Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8](S(O)(=O)=O)=[CH:9]2)=[CH:4][CH:3]=1.ClC1N=C(Cl)N=C(Cl)N=1>>[CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[OH:16])[CH:11]=1
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1
Agent: Clc1nc(Cl)nc(Cl)n1
Product: Oc1cccc2ccccc12

Procedure:
In an aqueous solvent, 23.9 parts of 7-amino-4-hydroxynaphthalene-2-sulfonic acid was condensed with 18.4 parts of 2,4,6-trichloro-s-triazine according to a normal method and the resultant condensate was condensed with 28.1 parts of 4-(2-sulfate ethylsulfonyl)aniline according to a normal method to obtain a naphthol derivative.
Reaction SMILES: C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([C:62](=[O:73])[C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[C:24]1[CH:61]=[CH:60][C:27]([CH2:28][C@@H:29]([C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:44]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]=[C:47]([OH:53])[C:48]=2[C:49]([O:51][CH3:52])=[O:50])=[O:36])[NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1)=O)(C1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[C:15](=[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]1[N:23]([C:62](=[O:73])[C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[C:24]1[CH:25]=[CH:26][C:27]([CH2:28][C@@H:29]([C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:44]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]=[C:47]([OH:53])[C:48]=2[C:49]([O:51][CH3:52])=[O:50])=[O:36])[NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:60][CH:61]=1)=[O:14]
Reactant: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cc(-c2ccccc2)cc(O)c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)C2C=CC=CC2=C=O)cc1)C(=O)NCCCCOc1cc(-c2ccccc2)cc(O)c1C(=O)OC

Procedure:
A solution of methyl 3-(4-{[4-{{2-[(benzhydryloxy)carbonyl]phenyl}[(benzyloxy)(oxo)acetyl]amino}-N-(methoxycarbonyl)-L-phenylalanyl]amino}butoxy)-5-hydroxy-1,1′-biphenyl-4-carboxylate (120 mg, 0.12 mM) in methanol (25 mL) was stirred for 16 hours over 10% Pd/C under an atmosphere of H2. The mixture was filtered, concentrated under reduced pressure and purified by preparative HPLC to give the desired product. MS (ESI(+)) m/e 728 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.15 (bs, 1H), 8.13-8.06 (m, 1H), 7.99-7.06 (m, 1H), 7.73-7.12 (m, 13H), 6.99-6.89 (m, 2H), 6.74-6.71 (m, 2H), 4.13-4.08 (m, 1H), 4.06-4.02 (m, 2H), 3.75 (s, 3H), 3.43 and 3.42 (2s, 3H total), 3.12-3.06 (m, 2H), 2.89-2.83 (m, 1H), 2.76-2.65 (m, 1H), 1.64-1.58 (m, 2H), 1.53-1.47 (m, 2H).
Reaction SMILES: [Cl-:1].[Cl-].[Ca+2].[CH2:4]([N:6]1[C:14]2[N:13]=[C:12]3[CH:15](O)[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][CH2:19][C:11]3=[CH:10][C:9]=2[CH:8]=[N:7]1)[CH3:5].Cl>C1C=CC=CC=1>[Cl:1][CH:15]1[C:12]2=[N:13][C:14]3[N:6]([CH2:4][CH3:5])[N:7]=[CH:8][C:9]=3[CH:10]=[C:11]2[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: [Cl-]
Reactant: CCn1ncc2cc3c(nc21)C(O)c1ccccc1CC3
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Reaction time: 8 h

