Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39]([C:40]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=O)=[CH:38][C:37]=2[O:36]1>O1CCCC1.O>[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39](/[C:40](/[C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:38][C:37]=2[O:36]1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cccnc1)c1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCC/C=C(\c1cccnc1)c1ccc2c(c1)OCO2
Temperature: 85 °C
Yield: 11.2 %

Procedure:
Sodium hydroxide (1 g, 60% in oil) was added to dimethyl sulfoxide (25 ml) under nitrogen and the mixture was heated at 85° C. with stirring for an hour. The reaction mixture was cooled to room temperature and 5-carboxypentyltriphenylphosphonium bromide (5.2 g, 11 mmoles) was added gradually. The mixture was stirred for 10 minutes and a solution of 3-(3,4-methylenedioxybenzoyl)pyridine (2.5 g, 0.11 mole) in tetrahydrofuran (10 ml) was added dropwise thereto. After completion of addition, the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, water (100 ml) was added and the neutral substance was extracted twice with toluene (50 ml). The aqueous layer was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the eluent. The eluant was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (Z)-7-(3,4-methylenedioxyphenyl)-7-(3-pyridyl)-6-heptenoic acid (0.4 g, 24.6%). Mp 90°-91° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:16])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:16])[CH2:10][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: C1COCCN1
Solvent: CC#N
Product: C[C@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Yield: 59.2 %

Procedure:
Heat a mixture of (R)-methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester (0.083 mol, 20 g) and morpholine (0.83 mol, 72.2 g) in acetonitrile (210 mL) to 65° C. for 16 h. Concentrate the reaction mixture, dilute the residue with water, extract with dichloromethane, combine organic layer and wash with water. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate under vacuum to obtain the title compound (12 g, 62%) as yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 1.13 (d, 3H), 1.43 (s, 9H), 2.21 (dd, 1H), 2.26-2.32 (m, 1H), 2.35-2.39 (m, 2H), 2.48-2.55 (m, 2H), 3.63-3.70 (m, 5H), 4.68 (br s, 1H, —NH).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:19]1([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:2]([N:22]1[CH2:21][CH2:20][N:19]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23]1)([CH3:4])[CH3:1]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Acetone (1.95 g) and NaBH(OAc)3 (7.12 g) were added to a solution of 3-piperazin-1-yl-phenol (2.00 g) in THF (40 ml), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered to give the titled compound (1.48 g, colorless powder).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:36][CH2:37][CH3:38])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
A solution of methyl 2-(4-methyl-2,6-diphenylpyrimidin-5-yl)acetate (150 mg; 0.471 mmol) in dry DMF (2.5 mL) was cooled to −15° C. LHMDS (0.518 mL; 0.518 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.069 mL; 0.707 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine and dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (1-10%) in heptane to give 94 mg (54%) of the title compound as a colorless oil. ESI/APCI(+): 361 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.CN(C)C1N=CC(B(O)O)=CC=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[O:49][CH2:48][C:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][C:41]4[S:42][C:43]([Cl:46])=[CH:44][CH:45]=4)[C:32]3=[O:47])[C:29]=2[CH:30]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CC1SC(Cl)=CC=1>>[Cl:46][C:43]1[S:42][C:41]([CH2:40][N:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]3([C:29]4[CH:30]=[C:25]([C:6]5[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH:26]=[CH:27][C:28]=4[O:49][CH2:48]3)[C:32]2=[O:47])=[CH:45][CH:44]=1
