Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:22][C:23]([C:25]1([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CN1C(=O)Cc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CN1C(=O)Cc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-tert-butyl 4-(1-amino-3-(4-(1-methyl-2-oxoindolin-6-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 21, step (i), 44 mg) in dichloromethane (5 mL) was treated with Burgess' reagent (25 mg) and stirred at room temperature for 24 h. The reaction was diluted with dichloromethane (50 mL) and washed with water (50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to the sub-titled compound (35 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][O:22]CC3C=CC=CC=3)[C:15]=2[CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC(C(Br)C=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][OH:22])[C:15]=2[CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCn1nc(COCc2ccccc2)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Product: CCn1nc(CO)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(1-ethyl-3-benzyloxymethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Step B) using a procedure analogous to that described for Pyrrolidine 1, Step E. RF: 0.21 (3:2 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.36 (t, J=7.2, 3H), 1.48 (s, 9H), 1.67–1.70 (m, 2H), 1.84–1.93 (m, 2H), 2.08 (s, 3H), 2.74–2.80 (m, 3H), 3.14 (br m, 1H), 4.10 (q, J=7.2, 2H), 4.12–4.26 (m, 2H), 4.59 (s, 2H).
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[CH3:24][NH2:25]>C1COCC1>[CH3:24][NH:25][C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH2:1][CH2:2][CH2:3][C:4]#[CH:5])[CH2:11][CH2:10]1)=[O:14]
Reactant: C#CCCCN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: C#CCCCN1CCN(C(=O)NC)CC1

Procedure:
A solution of 4-nitrophenyl 4-(pent-4-ynyl)piperazine-1-carboxylate (1.37 g) in THF (10 mL) was treated with 40% aq. MeNH2 (10 mL) at 70 C for 2 h. The mixture was concentrated and diluted with conc. NH4OH (5 mL) and water (15 mL). Extraction (DCM, 80 mL) and concentration gave N-methyl-4-(pent-4-ynyl)piperazine-1-carboxamide (0.659 g).
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.OC1C=CC([I:25])=CC=1C(OC)=O>>[I:25][C:13]1[CH:2]=[CH:3][C:4]2[O:8][CH:7]=[C:6]([CH2:9][CH2:10][NH2:11])[C:5]=2[CH:12]=1
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: NCCc1coc2cc(I)ccc12
Product: NCCc1coc2ccc(I)cc12

Procedure:
Synthesized as described for 2-(6-iodo-1-benzofuran-3-yl)ethanamine using methyl 2-hydroxy-5-iodobenzoate. 1H-NMR (400 MHz, DMSO-d6): δ 2.91 (t, J=7.7 Hz, 2H), 3.11 (m, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.8 Hz, 1H), 7.90 (s, 1H), 8.09 (bs, 2H), 8.11 (d, J=1.7 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:43]=[CH:42][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:41]=[CH:40][C:25]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:23]=[CH:24][C:25]([O:26][C@H:27]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]([OH:30])=[O:29])=[CH:40][CH:41]=2)=[CH:42][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCCOc2ccc(Cc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a mixed solution of ethyl (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate (660 mg, 1.15 mmol) in THF (30 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution (6 ml, 6 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 584 mg (yield: 92.8%)
Reaction SMILES: ClC1C=C2C(=CC=1)N=C([N:12]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[C:23]=1[F:35])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)C=C2.Br[C:37]1[CH:46]=[C:45]([CH3:47])[C:44]2[C:39](=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=2)[N:38]=1>>[CH3:47][C:45]1[C:44]2[C:39](=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=2)[N:38]=[C:37]([N:12]([CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[C:23]=2[F:35])[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:46]=1
Reactant: CCOc1cc(CN(c2ccc(C#N)cc2)c2ccc3cc(Cl)ccc3n2)c(F)c(OC(C)C)c1
Reactant: Cc1cc(Br)nc2c(C)cccc12
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2cc(C)c3cccc(C)c3n2)c(F)c(OC(C)C)c1