Procedure:
6 g. of pulverized CaCl2 are added with stirring to a solution of 11 g. of 1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol (0.04 mol.), from example 2, in 175 ml. of dry benzene. The suspension is saturated for 15 hours with anhydrous hydrogen chloride at room temperature. After standing overnight, the mixture is filtered and the benzene is evaporated in vacuo. The residue is extracted with ether, treated with charcoal, and refrigerated to crystallize 8.3 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine; m.p. 107°-110° (ether).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17](F)[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25].C(OCC)(=O)C.C1CCCCC1>O1CCCC1.O>[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25]
Reactant: Oc1cccnc1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2cccnc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a suspension of 198 mg (4.53 mmol) of sodium hydride (65% in oil, washed with pentane) in 2.5 ml of dry tetrahydrofuran a solution of 356 mg (3.74 mmol) of 3-hydroxypyridine in 5 ml of tetrahydrofuran is dropped and the mixture stirred for 1 hour at room temperature. After cooling to 0° C. 1.0 g (3.74 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester dissolved in 10 ml of tetrahydrofuran is added and stirring continued for 7 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4 and evaporated to give an oil which is fractionated by medium pressure chromatography on silica with ethyl acetate/cyclohexane 1:1. The fractions containing the product are combined and evaporated yielding 977 mg of 2-nitro-5-(pyridin-3-yloxy)-4-trifluoromethyl-benzoic acid methyl ester as white powder, m.p. 98-100° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:6]4[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=4)=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Product: Cc1ccc(Cc2ccc(-c3ccc(Cc4ccc(C)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 500 mL flask was charged with 4,4′-bis(chloromethyl)-1,1′-biphenyl (25.1 g) and toluene (300 mL). To the clear solution stirring at room temperature was added titanium tetrachloride (1 mL) and the mixture instantly became dark brown. After 5 minutes, a second 1 mL aliquot of catalyst was added. After stirring overnight at room temperature, ethanol (10 mL) was added to kill the catalyst, and the mixture became a light, cream colored suspension. The organic layer was concentrated to dryness under vacuum on a rotary evaporator. The tan solid was suspended in 200 mL boiling toluene and treated with MgSO4. Vacuum filtration through glass fiber filter paper gave a clear solution to which 200 mL heptane was added while hot. The slightly turbid solution was cooled to room temperature, then in a freezer overnight to complete crystallization. White crystals, 17.4 g, mp=161.8 C, were recovered. GC/MS, HNMR, CNMR and IR were all consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCCN1
Product: COC(=O)C1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Reaction of DL-proline methylester with toluene-4-sulfonyl chloride according to the general procedure of example 1d yielded (RS)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as a white solid, m.p.=93° C. and MS: m/e=283 (M+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CC([O-])=O.[Na+].BrBr.[NH2:17][C:18]([NH2:20])=[S:19]>CC(O)=O>[NH2:20][C:18]1[S:19][C:5]2[C:6](=[O:8])[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=2[N:17]=1
Reactant: NC(N)=S
Reactant: CC1CC(=O)CC(=O)C1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CC(=O)c2sc(N)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
5-Methyl-cyclohexane-1,3-dione (70.0 g, 0.555 mol) and NaOAc (68.3 g, 0.832 mol) are suspended in AcOH (700 mL) and Br2 (88.7 g, 0.555 mol) is added drop-wise while maintaining the reaction temperature between 15 and 20° C. After complete addition, the reaction is stirred at RT overnight. Thiourea (42.2 g, 0.555 mol) is added in portions and the reaction mixture is heated to 100° C. for 1 h. After cooling to RT, the AcOH is removed in vacuo. The resulting crude product is diluted with water (1 L), adjusted to pH=7 with NaHCO3 solution (3 M) and the resulting mixture is extracted with EtOAc (3×1 L). The organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated in vacuo and the residue is recrystallized from hexane to give 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (87.2 g, 86% yield).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[S:11](=[O:24])(=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])=O.C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[OH:10][C@@H:9]1[CH2:8][CH2:7][N:6]2[C@@H:5]1[C:3](=[O:2])[N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])[S:11]2(=[O:24])=[O:23]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1S(=O)(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a suspension of 1B (82 mg, 0.228 mmol) in 5 mL of acetonitrile at rt was added DCC (47 mg, 0.228 mmol) followed by p-nitrophenol (63 mg, 0.456 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 50:50 and 75:25) to afford the title compound (61 mg) as an off-white solid. 1H NMR (CD3OD) δ 2.21-2.23 (m, 2H), 2.37, 2.39 (s, 3H), 3.61-3.64 (m, 1H), 3.97-4.04 (m, 1H), 4.66, 4.68 (s, 1H), 4.79 (d, J=3.9, 1H), 7.45, 7.55 (d, J=8.3, 1H), 7.83 (d, J=8.3, 1H); 13C NMR (DMSO-d6) δ 15.47, 15.94, 35.32, 35.44, 48.21, 48.36, 69.77, 69.82, 73.74, 114.68, 115.59, 129.50, 132.70, 132.90, 134.25, 136.92, 138.96, 163.11, 163.59; HPLC a) column: Phenominex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.65 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.52 min retention time (100%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 11.86 min retention time (99%); MS (ES) m/z 340 [M−H]−.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]([CH3:29])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH3:28])[CH2:22][C:21]3[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=3[O:19]2)=[N:16][CH:17]=1>N1C=CC=CC=1.CO.[OH-].[Na+]>[OH:27][C:25]1[CH:24]=[CH:23][C:21]2[CH2:22][C:18]([C:15]3[N:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:1](=[O:3])[CH3:2])[CH3:29])=[CH:13][CH:14]=3)([CH3:28])[O:19][C:20]=2[CH:26]=1
Reactant: C[C@H](N)COc1ccc(C2(C)Cc3ccc(O)cc3O2)nc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)COc1ccc(C2(C)Cc3ccc(O)cc3O2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic anhydride (0.126 mL) was added dropwise to a solution of diastereomer of 2-(5-{[(2S)-2-aminopropyl]oxy}pyridin-2-yl)-2-methyl-2,3-dihydro-1-benzofuran-6-ol (500 mg) in pyridine (15 mL) at ambient temperature. After being stirred at ambient temperature for 2 hr, the mixture was diluted with methanol (15 mL) and 4 M sodium hydroxide (10 mL). The mixture was stirred at ambient temperature for 15 hr. The organic solvent was removed under reduced pressure, and the aqueous solution was acidified with 4 M hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (350 mg).
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:9]1([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]1)#[CH:8].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH:7]([C:9]1([O:14][Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:20][CH3:21])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[CH2:8]
Reactant: [H][H]
Reactant: C#CC1(O[Si](CC)(CC)CC)CCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C=CC1(O[Si](CC)(CC)CC)CCCC1

