Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([NH:8][NH2:9])=CC=1.Cl[C:11]1[C:16]([C:17]([O:19]CC)=O)=[CH:15][N:14]=[C:13]2CCC[C:12]=12>C(O)CCC>[N:8]1[C:11]2=[CH:12][CH:13]=[N:14][CH:15]=[C:16]2[C:17](=[O:19])[N:9]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: O=C1N=Nc2ccncc21

Procedure:
A mixture of 1.1 g of p-chlorophenylhydrazine and 1.9 of ethyl 4-chloro-6,7-dihydro-5H-cyclopenta[b]-pyridine-3-carboxylate (Example 2a) in 100 mL of n-butanol is refluxed for 24 hours under nitrogen atmosphere. The precipitate is collected and recrystallized from ethanol to yield 2-p-chlorophenyl-2,3,5,6,7,8-hexahydrocyclopentab]pyrazolo[3,4-d]pyridin-3-one, m.p. above 350°, showing IR peaks at 900, 835, 805, 798, 765, and 740 cm-1.
Reaction SMILES: FC1C=CC([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=CC=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1N=C=O>>[F:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: O=C=Nc1ccccc1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccccc4F)cc3)ccc2C1=O

Procedure:
The compound of example 226 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 2-fluoro phenyl isocyanate. The compound of example 226 was used directly without isolation for the preparation of compound of example 227.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:29]=[C:22]5[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH2:26][N:21]5[N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(C)(C)OC4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 139f (160 mg, 0.25 mmol) and lithium hydroxide (60 mg, 2.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 139 (60 mg, 40%) as a light yellow solid. MS-ESI: [M+H]+ 599.8. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.34 (s, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.79-7.76 (m, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 5.95 (s, 1H), 4.92 (bs, 1H), 4.73 (s, 2H), 4.42 (s, 2H), 3.80 (s, 2H), 3.60 (s, 3H), 1.40 (s, 9H), 1.26 (s, 6H).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH:8](OCC)(OCC)[O:9][CH2:10][CH3:11].C(OC(=O)C)(=O)C>>[CH2:10]([O:9][CH:8]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:11]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(C)=O

Procedure:
From acetylacetone (20 g, 0.20 mol), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 19.3 g, 62%; bp=95°-110° C. at 0.3 mm Hg; NMR (CDCl3) δ 1.3-1.6 (t, 3H), 2.4 (d, 6H), 4.3-4.5 (q, 2H), 7.8 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19]C(C2CCNCC2)=N[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:31]=[C:32]=[N:33]CCCN(C)C.C1C=CC2N(O)N=NC=2C=1.ONC(N)=N>CN(C=O)C.O>[NH2:33][C:32]1[N:22]=[C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:19][N:31]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: N=C(N)NO
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (2.0 g, 7.25 mmol), EDCI (1.53 g, 7.98 mmol) and HOBT (1.08 g, 7.98 mmol) in DMF (15 mL) was stirred at rt for 0.5 h. 1-Hydroxyguanidine (0.653 g, 7.98 mmol) was then added and the reaction mixture was stirred for an additional 0.5 h. The resulting solution was treated under microwave at 100° C. for 1.5 hrs. The mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were then washed with water (20 mL), and saturated sodium chloride (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (2:1 EtOAc/petroleum ether) to give (2S,5R)-2-(3-amino-1,2,4-oxadiazol-5-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.0 g, 44%). (ESI-MS (EI+, m/z): 316 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:27]([C:34]1[CH:49]=[CH:48][C:37]([O:38][CH:39](C)[CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])=[CH:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:27]([C:34]1[CH:49]=[CH:48][C:37]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:45])=[CH:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCc1ccc(OC(C)CCCCC(=O)O)cc1
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCc1ccc(OCCCCCC(=O)C2=C(O)COC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