Procedure:
According to the procedure for Intermediate 90.2, Intermediate 92.1 (100 mg, 0.424 mmol) afforded 97 mg of Intermediate 92.2 as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]>C(O)C.[Pd]>[NH2:17][C:14]1[CH:15]=[N:16][C:2]([CH3:1])=[C:3]([CH:13]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ncc(N)cc1C(=O)Nc1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 2-methyl-5-nitro-N-phenylnicotinamide (460 mg, 1.79 mmol) in 20 mL of ethanol is added Pd/C (40 mg). The reaction mixture is stirred under H2 atmosphere for 15 hours. The Pd/C is removed by filtering through a celite pad. The filtrate is dried to afford 5-amino-2-methyl-N-phenylnicotinamide as an off-white solid. MS m/z 228.1 (M+1).
Reaction SMILES: C([N:8]([CH2:32][C@H:33]([OH:54])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42]CC2C=CC=CC=2)=[C:38]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:37]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([NH:8][CH2:32][C@H:33]([OH:54])[CH2:34][O:35][C:36]4[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:37]=4)[CH2:14][CH2:13]3)=[CH:31][CH:30]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCc4ccc(F)cc4)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)NCc4ccc(F)cc4)cc3)CC2)ccc1O
Reaction time: 48 h

Procedure:
A mixture of 0.166 g of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N-(4-fluorobenzyl)benzamide (0.226 mmol) and of 0.117 g of 10% palladium-on-charcoal (50% in water) in a mixture of ethanol (5.3 ml) and tetrahydrofuran (4.02 ml) is placed under a hydrogen atmosphere and stirred for 48 hours. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.92 g, 52%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]3[CH2:22][C@H:21]3[CH3:23])=[O:19])[S:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.CCOC(C)=O>[Br:1][C:16]1[C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[CH:5]=2)=[N:13][S:14][C:15]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19]
Reactant: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1F
Yield: 97.1 %

Procedure:
Add bromine (0.15 mL, 0.47 g, 2.94 mmol) to (R,R)—N-[3-(3-fluoro-4-methoxy-phenyl)isothiazol-5-yl]-2-methylcyclopropanecarboxamide (0.45 g, 1.47 mmol) in dichloromethane (3 mL) dropwise. Monitor by TLC and stop bromine addition when complete. Dilute the reaction mixture with EtOAc (100 mL) and pour into aqueous Na2S2O3 (1 N). Collect the organic phase, wash with brine (50 mL) and water (80 mL), and evaporate. Chromatograph over silica gel, eluting with 10-50% EtOAc in hexane, to afford (R,R)—N-[4-bromo-3-(3-fluoro-4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide. Yield: 97.1%. ES-MS: m/e 387.0 (m+1).
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC([O-])(C)C.[K+].[CH3:12][S:13]([C:16]1[C:17]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[C:30]([S:38]([F:43])([F:42])([F:41])([F:40])[F:39])[CH:29]=2)=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=1)[C:21](OC)=[O:22])(=[O:15])=[O:14].Cl>CN(C=O)C.O>[CH3:12][S:13]([C:16]1[C:17]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[C:30]([S:38]([F:41])([F:43])([F:42])([F:39])[F:40])[CH:29]=2)=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=1)[C:21]([NH:4][C:3]([NH2:5])=[NH:2])=[O:22])(=[O:14])=[O:15]
Reactant: NC(N)=[NH2+]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(S(C)(=O)=O)c(S(F)(F)(F)(F)F)c2)cc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)c(S(F)(F)(F)(F)F)c2)c(S(C)(=O)=O)cc1C(=O)NC(=N)N
Reaction time: 16 h
Yield: 79.9 %