Reactant: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C12COc1ccc(Br)cc12
Reactant: COc1ccc(B(O)O)cn1
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: O=C1N(Cc2ccc(Cl)s2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: COc1ccc(-c2ccc3c(c2)C2(CO3)C(=O)N(Cc3ccc(Cl)s3)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 16.12 and making non-critical variations using (6-methoxypyridin-3-yl)boronic acid to replace 6-(dimethylamino)pyridin-3-ylboronic acid, and 5-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (20%) as a colorless solid: mp 60-62° C.; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.6, 2.2 Hz, 1H), 7.35 (dd, J=8.4, 1.6 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 7.07-6.98 (m, 2H), 6.95 (d, J=7.8 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.12 (d, J=15.8 Hz, 1H), 5.00 (d, J=9.2 Hz, 1H), 4.91 (d, J=15.8 Hz, 1H), 4.73 (d, J=9.2 Hz, 1H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.9, 163.2, 160.3, 144.5, 141.3, 137.2, 136.9, 132.2, 131.7, 130.1, 129.8, 129.6, 129.1, 128.5, 126.4, 126.0, 124.1, 123.9, 121.7, 110.9, 110.6, 109.0, 79.7, 60.4, 58.0, 53.5, 39.2; MS (ES+) 475.5 (M+1) 477.5 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH3:41]>>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc2cc(COCCCc3c[nH]cn3)ccc2c1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-naphthylmethane chloride are treated as described in Example 5.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Fc1ccc(CBr)nc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(F)cn2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 49.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.3 g; 1.14 mmol) is alkylated using 2-bromomethyl-5-fluoro-pyridine (0.22 g; 0.46 mmol) and K2CO3 (0.4 g; 0.23 mmol) at 35° C. for 18 h. After aqueous work-up and purification by RP chromatography the pure material (87 mg) is de-acetylated in MeOH (6 ml) using DBU (16 μl) at reflux. After aqueous work-up 5-amino-1-(5-fluoro-pyridin-2-ylmethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (75.0 mg) is obtained and used without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]C=1C(O)=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COc1c(C(=O)O)ccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(C(=O)Cl)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (118 μL, 1.35 mmol) was added dropwise to a partial solution of 1-methoxy-2-naphthoic acid (3-A) (210 mg, 1.04 mmol) in methylene chloride (2.0 mL). The mixture bubbled for several min and then cleared. After stirring for 3 h at room temperature, the mixture was evaporated in vacuo to give 1-methoxy-2-naphthoyl chloride (3-B). Methylene chloride (5.0 mL) was added followed by methylamine hydrochloride (330 mg, 5.05 mmol) and N,N-diisopropylethylamine (441 μL, 2.53 mmol) and the resulting mixture stirred at room temperature 18 h. Methylene chloride was added and the mixture washed with water, 1N HCl, 10% NaHCO3, brine, dried (MgSO4) and concentrated in vacuo to provide 1-methoxy-N-methyl-2-naphthamide (3-C).
Reaction SMILES: C1(CC(CC(N2CCCCC2)=O)C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.N(OCCC(C)C)=O.[C:45]1([CH2:55][CH:56]([CH2:72][C:73]([N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[O:74])[C:57]([NH:59][C@H:60]([C:67]([N:69]=[N+]=[N-])=[O:68])[CH2:61][C:62]2[N:66]=[CH:65][NH:64][CH:63]=2)=[O:58])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1.[N-]=[N+]=[N-].Cl.N[C@@H:86]([CH2:93][CH:94]([CH3:96])[CH3:95])[CH:87]([OH:92])[C:88]([O:90][CH3:91])=[O:89]>CN(C)C=O.C(N(CC)CC)C>[C:45]1([CH2:55][CH:56]([CH2:72][C:73]([N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[O:74])[C:57]([NH:59][C@H:60]([C:67]([NH:69][C@@H:86]([CH2:93][CH:94]([CH3:96])[CH3:95])[CH:87]([OH:92])[C:88]([O:90][CH3:91])=[O:89])=[O:68])[CH2:61][C:62]2[N:66]=[CH:65][NH:64][CH:63]=2)=[O:58])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)C(O)[C@@H](N)CC(C)C
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCCCC1)Cc1cccc2ccccc12
Agent: CC(C)CCON=O