To a stirring solution of 1.1 g (10.98 mmol) of tetronic acid in 25 mL of dimethylformamide is added 1.53 mL (10.98 mmol) of triethylamine and 400 mg of 4-dimethylaminopyridine at 0° C. Next, 2.28 g (11.98 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.38 g (10.98 mmol) of 6-(4-heptylphenoxy)heptanoic acid are added and the reaction mixture is stirred for 3 days at room temperature. The reaction mixture is acidified with 1.0N HCl and extracted with three 200 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo. Trituration of the crude product in ethyl acetate/hexane affords 2.1 g (50%) of 3-[6-(4-heptylphenoxy)-1-oxohexyl]-4-hydroxy-2(5H)-furanone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)=[CH:8][CH:7]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20].CCN(CC)CC>C(Cl)Cl>[CH3:22][S:19]([O:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:11][CH:10]=2)[CH2:13]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(4-(oxazol-2-yl)phenyl)piperidin-3-ol (85 mg, 0.348 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise mesyl chloride (0.033 mL, 0.418 mmol), followed by Et3N (0.058 mL, 0.418 mmol). The reaction was stirred at 0° C. for 5 min, and then at rt for 30 min. After this time, HPLC and LC/MS showed that the desired product formed and no there was no starting material remaining. The reaction was concentrated. The residue was dissolved in EtOAc, washed with water, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give the desired product 1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl methanesulfonate (110 mg, 0.341 mmol, 98% yield) as an off-white foam. Anal. Calcd. for C15H18N2O4S m/z 322.3, found: 323.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[I:28]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[I:28][C:12]1[S:11][C:10]([O:9][C:8]2[CH:15]=[CH:16][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:14][CH:13]=1
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Oc2ncc(I)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 7A (1.52 g, 6.5 mmole) in tetrahydrofuran (80 mL) at −78° C. was added a solution of 2.5M n-butyl lithium in hexane (2.84 mL, 7.1 mmole) and stirred for 2 hours. Solid iodine (1.80 g, 7.1 mmole) was added and the mixture was allowed to warm up to room temperature for an hour. The reaction mixture was diluted with ethyl acetate and added an aqueous solution of 10% sodium thiosulfate. The ethyl acetate layer was dried over magnesium sulfate, dried over magnesium sulfate and filtered through silica gel to remove polar impurities. The silica gel was washed with ethyl acetate until no UV active spot was apparent on TLC plate. Evaporation of the solvent yielded the title compound as light-yellow oil, 2.30 g (Quantitative). 1H NMR (300 MHz, CDCl3) δ ppm 7.29 (s, 1H) 7.09-7.22 (m, 2H) 6.84-6.96 (m, 2H) 4.42-4.61 (heptet, J=5.88 Hz, 1H) 1.34 (d, J=5.88 Hz, 6H). MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)C1C=CC=CC=1)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH:4][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: CCOc1ccc(N)c(F)c1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)c(F)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
2-Fluoro-3,4-diethoxyaniline (0.17 g) and N,N-diethylaniline (0.13 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.11 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(2-fluoro-3,4-diethoxyphenyl)carbamate (Compound No. 1) (0.23 g) in a yield of 94.4%. M.P., 79°-81° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.O>C(Cl)Cl>[Br:19][C:3]1[S:4][C:5]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2c1C(=O)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(Br)sc2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzothiophene (500 mg, 3.01 mmol) in CH2Cl2 (15 mL) was added NBS (536 mg, 3.01 mmol) at room temperature, and the mixture stirred for 3 hours at room temperature. The reaction mixture was poured into water (50 mL) and the whole was extracted with diethyl ether (100 mL). The organic layer was washed with water (100 mL×2), brine, dried over MgSO4, and concentrated in vacuo to provide the title product (686 mg, 93% yield).