Procedure:
546 mg of guanidinium chloride and 535 mg of KOtBu were stirred in 20 ml of anhydrous DMF at RT for 30 minutes. Then 500 mg of methyl 5-methanesulfonyl-4-(4-methanesulfonyl-3-pentafluorosulfanylphenoxy)-2-methylbenzoate were added, and the mixture was left to stand at RT for 16 h. The reaction mixture was poured into 20 ml of water, adjusted to pH=8 with aqueous HCl solution and extracted 3 times with 50 ml of EA each time. The combined EA phases were then washed with 20 ml of a 5% aqueous NaHCO3 solution and dried over MgSO4, and the solvent was removed in vacuo. 420 mg of an amorphous solid were obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: O=Cc1ccncc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccncc1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide in dry tetrahydrofuran (15 mL) at 0° C. was added n-butyl lithium (3.87 mL, 3.87 mmol) with constant stirring, yellow colour was observed. The yellow colour suspension was allowed to stir at room temperature for 40 min. After 40 min, the reaction mixture was cooled to 0° C. and 3-bromoisonicotinaldehyde (0.6 g, 3.23 mmol) in tetrahydrofuran (5 mL) was added drop wise, the yellow colour was disappeared. Reaction mass was allowed to stir at 0° C. to room temperature for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ether (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.69 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.41 (d, J=4.8 Hz, 1H), 7.02-6.95 (m, 1H), 5.95-5.91 (d, J=17.6 Hz, 1H), 5.60-5.57 (d, J=10.8 Hz, 1H). MS (M+2): 185.8.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Br:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Br:37])[CH:31]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.57 min. MS (ESI+): mass calcd. for C23H17BrFIN4O5S2, 719.34; m/z found, 719/721 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.31 (s, 1H), 8.36 (dd, J=7.0, 0.7, 1H), 8.22 (dd, J=8.8, 0.7, 1H), 8.08 (d, J=1.5, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32 (dd, J=8.2, 1.5, 1H), 7.23 (dd, J=6.5, 2.1, 1H), 7.06-6.99 (m, 1H), 6.98-6.89 (m, 2H), 6.46 (d, J=6.9, 1H), 4.93 (q, J=5.5, 1H), 3.82 (s, 3H), 3.25-3.08 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([O:38][P:39]([OH:42])([OH:41])=[O:40])[C@@H:24]3[OH:43])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:44])[C@H:8]2[OH:45])[CH:4]=[C:3]([C:46]([NH2:48])=[O:47])[CH:2]=1.P(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(O)(O)=O>C(O)C(N)(CO)CO>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:46]([NH2:48])=[O:47])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:45])[C@@H:9]4[OH:44])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:43])[C@H:25]3[O:38][P:39]([OH:42])([OH:41])=[O:40])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NC(CO)(CO)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Product: 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](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
A mixture of substrate (5 mM), oxidized cofactor NADP+ (10 μM), glucose 6-phosphate (20 mM) in 50 mM Tris buffer pH 7.5 (0.8 ml) was admixed with G6PDH (10 u), after the enzyme (100-200 μg) had been added, and the reaction was carried out at 30° C. (140 rpm) for 48 hours.
Reaction SMILES: N[C@@H](CC1C=CC(OCCCC)=CC=1)C(NC)=O.N[C@@H](CC1C=CC(OCC#CC)=CC=1)C(OC)=O.[CH2:37]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:71]=[CH:72]/[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][S:79]([CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])(=O)=O)[C@@:58]([OH:70])([CH2:66][CH2:67][O:68][CH3:69])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:56])[C:50](=[O:53])[NH:51][CH3:52])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40].C(OC1C=CC(C[C@H](NC([C@@H](/C=C/CCCCCCS(CCCCCCC)(=O)=O)[C@@](O)(CCOC)C(O)=O)=O)C(=O)NC)=CC=1)CCC>>[CH2:37]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:71]=[CH:72]/[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][S:79][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[C@@:58]([OH:70])([CH2:66][CH2:67][O:68][CH3:69])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:56])[C:50](=[O:53])[NH:51][CH3:52])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Agent: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)O
Agent: CCCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Product: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (ESI (LC/MS positive mode) m/z 721 (M+H); Rt 2.85 min.) was synthesized by using (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide and conditions at 50° C., for 2.5 days instead of methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate and the conditions in Step C-6. Then, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate was first synthesized (ESI (LC/MS positive mode) m/z 753 (M+H); Rt 2.17 min.) under conditions similar to those in Step C-7. Subsequently, (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoic acid (No. 5514408) was synthesized by the reaction under conditions similar to those in Step C-8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH:15]1([N:20]2[C:29]3[N:28]=[C:27]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:42](O)=[O:43])=[C:35]5[C:39]=4[O:38][C:37]([CH3:41])([CH3:40])[CH2:36]5)[N:26]=[CH:25][C:24]=3[N:23]([CH3:45])[C:22](=[O:46])[C@H:21]2[CH2:47][CH3:48])[CH2:19][CH2:18][CH2:17][CH2:16]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:15]1([N:20]2[C:29]3[N:28]=[C:27]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:42]([NH:14][C@H:11]5[CH2:12][CH2:13][C@H:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[CH2:9][CH2:10]5)=[O:43])=[C:35]5[C:39]=4[O:38][C:37]([CH3:40])([CH3:41])[CH2:36]5)[N:26]=[CH:25][C:24]=3[N:23]([CH3:45])[C:22](=[O:46])[C@H:21]2[CH2:47][CH3:48])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CN1CCN([C@H]2CC[C@H](N)CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reaction time: 2 h

