Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C.O>C(OCC)(=O)C.ClCCl.CN(C=O)C.[Pd]>[NH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)[C:18]([CH3:19])=[O:20]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(=O)Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(NC(C)=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Ethyl 5-nitroindole-2-carboxylate (1, 1 g, 4.27 mmol) was dissolved in ethyl acetate (100 mL) and 5% Pd/C (100 mg) was added. The reaction mixture was hydrogenated for 1 h at room temperature at a pressure of 60 lb/inch2. The reaction mixture was filtered and the solvent was removed in vacuo. A grey powder of 2 was obtained and was used without further purification. A solution of acetyl chloride (174 mL, 2.44 mmol) in dichloromethane (5 mL) was added to a solution of 2 (0.417 g, 2.04 mmol) in DMF (2 mL), dichloromethane (5 mL) and triethylamine (339 mL, 2.44 mmol) dropwise at 0° C. under N2. The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL×2). The solution was dried using sodium sulfate and solvent was removed in vacuo. A grey powder 3 was obtained (437 mg, 87% yield). An analytical sample was recrystallized in ethyl acetate. mp: 202°-203° C. 1H NMR (DMSO-d6, ppm): 11.74 (s, 1 H, NH), 9.78 (s, 1 h, NH), 7.99 (s, 1 H, Ar--H), 7.38-7.30 (m, 2 H, Ar--H), 7.09-7.08 (m, 1 H, Ar--H), 4.36-4.30 (q, 2 H, J=7.0, 13.7 Hz, CH2 CH3). 2.03 (s, 3 H, CH3CO), 1.36-1.31 (t, 3 H, J=7.0 Hz, CH2CH3). Anal. (C13H14N2O3), C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[C:13](Cl)(=O)C>CO>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:3]=1[C:1]#[N:2]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(F)cc1C(=O)O
Solvent: CO
Product: COC(=O)c1cc(F)ccc1C#N

Procedure:
To a stirred suspension of 16.0 g (96.9 mmol) 2-Cyano-5-fluoro-benzoic acid (Apollo) and 161 ml methanol were added 30.4 g (387.6 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 21a was obtained in 86.0 yield (14.9 g; 83.3 mmol)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[O:23][CH3:24])=[C:10]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:18][C:17]=2[O:23][CH3:24])=[C:10]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(O)cc1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCC(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl bromoacetate (57 ul) was added to a mixture of the product from step (v) (0.2 g) and K2CO3 (0.251 g) in DMF (10 ml) and the mixture stirred at rt for 24 h. The mixture was partitioned between EtOAc/water, the organics separated, dried and evaporated under reduced pressure. The residue was purified by RPHPLC to afford the title compound, 0.057 g
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])([C:9]([O-:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O=S(Cl)Cl.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C1C=CC=CC=1>[CH2:18]([N:20]([CH2:21][CH3:22])[C:9]([C:3]([CH2:1][CH3:2])([CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])[CH3:19]
Reactant: CCNCC
Reactant: CCOC(=O)C(CC)(CC)C(=O)[O-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CC)(CC)C(=O)N(CC)CC
Reaction time: 18 h

