Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][P:9]([O:44]CC)([O:11][CH:12]([O:14][C:15](=[O:43])[N:16]([C:40](=[O:42])[CH3:41])[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:37][C:36]4[C:32](=[N:33][N:34]([CH3:38])[CH:35]=4)[CH2:31]3)=[C:26]([F:39])[CH:25]=2)[CH2:19]1)[CH3:13])=[O:10])[C:2]1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:1]([O:8][P:9]([OH:44])([O:11][CH:12]([O:14][C:15](=[O:43])[N:16]([C:40](=[O:42])[CH3:41])[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:37][C:36]4[C:32](=[N:33][N:34]([CH3:38])[CH:35]=4)[CH2:31]3)=[C:26]([F:39])[CH:25]=2)[CH2:19]1)[CH3:13])=[O:10])[CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(OCc1ccccc1)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(C)=O

Procedure:
A solution of 20b (1 equiv.) in methanol is passed through an “H-cube” hydrogenator equipped with a 10% Pd on carbon cartridge under 30 bar of hydrogen at a flow rate of 1 mL/min. The reaction mixture is concentrated in vacuo and purified directly by HPLC (C-18 column, 5-55% gradient elution, MeCN:H2O) to give the title compound. Theoretical MS 570 (M+1)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (610 mg), lithium hydroxide monohydrate (154 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (3.7 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. Colorless crystals were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (583 mg, yield: 98%). This was recrystallized from ethyl acetate-hexane. Melting point: 152–153° C.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH2:13]([C:16]1([CH2:33][CH:34]=[CH2:35])[C:31](=[O:32])[N:19]2[CH2:20][CH2:21][NH:22][C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[C@@H:18]2[CH2:17]1)[CH:14]=[CH2:15].[CH:36]([C:39]1[CH:40]=[C:41]([C@H:49]([NH:51][CH3:52])[CH3:50])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)([CH3:38])[CH3:37]>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH2:33]([C:16]1([CH2:13][CH:14]=[CH2:15])[C:31](=[O:32])[N:19]2[CH2:20][CH2:21][N:22]([C:5]([N:51]([C@@H:49]([C:41]3[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:39]([CH:36]([CH3:38])[CH3:37])[CH:40]=3)[CH3:50])[CH3:52])=[O:11])[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[C@@H:18]2[CH2:17]1)[CH:34]=[CH2:35]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN[C@H](C)c1cc(C(C)C)cc(C(F)(F)F)c1
Reactant: C=CCC1(CC=C)C[C@H]2[C@H](c3ccccc3C)NCCN2C1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1(CC=C)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C(C)C)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of triphosgene (72 mg, 0.242 mmol) in EtOAc (2 mL) at 0° C. was added solution of (1S,8aS)-7,7-diallyl-1-o-tolylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (150 mg, 0.484 mmol), DMAP (6.2 mg, 0.05 mmol) and TEA (151 mg, 1.5 mmol) in EtOAc (15 mL). The mixture was stirred for 1.5 h, followed by addition of (R)-1-(3-isopropyl-5-(trifluoromethyl)phenyl)-N-methylethanamine (142 mg, 0.58 mmol) in EtOAc (10 mL) and TEA (151 mg, 1.5 mmol). The reaction was stirred at 50° C. for 48 h and quenched with water. The resulting mixture was extracted with EtOAc. The organic layer was washed with 1 M aqueous HCl solution, dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (100 mg, yield: 36%) as yellow solid; m/z (ES+): 582 [M+H]+.