Procedure:
The crude compound (trans)-4-(4-methylpiperazin-1-yl)cyclohexanamine 17b (60 mg, 0.30 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (153 mg, 0.33 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (96 mg, 0.30 mmol) and diisopropylethylamine (96 mg, 0.75 mmol) were dissolved in 25 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added dropwise with saturated sodium bicarbonate solution to adjust pH to 8 to 9, extracted with dichloromethane (30 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-N-[(trans)-4-(4-methylpiperazin-1-yl)cyclohexyl]-3H-benzofuran-4-carboxamide 17 (70 mg, yield: 33.0%) as a white solid.
Reaction SMILES: COC[O:4][C:5]1[C:13]([CH:14](OC)[O:15][CH3:16])=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH:7](O)[N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:20].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[OH:4][C:5]1[C:13]([CH2:14][O:15][CH3:16])=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:20]
Reactant: COCOc1c(C(OC)OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COCc1cc(I)c2c(c1O)CNC2=O
Yield: 85.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (200 mg, 0.379 mmol) was dissolved in nitromethane (10 mL), and the solution was treated with trifluoroacetic acid (0.584 mL, 7.58 mmol) and triethylsilane (0.612 mL, 3.79 mmol), followed y purification by slurry using chloroform to obtain 4-hydroxy-5-methoxymethyl-7-iodoisoindolinone (103 mg, yield-86%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])(=[O:3])[CH3:2].[O:29]=O>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:29])[C:18]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC
Reactant: O=O
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
To a solution (20 ml) of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (1.1 g) in dimethylforamide is added bis(salicylidene)ethylenediiminocobalt(II) (40 mg), and the mixture is stirred at room temperature in an oxygen gas stream at atmospheric pressure for 72 hours. The solvent is distilled off and the product is extracted with ether. The ether layer is washed with water and dried over anhydrous sodium sulfate, and solvent is distilled off to give crude crystals. Recrystallization from ether-hexane (1:1) gives orange-yellow needles of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (0.84 g). m.p. 47° C.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.COC(OC)C.[CH2:17]1[CH2:27]CN2C(=NCCC2)[CH2:19][CH2:18]1>CN(C=O)C>[CH3:19][C:18]1[CH:17]=[CH:27][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1ccncc1
Reactant: C1CCC2=NCCCN2CC1
Agent: COC(C)OC
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccncc2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Isonicotinamidine hydrochloride (5.00 g, 31.7 mmol) and acetaldehyde dimethylacetal (8.44 mL, 63.5 mmol) were combined and heated to 110° C. in anhydrous DMF (35 mL) in the presence of DBU (14.20 mL, 95.2 mmol) for 3 h. The reaction mixture was cooled to 20° C., then stirred for 16 h, before being concentrated in vacuo. The residue was partitioned between H2O (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2×50 mL), then the combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Flash column chromatography (EtOAc) of the residue gave 4-methyl-2-pyridin-4-yl-pyrimidine: δH ((CD3)2SO): 2.57 (3H, s), 7.45 (1H, d), 8.21-8.26 (2H, m), 8.72-8.77 (2H, m), 8.82 (1H, d). To a solution of this compound (1.06 g, 6.17 mmol) in anhydrous dioxane (20 mL) was added SeO2 (2.05 g, 18.51 mol), then the mixture was heated to reflux for 90 h. The reaction mixture was cooled to 20° C. then filtered, washing with EtOAc. The filtrate was evaporated to dryness, then the residue was suspended in CH2Cl2. The suspension was filtered, washing with CH2Cl2, then the filtrate was evaporated to dryness to furnish the title compound: δH (CDCl3): 7.80 (1H, d), 8.38 (2H, d), 8.83 (2H, d), 9.13 (1H, d), 10.15 (1H, s).