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[CH:24]=[C:23]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[NH:22][N:21]=1>O1CCCC1>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[NH:22][N:21]=[C:20]([NH:19][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:24]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.10 gms.) is reacted with 0.1480 gms. of 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: OB(O)c1cnc2ccccc2c1
Product: Ic1cc(-c2cnc3ccccc3c2)ncn1

Procedure:
The compound was prepared according to Example 1 using quinolin-3-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: CS(Cl)(=O)=O.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([O:26][CH3:27])[CH:19]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.[Cl-:37].[Li+]>C1COCC1.O.[Cl-].[Na+].O>[C:9]([Si:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][Cl:37])=[C:20]([O:26][CH3:27])[CH:19]=1)([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CO
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CCl
Reaction time: 0.67 h
Yield: 111.8 %

Procedure:
Methanesulfonyl chloride (4.02 mL) was added to the mixture of the product from step (ii) (8.47 g), diisopropylethylamine (13.4 mL) and lithium chloride (3.29 g) in THF (105 mL) at RT and stirred for 40 mins. The mixture was diluted with water and brine, and extracted with EtOAc. The combined organic solutions were washed with brine, dried and concentrated to give 10.0 g of the subtitle compound as a yellow oil; 1H NMR: 7.23 (1H, dd), 6.44-6.49 (2H, m), 4.63 (2H, s), 4.06 (2H, t), 3.85 (3H, s), 3.79 (2H, t), 1.94-2.02 (2H, m), 0.89 (9H, s), 0.04 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N+:38]([O-])=O)(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:42])(=[O:41])[N:19]=1.[NH4+].[Cl-]>CO.O1CCCC1.O.[Fe]>[NH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:29]([NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:3]3[C:4](=[O:17])[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][N:7]=4)=[N:19][S:20](=[O:42])(=[O:41])[C:21]=2[CH:27]=1)(=[O:31])=[O:30]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4[N+](=O)[O-])ccc3N2)c(O)c2cccnc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4N)ccc3N2)c(O)c2cccnc21
Temperature: 60 °C
Yield: 92.4 %

Procedure:
A mixture of the product of Example 409A (8 mg, 0.013 mmol), iron powder (5.0 mg, 0.089 mmol), and NH4Cl (1Mg, 0.019 mmol) in methanol:tetrahydrofuran:water (2:2:1,10 mL) was heated at 60° C. for 2 hour. The solution filtered through Celite® and washed with THF. The solution was concentrated and the residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried with MgSO4, filtered and concentrated to give title compound (7 mg, 92%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.62 Hz, 6 H) 1.54 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 2 H) 6.06 (s, 2 H) 6.59 (t, J=7.17 Hz, 1 H) 6.78 (d, J=8.46 Hz, 1 H) 7.23 (m, 1 H) 7.46 (m, 4 H) 7.63 (d, J=8.82 Hz, 1 H) 8.53 (dd, J=8.09, 1.84 Hz, 1 H) 8.87 (dd, J=4.41, 1.84 Hz, 1 H) 10.79 (s, 1 H) 14.00 (s, 1 H). (ESI−) m/z 581 (M−H)−.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])=O)[C:22]=5[N:21]=4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:3][N:2]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.CO>[CH:32]([NH:35][C:29]([C:28]1[C:22]2[N:21]=[C:20]([C:19]3[C:13]4[C:14](=[N:15][CH:16]=[C:11]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=[N:2][CH:3]=5)[CH:12]=4)[NH:17][N:18]=3)[NH:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: O=C(O)c1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of Compound 17 (25 mg, 0.06 mmol), isopropylamine (11 μl, 0.12 mmol), HATU (23.4 mg, 0.06 mmol) and DIPEA (35 μl, 0.48 mmol) in DMSO (1 mL) was stirred at room temperature overnight. The solution was diluted with MeOH (0.4 mL) and purified by Gilson HPLC (10% to 90% of 0.1% TFA in ACN/0.1% TFA in H2O) to yield Compound 18 (9 mg, 33%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 9.79 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.78 (s, 1H), 8.57 (d, 1H, J=8.4 Hz), 8.16 (m, 2H), 8.04 (m, 1H), 7.87 (d, 1H, J=7.8 Hz), 7.69 (d, 1H, J=6.9 Hz), 7.32 (t, 1H, J=7.8 Hz), 3.99 (m, 1H), 0.86 (d, 6H, J=6 Hz); MS (ESI) m/z: 448 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9].C(=O)=[O:22].