Procedure:
Lindlar catalyst (250 mg) was prehydrogenated in hexane (40 ml) and pyridine (0.25 ml) for 30 min.; after addition of 1-Ethinyl-1-triethylsilanyloxy-cyclopentane (11.22 g; 50.0 mmole) dissolved in hexane (80 ml) hydrogenation was continued at ambient temperature and normal pressure until the uptake of hydrogen ceased; the catalyst was removed by filtration through a plug of neutral alumina (act. 3); after removal of the solvent under reduced pressure the crude product was purified by distillation. 1-Vinyl-1-triethylsilanyloxy-cyclopentane (B1) was obtained as a colourless oil; bp.: 100° C. (0.2 mbar), Kugelrohr.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.ClCC1C(C(F)(F)F)=NC=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: ClCc1cnccn1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: FC(F)(F)c1ncccc1CCl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(Cc2cnccn2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 5.9, making non-critical variations using 2-(chloromethyl)pyrazine to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 216-218° C.; 1H NMR (300 MHz, CDCl3) δ8.65-8.62 (m, 1H), 8.58-8.50 (m, 2H), 7.27-7.15 (m, 2H), 7.09-7.01 (m, 1H), 6.91-6.85 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.13 (ABq, J=55.5, 16.1 Hz, 2H), 4.81 (ABq, J=81.0, 9.0 Hz, 2H), 4.24-4.09 (m, 4H); 13C NMR (300 MHz, CDCl3) δ177.5, 155.2, 151.2, 144.6, 144.2, 143.9, 143.8, 141.7, 138.3, 132.2, 128.8, 124.0, 123.7, 120.8, 111.7, 109.1, 99.4, 80.0, 64.5, 63.8, 58.0, 43.7; MS (ES+) m/z 387.8 (M+1); Anal. Calcd for C22H17N3O4: C, 68.21; H, 4.42; N, 10.85. Found: C, 67.81; H, 4.39; N, 10.84.
Reaction SMILES: [C:1]([C@H:5]([N:9]([C:11](=[O:20])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[NH2:10])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([C:23]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])[CH3:22]>>[C:1]([C@H:5]([N:9]([C:11](=[O:20])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[NH:10][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:23]=1[CH2:21][CH3:22])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1c(OC)cccc1C(=O)Cl
Reactant: CCC[C@@H](N(N)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Product: CCC[C@@H](N(NC(=O)c1cccc(OC)c1CC)C(=O)c1cc(C)cc(C)c1)C(C)(C)C

Procedure:
Briefly, benzyl carbazate (compound A) was reacted with pivaldehyde to give (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester (compound B). Compound B was reacted with (S,S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (Compound C; see Leighton et al., J. Am. Chem. Soc. 125:9596 (2003) and WO 03/074534) to give (R)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid benzyl ester (compound D). Compound D was reacted with 3,5-dimethyl benzoyl chloride to give (R)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (compound B). Compound E was hydrogenated to give (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-hydrazide (compound F). Compound F was reacted with 2-ethyl-3-methoxybenzoyl chloride to give Compound 1. The crude material was triturated first with ether (2% ethanol) and then with 1:1 hexanes:ether in a fritted glass Büchner funnel. The product was then washed with deionized water with thorough mixing and allowed to dry in air. Compound 1 was isolated as a white powder.
Reaction SMILES: [CH2:1]([NH2:9])[C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].C(NCC)C.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CC(O)C>[NH:9]([C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:1][C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3]
Reactant: NCC(=O)NCC(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(C)O
Solvent: CCNCC
Product: O=C(O)CNC(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
6.6 g (50 mmol) of Gly-Gly (manufactured and sold by PEPTIDE INSTITUTE INC., Japan) was dissolved in a mixed solvent comprised of 20 ml of H2O, 40 ml of 2-propanol and 15 ml of diethylamine to obtain a solution. To the obtained solution was gradually added 18.1 g (65 mmol) of trityl chloride, followed by stirring for 1 hour. To the resultant reaction mixture was added H2O, to thereby generate a precipitate. The generated precipitate was recovered, washed with water and, then, dissolved in 5 ml of acetic acid, to thereby obtain an acidic solution. The solvents were distilled off from the obtained acidic solution under reduced pressure, to thereby obtain 13.1 g of Trt-Gly-Gly (192).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.CC#N.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:26][C:6]=3[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][CH2:9][C:10]=12)=[O:16])[CH3:19]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(C#CC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 439 %