Reaction SMILES: [C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[S:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)SC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)SC(=S)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of S-t-butyl thiobenzoate (1.94 g, 0.01 mol) and Lawesson's reagent (2.43 g, 0.006 mol) in anhydrous toluene (10 mL) was refluxed for 25 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue subjected to column chromatography (Kieselgel-60, 70-230 mesh, petroleum spirit/diethyl ether 19:1) The title compound was obtained as an oil, 1.37 g (65.5%). 1H-nmr (CDCl3) d (ppm): 1.69 (s, 9H, 3×CH3), 7.36 (m, 2H, meta-ArH), 7.50 (m, 1H, para-ArH) and 7.88 (d, 2H, ortho-ArH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:2].[C:27](O)(=O)[CH3:28]>>[CH3:27][C:28]1[N:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([O:8][C:7]3[CH:25]=[CH:26][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:10][CH:11]=2)[C:15]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CCOc1ccc(Oc2ccc(CNc3c(C)cccc3N)cc2)cc1
Reactant: CC(=O)O
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4cccc(C)c43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[4-(4-ethoxyphenoxy)benzylamino)-3-methylaniline (0.348 g) and acetic acid (5 ml) was heated under reflux for 6 hours and then cooled to room temperature. Excess acetic acid was removed by distillation under reduced pressure, and toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, followed by stirring for 10 minutes. The toluene layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 2,7-dimethyl-1-[4-(4-ethoxyphenoxy)benzyl]benzimidazole (0.315 g) as white crystals. m.p., 124.1° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[S:48][C:19]3[N:20]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)[C:21](=[O:32])[N:22]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:23](=[O:24])[C:18]=3[CH:17]=2)[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([C:16]2[S:48][C:19]3[N:20]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[NH:3][C:4](=[O:7])[O:5][N:47]=5)=[CH:38][CH:39]=4)[C:21](=[O:32])[N:22]([CH2:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[C:23](=[O:24])[C:18]=3[CH:17]=2)[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CC(C)(C)C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.87 g), sodium hydrogencarbonate (1.32 g) and dimethyl sulfoxide (8 mL) was stirred at 50° C. for 30 min, 4′-{[6-cyclopropyl-3-(3,3-dimethyl-2-oxobutyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (8 mL). N,N′-Carbonyldiimidazole (0.31 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 72%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:10]=1[C:11](Cl)=[O:12].Cl.Cl.[NH2:22][CH2:23][C:24]1[C:25]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[NH:27][CH:28]=1.O>O1CCCC1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[NH:27][CH:28]=[C:24]([CH2:23][NH:22][C:11](=[O:12])[C:10]3[C:9]([F:8])=[CH:17][C:16]([F:18])=[CH:15][C:14]=3[F:19])[C:25]=2[C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: NCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.5 %

Procedure:
265 μl (1.905 mmol) of triethylamine and 96 mg (0.493 mmol) of 2,4,6-trifluorobenzoyl chloride were added to a suspension of 162 mg (0.476 mmol) of 4-aminomethyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole dihydrochloride [prepared as described in Example 5 above] in 3.3 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 4 hours. At the end of this time, water was added to the reaction mixture and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was washed with diethylether to give 78 mg (yield 38%) of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH3:37])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:8])=[O:4].[O:39]=C1O[C@H]([C@H](CO)O)C(O)=C1O.O=O>C(O)(=O)C.O>[NH2:1][C:2]([CH3:37])([CH3:38])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[C:24](=[O:39])[CH2:23][CH2:22][CH:21]3[OH:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:8])=[O:4]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3C(=O)CCC3O)c2N(Cc2ccsc2)C1=O

Procedure:
(2R)-2-(2-Amino-2-methylpropanamido)-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (1.08 g) was dissolved in acetic acid (30 mL), and a solution of L-(+)-ascorbic acid (3.52 g) and Cu(ClO4)2.6H2O (741 mg) in water (40 mL) was added thereto, followed by stirring at room temperature for 15 minutes while oxygen gas was bubbled into the mixture. Saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was washed with ethyl acetate twice. Sodium bicarbonate (88.2 g) was added to the aqueous layer, and the mixture was extracted with chloroform twice. The organic layer was concentrated under reduced pressure, and the thus-recovered residue was purified through chromatography, whereby the title compound (0.5 mg) was yielded.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(Cl)Cl>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCBr
Yield: 106.3 %

Procedure:
Imidazole (1.1 g, 16.56 mmol) and TBS-Cl (1.37 g, 9.11 mmol) were added to a stirring solution of 6-bromohexanol (1.5 g, 8.28 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred over night then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (2.6 g) as clear oil. The compound was used with no further purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[N:13]=[CH:12][C:11]=1[NH2:20])[CH2:2][CH2:3][CH3:4].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:21]1[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCNc1c(N)cnc2cccnc12
Reactant: CCCCC(=O)Cl
Product: CCCCOCCCn1c(CCCC)nc2cnc3cccnc3c21
Yield: 63.1 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) was reacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resulting amide intermediate was cyclized to provide 2.9 g of 1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine as a colorless oil. A small portion was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide a pure sample as a white powder, m.p. 56.5-57.5° C. Analysis: Calculated for C20H28N4O: %C, 70.56; %H, 8.29; %N, 16.46; Found: %C, 70.48; %H, 8.25; %N, 16.61. 1H NMR (300 MHz, CDCl3): δ9.32 (s, 1H), 8.90 (dd, J=4.3,1.6 Hz, 1H), 8.49 (dd, J=8.5,1.6 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz, 1H), 4.94 (t, J=7.0 Hz, 2H), 3.45-3.39 (m, 4H), 3.04 (t, J=7.9 Hz, 2H), 2.26 (pentet, J=6.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.62-1.48 (m, 4H), 1.45-1.33 (m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:39]([O:43]C=C)[CH:40](C)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([C:39](=[O:43])[CH3:40])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: C=COCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (Example 12) (10.2 g, 21.23 mmol) in DMF (100 mL) under nitrogen atmosphere at room temperature were sequentially added triethylamine (2.58 g, 25.47 mmol), TlOAc (6.15 g, 23.35 mmol), isobutylvinylether (14 mL, 106.14 mmol), DPPP (0.87 g, 2.12 mmol) and Pd(OAc)2 (0.24 g, 1.06 mmol). The reaction temperature was raised to 100° C. and stirred for 3 hours, cooled to room temperature, filtered and treated with HCl (5%, 250 mL) and stirred for another 2 hours. The reaction mixture was repeatedly extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and the solvent evaporated. Triethylamine and DMF were destined off under reduced pressure to yield 9 g (98%); 1H NMR (CDCl3) δ1.22 (m, 12H), 2.52-2.70 (m, 7H), 3.40 (br, 2H), 4.34 (t, 1H), 5.10 (s, 1H), 6.90 (d, 1H), 7.17-7.40 (m, 10H), 7.82 (m, 1H) and 7.92 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[O:13]([CH2:24][CH2:25][NH2:26])[C@@H:14]1[O:22][C@@H:21]([CH3:23])[C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@@H:15]1[OH:16].[CH2:27](Cl)[CH2:28]Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C@@H:14]1([O:13][CH2:24][CH2:25][NH:26][C:7]([C:5]2[CH:6]=[N:1][CH:2]=[C:3]([C:10]([NH:26][CH2:25][CH2:24][O:13][C@@H:14]3[O:22][C@@H:27]([CH3:28])[C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@@H:15]3[OH:16])=[O:12])[CH:4]=2)=[O:9])[O:22][C@@H:21]([CH3:23])[C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@@H:15]1[OH:16]
Reactant: ClCCCl
Reactant: C[C@@H]1O[C@@H](OCCN)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=C(O)c1cncc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)c2cncc(C(=O)NCCO[C@@H]3O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]3O)c2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3,5-pyridinedicarboxylic acid (311 mg, 1.861 mmol) in DMF (30 mL) at room temperature was added 2-aminoethyl α-L-fucopyranoside (2.077 g, 9.30 mmol), DMAP (568 mg, 4.65 mmol), and EDC (1784 mg, 9.30 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated. The residue was purified by flash chromatography on C18 reverse phase silica gel (300 g), eluting with AcCN in water) to give the title compound. UPLC Method B: m/e=578.31 [M+1]; Rt=0.25 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].Cl.[F:23][C:24]([F:34])([F:33])[C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:30]1[CH2:31][CH2:32][CH:28]([NH:27][C:25](=[O:26])[C:24]([F:34])([F:33])[F:23])[CH2:29]1)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCC(NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.2 %