Procedure:
To a solution of monoethyl diethylmalonate (28 g. 0.15 mole) in dry benzene (300 ml.) is added SOCl2 (15 ml., 0.21 mole) at 26°-28° in 2 min, with mechanical stirring. The reaction solution is gradually heated to 78° over 25 min, then is heated an additional 45 min at 85°-90° . The mixture is concentrated to dryness under reduced pressure, benzene (100 ml.) is added, and the mixture is again concentrated to dryness. The resultant oily residue dissolved in benzene (200 ml.) is treated dropwise with a solution of diethylamine (30 ml., 0.29 mole) in benzene (90 ml.) at 5°-15° over 17 min, and the reaction mixture is refluxed for 7 hours. The mixture is stored for 18 hours at room temperature and is filtered (to remove insoluble salt), is washed with benzene (50 ml.), is dried over MgSO4 and activated charcoal for 15 min, is filtered, and is concentrated to dryness under reduced pressure (bath at 50°-60°). This will yield 29 g. (79%) of ethyl 2-(N,N-diethylcarbamoyl)-2-ethylbutyrate.
Reaction SMILES: [I-:1].[I-].[I-].[C:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([CH3:28])[C:16]3[C:25]([CH:26]=2)=[S+:24][C:23]2[C:18](=[C:19]([CH3:27])[CH:20]=[CH:21][CH:22]=2)[N:17]=3)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].C(N1CC[N:35]([C:38]2C=C(C)[C:41]3[C:50]([CH:51]=2)=[S+]C2C(=C(C)C=CC=2)N=3)[CH2:34]C1)(=O)C.C(N1CCN(C2C=C(C)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)CC1)(=O)C.CO>>[I-:1].[C:4]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[C:15]([CH3:28])[C:16]3[C:25]([CH:26]=2)=[S+:24][C:23]2[C:18](=[C:19]([CH3:27])[CH:20]=[C:21]([N:35]([CH3:34])[CH2:38][CH2:51][CH2:50][CH3:41])[CH:22]=2)[N:17]=3)[CH2:11][CH2:12]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCN(c2cc(C)c3nc4c(C)cccc4[s+]c3c2)CC1
Agent: [I-]
Solvent: CO
Product: CCCCN(C)c1cc(C)c2nc3c(C)cc(N4CCN(C(C)=O)CC4)cc3[s+]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-acetylpiperazin-1-yl)-1,9-dimethylphenothiazin-5-ium triiodide (73 mg, 0.1 mmol) in methanol (5 mL) methyl(n-butyl)amine (0.034 mL, 25.2 mg, 0.3 mmol) was added. Reaction mixture was stirred for 24 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[K+].[Br-]>>[Cl:33][C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:19][CH:20]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 85A. mp 98-100° C.; IR (KBr) cm−1: 3038, 2854, 1729, 1508, 1240, 1124; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.57-7.62 (m, 1H), 7.39-7.53 (m, 2H); 7.12-7.20 (m, 2H), 6.84-6.96 (m, 3H), 6.26 (d, 1H, J=8.6 Hz), 5.05 (s, 2H), 4.58 (s, 2H), 4.09 (t, 2H, J=4.9 Hz), 3.92 (s, 2H), 2.55 (t, 2H, J=6.5 Hz), 1.83 (pentet, 2H); MS m/z 503 (M−1). Anal. Calc'd for C25H22Cl2O5S: C, 59.41; H, 4.39. found: C, 59.20; H, 4.20.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:20][C:21]1[CH:26]=[CH:25][C:24](/[N:15]=[N:14]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Nc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Nc1ccc(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Reaction time: 480 h
Yield: 22.2 %

Procedure:
Diazonium salt 1 (11.1 mg, 0.0349 mmol) and aniline (32.0 mg, 0.344 mmol) were dissolved in 0.19 g of 95% ethanol. After 20 d, the solution was filtered through Celite 545. Evaporation of the solvent gave an orange oil, which was purified by SiO2 column chromatography (8:2 hexane/ethyl acetate) and following preparative TLC (SiO2, CH2Cl2) afforded 27e as orange crystals (2.5 mg, 22%); m.p. 153.0-154.5° C. IR (ATR): {tilde over (v)}=3417, 2915, 1666, 1628, 1603, 1507, 1398, 1302, 1148, 1092, 834 cm−1. MS (GC, EI): m/z=323 [M+], 197, 120, 94, 65. 1H NMR (500 MHz, CDCl3): δ=7.88-7.82 (m, 6H), 6.76 (d, J=8.8 Hz, 2H), 2.20 (br. s, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.1 (C), 150.5 (C), 145.3 (C), 126.9 (2CH), 125.8 (2CH), 122.2 (2CH), 114.5 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:66][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-propyloxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry isopropyl alcohol (3 ml) is added benzyl amine (86.5 mg). The mixture is stirred at r.t. for 30 minutes, and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[Si:11](Cl)([C:14](C)(C)C)([CH3:13])[CH3:12]>C1COCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-hexandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 6-trimethylsiloxy-1-hexanol. To a solution of 6-trimethylsiloxy-1-hexanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 6-trimethylsiloxy-1-hexyl triflate (40) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12].C([Mg]Cl)(C)C.[CH:18](=[O:22])[CH2:19][CH2:20][CH3:21].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12]
Reactant: CCCC=O
Reactant: Cn1cnc2c(Cl)nc(I)nc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1nc(Cl)c2ncn(C)c2n1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-2-iodo-9-methyl-9H-purine (3.7 g, 12.6 mmol) in anhydrous THF (48 ml) at −78° C. under an atmosphere of nitrogen was added isopropylmagnesium chloride (8 ml, 15.12 mmol). After 30 minutes butyraldehyde (1.7 ml, 16.38 mmol) was added at −78° C. dropwise. The reaction mixture was stirred at −78° C. for 8 h and then allowed to warm to RT overnight. The reaction was quencend with a saturated solution of NH4Cl. The aqueous phase was extracted with DCM (three times). The organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography (gradient DCM/MeOH: 98/2 to DCM/MeOH: 96/4).
Reaction SMILES: CCN(CC)CC.[OH:8][CH2:9][C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:25][P:26](Cl)(Cl)=[O:27]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:25][P:26]1(=[O:27])[O:24][CH2:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:9][O:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Reactant: CP(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COP(C)(=O)OC2
Temperature: 0 °C