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C(CC(=O)N1CCCCC1)Cc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCCCC1)Cc1cccc2ccccc12

Procedure:
To a suspension of 200 mg of N-[2-(1-naphthylmethyl)-3-(piperidinocarbonyl)propionyl]-L-histidine hydrazide in 2 ml of dry N,N-dimethylformamide were added successively 0.26 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.066 ml of isoamyl nitrite with stirring at -20° C. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C. and neutralized with 0.19 ml of triethylamine to prepare a solution of N-[2-(1-naphthylmethyl)-3-(piperidinocarbonyl)propionyl]-L-histidine azide. The cold azide solution was added dropwise to a solution of 88 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.058 ml of triethylamine in 2 ml of dry N,N-dimethylformamide with stirring under ice-cooling, and then the mixture was stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was separated by silica gel flash column chromatography (eluent: chloroform/methanol=20/1 by volume), and fractions containing desired product which has Rf1 value of 0.54 were combined to obtain 141 mg of methyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(piperidinocarbonyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:11][CH3:20])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Preparation of (2R)-3-methyl-2-[4(trifluoromethylsllfonyloxy)phenyl]butanoic acid. To a solution of commercial 2-(4-chlorophenyl)-3-methylbutyric acid (1 g, 4.7 mmol) in CH3OH (10 mL), few drops of conc. H2SO4 were added, and the resulting mixture was left stirring at room temperature overnight. After solvent evaporation under vacuum, CH2Cl2 (10 mL) and H2O (10 mL) were added; the two phases were separated and the organic one dried over Na2SO4, filtered and evaporated under vacuum to give the intermediate methyl 2-(4-chlorophenyl)-3-methylbutanoate as an oily residue (quantitative yield). This intermediate was transformed in the related methyl 2-(4-hydroxyphenyl)-3-methylbutanoate according a known procedure3: a mixture of methyl 2-(4-chlorophenyl)-3-methylbutanoate (1.06 g, 4.7 mmol), 60% sodium hydride (0.56 g, 14.1 mmol) and H2O (85 μL, 4.7 mmol) was heated to 45° C. while kept at argon atmosphere for 3 days (1H-NMR analysis). The solvent was evaporated and the residue diluted with EtOAc and washed with 1N HCl (2×5 mL); the solvent was evaporated under vacuum and the crude residue was purified by flash chromatography (CHCl3/CH3OH 85:15) to give the pure intermediate as an oil (0.75 g, 77% yield). 1H-NMR (CDCl3) δ 7.18 (d, 2H, J=7 Hz), 6.82 (d, 2H, J=7 Hz), 5.75 (bs, 1H, OH), 3.70 (s, 3H), 3.15 (d, 1H, J=14 Hz), 2.55 (m, 1H), 1.10 (d, 3H, J=7 Hz), 0.72 (d, 3H, J=7 Hz). The steps of insertion of the triflate group and the following hydrolysis were performed as described1 and 3-methyl-2-[4-(trifluoromethylsulfonyloxy)phenyl]butanoic acid was obtained as a colourless oil (0.91 g, 78% yield calculated from the 4-hydroxy methyl ester derivative). The optical resolution was performed as described.4 (2R)-3-methyl-2-[4-(trifluoromethylsulfonyloxy)phenyl]butanoic acid (0.32 g, 35% yield) was obtained as a white solid. [α]D25 (c=1, CH3OH): −50°; 1H-NMR (CDCl3) δ 7.55 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 3.15 (d, 1H, J=14 Hz), 2.55 (m, 1H), 1.10 (d, 3H, J=7 Hz), 0.72 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@@H:7]([O:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:6]1[NH:32][C:33]([O:35]CC(Cl)(Cl)Cl)=O)(=[O:3])[CH3:2].