:21]=1>O.C1C=CC=CC=1.C(O)C>[Cl:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH2:12][CH:11]([OH:20])[C:10]=2[CH:21]=1
Reactant: COc1cc2c(cc1Cl)C(=O)Cc1ccccc1S2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1Cl)C(O)Cc1ccccc1S2
Yield: 83 %

Procedure:
A solution of sodium borohydride (0.5 g) in water (3.5 ml), containing 0.1 ml of 15% sodium hydroxide solution was slowly added dropwise to a solution of the ketone from the preceding preparation (6.2 g) in a mixture of benzene (40 ml) and ethanol (100 ml). The stirred mixture was refluxed for 3 hours, the volatile components evaporated under diminished pressure, the residue diluted with water and extracted with benzene. A conventional isolation procedure, followed by crystallization of the crude product from ethanol (25 ml), yielding 5.2 g (83%) of 8-chloro-10-hydroxy-7-methoxy-10,11-dihydrodibenzo(b,f)thiepine, m.p. 130°-132° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C([N:16]([CH:19]([CH3:21])C)[CH2:17][CH3:18])(C)C.[C:22]1(C)C=CC=CC=1>>[N:16]1[CH:17]=[CH:18][CH:22]=[CH:21][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1
Product: COC(=O)Cc1ccc(-c2ccccn2)cc1

Procedure:
Under argon, 7.85 g (34.3 mmol) of methyl 4-bromophenylacetate are initially charged in 95 ml of toluene and, at room temperature, admixed with 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of 2-trimethyl-stannylpyridine and 0.4 g (0.3 mmol) of tetrakis(triphenylphosphane)palladium(0). The mixture is then heated under reflux for 18 h. After cooling, the mixture is washed with in each case 100 ml of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase is discarded. The acidic and the basic aqueous phase are neutralized and in each case extracted with 100 ml of dichloromethane, and the combined organic phases are dried over sodium sulphate and freed from the solvent under reduced pressure. Example VII is obtained after silica gel chromatography (toluene/ethyl acetate gradient 5:1-1:1) as a colourless oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].[CH2:20](I)[CH3:21].O>C1COCC1>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH2:20][CH3:21]
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Reactant: CCI
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Temperature: -78 °C
Yield: 70 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)-2-phenylethene (0.53 g, 1.7 mmol) in THF (10 mL) was added t-Butyl Li (1.1 mL, 1M in THF) at −78° C. After the addition complete, the solution was slowly heated to reflux for 30 min and then cooled down to −78° C. Ethyl iodide (1.2 eq, 0.27 mL) was added to the solution. Water (10 mL) was added after the completion of the reaction. THF was evaporated and the mixture was extracted with CH2Cl2 (3×5 mL). The extract was combined and dried over anhydrous magnesium sulfate. Evaporation of the solution followed by flash chromatography using 20% ether in hexane gave 1,3-dimethoxy-2-ethyl-5-(2-phenylethenyl)benzene in 70% yield. 1HNMR (CDCl3, ppm): δ 1.12 (t, J=7.2 Hz, 6H), 2.70 (q, J=7.2 Hz, 2H), 3.91 (s, 6H), 6.74 (s, 2H), 7.07 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])O.[K+].O>ClCCl>[CH2:29]([O:28][C:26]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Benzyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (45.2 mg) was dissolved in dichloromethane (0.9 ml), added with ethyl chloroformate (27 μl) and potassium hydrogencarbonate (28 mg) and stirred at room temperature for 30 minutes. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 38.3 mg of the title compound. Yield: 90%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([N:13]3[CH2:16][C:15](=O)[CH2:14]3)=[O:12])[S:8][C:7]=2[CH:18]=1.[C:21]([NH:28][CH2:29][CH2:30][NH2:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][CH2:30][NH:31][CH:15]1[CH2:16][N:13]([C:11]([C:9]2[S:8][C:7]3[CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[O:12])[CH2:14]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a mixture of 1e (62 mg, 0.207 mmol), N-Boc-ethylenediamine 1f (100 mg, 0.62 mmol), and acetic acid (0.3 mL) in 1,2-dichloroethane (3 mL) was added Na(OAc)3BH (53 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight, and was then quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 4% MeOH/CH2Cl2) gave intermediate 1g as colorless oil (30 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([O:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:15])/[CH2:11][CH2:12][CH2:13]I)=[O:4].C(N(CC)CC)C.[CH3:25][C:26](C)(C)[C:27](Cl)=O>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([O:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:15])/[CH2:11][CH2:12][CH:13]=[C:26]([CH3:27])[CH3:25])=[O:4]
Reactant: C/C(=C\CCCOC(=O)C(C)(C)C)CCCI
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CCCOC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 10.00 g (54.94 mmol) of Example 2 Part D alcohol in 50 mL of dichloromethane at 0° C. was added 0.67 g (5.50 mmol) of 4-dimethylaminopyridine (DMAP) and 11.49 mL (82.41 mmol) of triethylamine followed by the addition of 8.12 mL (65.93 mmol) of trimethylacetyl chloride over 15 min. The reaction mixture was stirred for 1 h at 0° C. and 2.5 h at room temperature. The suspension was diluted with 200 mL of dichloromethane and 300 mL of water. The layers were separated and the organic fraction was washed with solutions of KHSO4, NaHCO3 and NaCl, dried (MgSO4) and concentrated to provide title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5]I)[CH3:2].[CH2:10]([NH:17][C:18]1[C:19]([F:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:10]([N:17]([C:18]1[C:19]([F:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21]2)[CH2:5][C:4]([N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])=[O:7])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)C(=O)CI
Reactant: O=C1CCc2c1ccc(NCc1ccccc1)c2F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)C(=O)CN(Cc1ccccc1)c1ccc2c(c1F)CCC2=O

Procedure:
As presented in the following reaction formula, N,N-diethyl-2-iodoacetamide (723 mg, 3 mmol) was added dropwise at room temperature to a mixture of 5-(benzylamino)-4-fluoro-2,3-dihydro-1H-inden-1-one (370 mg, 1.5 mmol) and cesium carbonate (Cs2CO3: 940 mg, 3 mmol) in acetonitrile (CH3CN; 20 mL). Then, the mixture was refluxed for 48 hours. The mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by pre-TLC (product of Merck Co., Ltd.) to give 2-(benzyl(4-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)amino)-N,N-diethylacetamide represented by Structural Formula (2) (5 mg, yield: 1%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1.C(N([CH:44]([CH3:46])C)CC)(C)C.[C:47]([O-])([OH:49])=[O:48].[Na+]>>[CH2:44]([O:49][C:47]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1)=[O:48])[CH3:46]
Reactant: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Reactant: O=C([O-])O
Reactant: CCN(C(C)C)C(C)C
Agent: [Na+]
Product: CCOC(=O)NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.02 g (0.4 mmol) of 1-(N-(3-aminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine and 0.02 mL (0.12 mmol) of diisopropylethylamine in 2 mL of CH2C2 was added 0.007 mL (3 mmol) of ethylchlorofornate and the reaction mixture was stirred overnight at rt. To the reaction mixture was added 1 mL of sat'd NaHCO3 solution and the mixture was partitioned between EtOAc and water. The organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:3) to give 15 mg of the title compound. Mass Spectrum (EI) m/e 575 (M+1).