Procedure:
Et3N (943 μL, 6.76 mmol) and tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (790 mg, 3.22 mmol) were combined in CH2Cl2 (25 mL) and cooled to 0° C. A solution of methylphosphonic dichloride (428 mg, 3.22 mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h. The reaction was then allowed to warm to room temperature over 1 h. It was subsequently diluted with saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to give the desired product as a colorless solid that was used without purification. MS: cal'd 306 (MH+), exp 306 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[O:3]1.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([NH:20][C:21]([NH:14][S:11]([C:10]1[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:13])=[O:12])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Yield: 84.3 %

Procedure:
A solution of 19 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide prepared in Example 2 and 9.9 g of n-butyl isocyanate in 200 ml of 2-butanone was refluxed with 11.5 g of anhydrous potassium carbonate for 7 hours. The resulting mixture was concentrated to dryness in vacuo. The residue was taken up in 400 ml of water and extracted once with 100 ml of ethyl ether. The aqueous layer was acidified with 2N HCl and the resulting mixture was filtered and suction dried. The still slightly wet solid was washed once with 100 ml of hot acetonitrile, then suction dried an additional 8 hours to give 23 g of N-(butylaminocarbonyl)-2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide, m.p. 200°-203° C.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:37]([C:35]1[CH:34]=[CH:33][C:32]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[C:31]([O:30][CH3:29])[CH:36]=1)#[N:38]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1cc(C#N)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-methoxy-4-cyanophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.50 mg, 76.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.38 (s, 1H), 7.37 (d, 2H, J=2.4 Hz), 7.20 (m, 4H), 7.10 (d, 1H, J=2.4 Hz), 7.08 (s, 1H), 6.99 (apparent d, 1H, J=8.3 Hz), 6.76 (apparent d, 1H, J=8.3 Hz), 5.43 (apparent dd, 1H, J=5.1, 8.0 Hz), 3.91 (s, 3H), 3.34 (m, 2H), 2.63 (m, 2H), 2.63 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.7 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:32]([OH:35])([CH3:34])[CH3:33].O[C:37]1[CH:42]=[CH:41][C:40]2[C:43]3([CH2:59][O:60][C:39]=2[CH:38]=1)[C:51]1[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=1)[N:45]([CH2:52][C@H:53]1[CH2:57][CH2:56][CH2:55][O:54]1)[C:44]3=[O:58]>>[CH3:33][CH:32]([O:35][C:37]1[CH:42]=[CH:41][C:40]2[C:43]3([CH2:59][O:60][C:39]=2[CH:38]=1)[C:51]1[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=1)[N:45]([CH2:52][C@H:53]1[CH2:57][CH2:56][CH2:55][O:54]1)[C:44]3=[O:58])[CH3:34]
Reactant: CC(C)O
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Oc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a stirred solution of triphenylphosphine (0.23 g, 0.89 mmol) in anhydrous tetrahydronfuran (200 mL) at 0° C. under nitrogen were added diethyl azodicarboxylate (0.14 mL, 0.89 mmol), isopropanol (0.23 mL, 2.97 mmol) and 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1H)-one (0.20 g, 0.59 mmol). The reaction mixture was stirred at ambient temperature for 16 h, and then the reaction was quenched with ammonium chloride solution. The solvent was removed, and the residue was dissolved in ethyl acetate (100 mL), which was washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness, and the residue was purified by flash chromatograph with 25% ethyl acetate in hexanes to afford 6-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.19 g, 85%) as colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.33-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.58 (d, J=8.4 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 6.33 (dd, J=8.4, 2.1 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53-4.43 (m, 1H), 4.33-4.23 (m, 1H), 4.00-3.66 (m, 4H), 2.10-1.66 (m, 4H), 1.31 (d, J=6.0 Hz, 6H); MS (ES+) m/z 380.0 (M+1), 402.0 (M+23).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:46][C:47]([NH:49][C:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C:24]([N:26]([CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)[C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[O:25]>>[S:40]1[CH:41]=[C:37]([CH2:36][N:26]([C@@H:27]([CH3:35])[CH:28]([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[CH2:46][C:47](=[O:48])[NH:49][C:50]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 66 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH3:29])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC4CCOCC4C)C3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methyltetrahydro-4H-pyran-4-one (100 mg, 0.90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of four isomers. LCMS calculated for C26H39F3N4O2: (M+1) 497.3; found 497.2 for four isomers.