Procedure:
A mixture of 1.00 g of ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 2.1 g of 3-trifluoroacetylaminopyrrolidine hydrochloride, 1.46 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 20 ml of N,N-dimethylformamide was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo, and, to a suspension of the residue in 20 ml of methanol, 30 ml of water was added. The precipitate was collected by filtration to give 1.22 g of the desired compound, which was recrystallized from a mixture of chloroform and ethanol to give colorless crystals, m.p. 255°-257° C. (decomp.).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5](=[C:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:5](=[C:12]1[CH2:16][CH2:15][N:14]([C:1]([Cl:4])=[O:2])[C:13]1=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCC1=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cl)N1CCC(=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g (20.5 mmols) of phosgene are added to a suspension of 3.0 g (18.6 mmols) of 3-benzylidene-2-pyrrolidinone 50 ml in abs. ethyl acetate at -20°. A solution of 3.8 g (20.5 mmols) of tri-n-butylamine in 20 ml of abs. ethyl acetate is added dropwise to this mixture at 0° to 5°. After stirring for 4 hours at room temperature, dry nitrogen is passed through the mixture for 30 minutes and the mixture is then concentrated. Water is added to the oily residue, whereupon the acid chloride precipitates in the solid form. It is filtered off and dried over P2O5 and KOH is a desiccator. 3.5 g (84.5%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([OH:31])[CH:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N+:42]([O-:44])=[O:43]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([O:31][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N+:42]([O-:44])=[O:43])[CH:12]([N:16]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(O)C(C(O)CCOCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(CCOCc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Reaction time: 3 h

Procedure:
8.00 g (19 mmol) racemic (2S,3R and 2R,3S)-5-Benzyloxy-2-dibenzylamino-3-hydroxy-pentanoic acid in 25 ml dimethylformamide were added at 0° C. to a suspension of 1.83 g (42 mmol) sodium hydride (55%) in 25 ml dimethylformamide. The suspension was stirred for 3 hours and then 6.67 g (42 mmol) 2,5-difluoro-nitrobenzene in 10 ml dimethylformamide were added. After stirring overnight the mixture was poured under ice water and the pH was adjusted to 1. Extraction with ethylacetate and chromatography on silicagel with heptane/ethylacetate (2:1 to 1:1) yielded 9.1 g (85%) racemic (2S,3R and 2R,3S)-5-benzyloxy-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid as yellow oil, MS m/e (%): 559.3 (M+H+, 100).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31](=[N:3][OH:2])[NH2:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: [NH3+]O
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(C3(C)CC3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(C3(C)CC3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a solution of hydroxylammonium chloride (117 mg) in dimethylsulfoxide (1.7 mL) was added sodium hydrogen carbonate (170 mg), and the mixture was stirred at 50° C. for 1 hour. Then, a solution of 6-[6-methoxy-2-(1-methylcyclopropyl)-1H-indol-3-ylmethyl]pyridine-2-carbonitrile (53.6 mg) in dimethylsulfoxide (1.7 mL) was added dropwise thereto, followed by stirring at 80° C. for 2.5 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (62.9 mg). 1H-NMR (CDCl3) δ ppm: 0.68-0.76 (2H, m), 0.84-0.92 (2H, m), 1.34 (3H, s), 3.82 (3H, s), 4.35 (2H, s), 5.68 (2H, br s), 6.69 (1H, dd, J=2.3, 8.8 Hz), 6.82 (1H, d, J=2.3 Hz), 6.98-7.05 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.50 (1H, t, J=7.8 Hz), 7.66-7.73 (1H, m), 7.82 (1H, br s). ESI-MS (m/z): 351 (M+H)+