[CH2:24]([Li])[CH2:25][CH2:26]C.CCCCCC.[Cl-].[NH4+]>O1CCCC1.CC(C)=O>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15]([C:25]([OH:22])([CH3:26])[CH3:24])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9]
Reactant: O=C=O
Reactant: Cc1ccc(Br)cc1CN(C)C/C=C/C#CC(C)(C)C
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)O)cc1CN(C)C/C=C/C#CC(C)(C)C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Compound 32 (1.10 g) was dissolved in tetrahydrofuran (10 ml), and the solution was cooled to −78° C. by use of a mixture of dry ice and acetone solvent. n-butyl lithium in n-hexane (1.63 M: 2.1 ml; 1.04 eq) was slowly added dropwise to the mixture, and stirred for 5 minutes, followed by dropwise addition of acetone (290 μl; 1.2 eq). The mixture was stirred for 15 minutes, and gradually brought to room temperature. Saturated aqueous ammonium chloride solution was added dropwise to the mixture, and the reaction was stopped, followed by extraction with ether (120 ml). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane ethyl acetate=5:1), to thereby yield 520 mg of the target compound (yield: 50.4%).
Reaction SMILES: ClC(OCC(Cl)(Cl)Cl)=O.C(N(CC)CC)C.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[C:30]3[C:31]([CH3:45])=[C:32]([NH:36][C:37](=O)[O:38]CC(Cl)(Cl)Cl)[C:33]([CH3:35])=[CH:34][C:29]=3[O:28][CH2:27]2)=[CH:22][CH:21]=1)([CH3:19])[CH3:18].[C:46]([NH2:50])([CH3:49])([CH3:48])[CH3:47]>CS(C)=O.O>[C:46]([NH:50][C:37]([NH:36][C:32]1[C:33]([CH3:35])=[CH:34][C:29]2[O:28][CH2:27][C@H:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)[C:30]=2[C:31]=1[CH3:45])=[O:38])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)N
Reactant: Cc1cc2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of (+)-(3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine (1.0 g, 3.55 mmol) obtained in Reference Example 141 in THF (10 mL) was added dropwise with ice-cooling 2,2,2-trichloroethyl chloroformate (0.49 mL, 3.55 mmol), was added triethylamine (0.52 mL, 3.73 mmol) and the reaction mixture was stirred for 30 minutes, and then the reaction solution was warmed to room temperature. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The solution of the obtained 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate (1.60 g, 3.50 mmol) and tert-butylamine (779 mg, 10.65 mmol) in dimethylsulfoxide (20 mL) was stirred at 45° C. for 5 hours under an argon atmosphere. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 1.19 g (yield: 88%) of the title compound. Melting point: 205-206° C. (ethyl acetate-hexane). [α]D20=+81.0° (c=0.51, chloroform).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl 6-bromohexanoate was prepared by dropwise addition of a solution of 6-bromohexanoyl chloride (20.0 mL) in 100 mL of methylene chloride to a solution of 66.22 mL of benzyl alcohol in 60 mL of pyridine. The mixture was cooled using an ice-water bath for 90 min, then stirred at room temperature for 18 h. The solution was extracted with 200 mL of 1 N HCl followed by 2×150 mL of sat. NaHCO3. The extracts were discarded and the solution dried over Na2SO4. The solution was filtered and the solvent removed in vacuo to give an oil. This oil was purified on silica gel, eluting with a gradient of chloroform in hexanes. Fractions containing the product (TLC Rf 0.52, CHCl3/hexanes 6:4) were combined and the solvent removed to give 24.4 g.