[C:41](O)(=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C>>[C:1]([O:4][C@H:5]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@@H:7]([O:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:6]1[NH:32][C:33](=[O:35])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH3:41])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: COC(=O)CC(CC(=O)OC)O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)OCC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)N[C@H]1[C@H](OC(CC(=O)OC)CC(=O)OC)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2-Methoxycarbonyl-1-(methoxycarbonylmethyl)ethyl 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranoside was reacted with tetradecanoic acid in the same manner as in Example 8, Step 1 to obtain the titled compound as a white waxy solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@@H:14]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:17][C:16]([CH3:27])([CH3:26])[O:15]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:33](=[O:36])[CH2:34][CH3:35]>C1COCC1>[CH2:1]([N:8]1[C:12]([CH:33]([OH:36])[CH2:34][CH3:35])=[C:11]([CH2:13][C@@H:14]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:17][C:16]([CH3:26])([CH3:27])[O:15]2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1cn(Cc2ccccc2)nn1
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1nnn(Cc2ccccc2)c1C(O)CC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzyl-4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-1,2,3-triazole (11 mg, 0.029 mmol) in THF (0.3 mL) at −78° C. was added n-butyllithium (21 μL, 1.6M) to produce a deep red solution. After 5 minutes, propanal (2.3 μL, 1.1 eq) was added and the mixture was warmed to room temperature. After standard workup, the title compound was isolated by silica gel chromatography (7 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 3H), 7.30 (m, 2H), 5.35 (d, 7.6 Hz, 1H), 5.32 (d, 7.6 Hz, 1H), 4.52 (m, 1H), 3.86 (m, 1H), 3.64 (m, 1H), 3.03 (dd, 3.6 Hz, 16.4 Hz, 1H) 2.96 (dd, 6.8 Hz, 16.4 Hz, 1H), 1.55-1.17 (m, 12H), 1.27 (s, 3H), 1.25 (s, 3H), 1.00 (t, 7.3 Hz, 3H), 0.88 (t, 5.2 Hz, 3H). LRMS (APCI+) found 430.6, [M]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:73]=[CH:72][C:65]([CH2:66][N:67]2[CH2:70][CH:69]([OH:71])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:63]=[CH:64][C:65]([CH2:66][N:67]4[CH2:70][CH:69]([OH:71])[CH2:68]4)=[CH:72][CH:73]=3)[CH3:59])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}azetidin-3-ol dihydrochloride (40 mg, 0.12 mmol) and DCM (10 mL).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[O:11]=[C:9]1[C:10]2=[C:2]([S:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=[CH:4][N:5]2[N:6]=[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[N:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Temperature: 70 °C
Yield: 28 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (700 mg, 1.46 mmol) was dissolved in 50 mL dimethylformamide in a pressure reactor. Phenyl hydrosulfide (241 mg, 2.19 mmol), potassium carbonate (302 mg, 2.19 mmol) and copper(I) iodide (416 mg, 2.18 mmol) were added under argon atmosphere and the reaction mixture heated at 70° C. overnight. The reaction mixture was cooled at room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase using Isolera® Purification System to give 190 mg (28% yield) to the title compound. Purity 100%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[C:11]([C:10]1([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])[CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:13])[CH3:12]
Reactant: CC(=O)CC(=O)NCc1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C1(C(=O)NCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of N-benzyl-3-oxobutanamide (100.00 g, 522.93 mmol), K2CO3 (216.50 g, 1568.79 mmol) in DMF (1 L) was added 1,4-dibromobutane (169.36 g, 784.4 mmol) dropwise at rt. After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was added water (500 mL) and extracted with EtOAc (500 mL×3). The combined organic phases were washed with brine (500 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/8) to give the product as a white solid (69.50 g, 54%).
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OCC)(=O)C1C(=CC=CC=1)[C:13](OCC)=[O:14]>>[CH:7]1[CH:6]=[CH:5][C:4](/[CH:3]=[CH:2]/[CH2:13][OH:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccccc1C(=O)OCC
Reactant: c1ccc2[nH]ccc2c1
Product: OC/C=C/c1ccccc1

Procedure:
Indole--10% in Diethyl Phthalate: 2%