Procedure:
A mixture of 5 (300 mg, 0.732 mmol) available from procedure [0051] in triethyl amine (5 mL) and CH3CN (8 mL) was stirred with 3,3-dimethyl-1-butyne (12.3 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) acetate (38.3 mg, 0.051 mmol) and heated to reflux under nitrogen. After 5 hours, the reaction mixture was cooled to rt and filtered. The filtrate was concentrated under vacuum and the residue was treated with H2O (10 mL), and extracted with CH2Cl2 (3×10 mL). The organic layers were combined and washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified via flash chromatography (silica gel, EtOAc/hexanes: 1/1) to furnish the t-butylacetylene 24(XLi340) as a yellow powder (271 mg, 90%): mp: 155-156° C.; IR (KBr) 2358, 1717, 1489, 1248, 1074, 803, 668 cm−1; 1HNMR (CDCl3) δ 1.25 (s, 9H), 1.45 (t, 3H, J=7.1 Hz), 4.05 (d, 1H, J=12.3), 4.45 (2H, J=7.1 Hz), 5.95 (d, 1H, J=12.3 Hz), 7.3-7.7 (m, 8H), 7.95 (s, 1H); MS (EI) m/e (relativity intensity) 412 (M+, 46), 365 (46), 337 (100), 322 (8), 277 (16), 219 (14). Anal. Calcd. For C26H25N3O2.½H2O, C 74.26, H 6.23, N 9.99. Found. C, 74.50; H, 6.29; N, 9.89.
Reaction SMILES: [C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][S:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][S:17]([CH3:18])=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1CSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1CS(C)=O
Reaction time: 0.08 h

Procedure:
3-Methoxy-2-methylsulfanylmethyl-benzoic acid N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazide in CH2Cl2 was stirred at room temperature with 1.0 eq of m-chloroperbenzoic acid. The reaction was complete within 5 min as indicated by TLC. The reaction mixture was washed with saturated NaHCO3 and the organic layer was stripped under vacuum. The residue was mixed with 1-2 mL of 1:1 ether:hexane and the solution was removed with a pipette, leaving the product which was then dried under vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH3:21])[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C>CCO>[CH3:35][O:34][C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[C:31]=1[O:32][CH3:33])[CH2:27][N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:15]1[CH3:21]
Reactant: COc1cc2c(cc1OCc1ccccc1)CCNC2C
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cc(OC)c(OC)c(OC)c1)C2C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
A solution of 250 (170 mg, 0.6 mmol), 3,4,5-trimethoxybenzyl chloride (156 mg, 0.72 mmol) and triethyl amine (0.17 ml, 1.2 mmol) in EtOH (3 ml) was heated in the microwave at 130° C. for 1.5 h, then at 170° C. for 30 min. The reaction mixture was concentrated in vacuo. Purification (flashmaster: 20 g, gradient elution 100% hex to 50% hex:50% EtOAc over 25 min) afforded The title compound (58 mg, 21%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.36 (3H, d, J=6.7 Hz, CH3CH), 2.47-2.55 (1H, m, one of CH2), 2.67-2.84 (2H, m, 2×CH, CH2), 2.98-3.07 (1H, m, one of CH2), 3.59-3.73 (2H, m, CH2), 3.83 (9H, s, 3×OCH3), 3.88 (3H, s, OCH3), 5.09 (2H, s, CH2), 6.56-6.62 (4H, m, 4×CH), 7.27-7.44 (5H, m, 5×CH, phenyl). LC/MS (ES+) tr=1.26 min, m/z 464.34 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:10]2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:10]2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)Cc1nn(Cc2ccc(N)cc2)c2ncccc12
Yield: 85.1 %

Procedure:
Methyl 2-[1-(4-nitrobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetate (75 mg, 0.23 mmol) was dissolved in 10 mL tetrahydrofuran. 10% Pd/C (5 mg) was added, and reacted under hydrogen atmosphere for 2 hours. It was filtered, and the filtrate was rotate evaporated to dryness directly to obtain a white solid 58 mg, at a yield of 87%.