Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)#[N:2]>CCOC(C)=O.[Pd]>[NH2:24][C:23]1[C:3]([C:1]#[N:2])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a solution of (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 1e, 13 g, 36 mmol) in EtOAc (200 mL) was added Pd/C (3.82 g, 3.6 mmol 10% solution) and the mixture was stirred at room temperature under H2 for 6 hours until the reaction was complete. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (EtOAc/hexanes) to yield the title compound (11 g, 92.3%). (M+H)-Boc=232.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](C=O)=[C:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].Cl.[NH2:47][OH:48]>CN1CCCC1=O.C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](=[N:47][OH:48])[CH:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C=O)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4=CC(F)C(=NO)C=C4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 117 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene (272 mg) obtained in Example 180-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto was hydroxylamine hydrochloride (34 mg). The mixture was heated under stirring at 117° C. overnight. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (177 mg) as colorless caramel. APCI-Mass m/Z 693/695 (M+NH4).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:13][C:12]3[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH2:14][CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH:11]=3)[C:6]2=[O:22])[CH2:3][CH2:2]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[CH2:13][C:12]3[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([CH2:27][C:26]5[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=5)[CH2:17][CH2:16]4)[CH:11]=3)[C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC1CC1)C2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(CC2CCN(Cc3cccc(F)c3)CC2)cc2c1C(=O)N(CC1CC1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Cyclopropylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (30 mg, 0.110 mmol) in methanol (2 mL) was slowly added acetic acid (1 mL). After stirring at room temperature for 5 minutes, 3-Fluoro-benzaldehyde (12.8 μL, 0.121 mmol) and sodium cyanoborohydride (8 μL, 0.111 mmol) were added dropwisely. The mixture stirred at room temperature for 2 hours and was neutralized with saturated sodium bicarbonate (10 mL). The aqueous mixture was extracted with dichloromethane and the organics were dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (10-40% ethyl acetate in hexanes) provided the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.70-7.23 (m, 1H), 7.09-7.03 (m, 3H), 6.97-6.92 (m, 2H), 4.41 (s, 2H), 3.48-3.44 (m, 4H), 2.88-2.85 (d, 2H), 2.71 (s, 3M), 2.60-2.57 (d, 2H), 1.93 (t, 2H), 1.64-1.50 (m, 3H), 1.36-1.28 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.34-0.32 (m, 2H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:18][C:19]2[C:20]([CH3:26])=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[CH3:31][O-:32].[K+]>O.CC(OC)(C)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:18][C:19]2[C:20]([CH3:26])=[N:21][C:22]([O:32][CH3:31])=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)ccc1O[C@@H](CC(C)C)[C@H]1CCN(Cc2ccccc2)C1
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccc(O[C@@H](CC(C)C)[C@H]2CCN(Cc3ccccc3)C2)c(C)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 200 mL RB flask equipped with a magnetic stir bar and N2 inlet was charged with (S)-1-benzyl-3-((S)-1-(6-chloro-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine (5.46 g, 14.65 mmoles) and DMSO (30 mL). Add potassium methoxide (4.11 g, 58.61 mmoles) in one portion with stirring. Stir the reaction mixture in an oil bath at 100° C. for 1 hour. Dilute with H2O (60 mL) and MTBE (60 mL). Separate the layers and wash organic layer with H2O (2×30 mL), followed by brine (30 mL), and then dry over Na2SO4. Filter and concentrate the crude material (in toluene). Load onto silica (225 g, wet with toluene), and elute with the following: hexanes (2×500 mL), 50% MTBE/hexanes (6×500 mL). Concentrate the appropriate fractions to give (S)-1-benzyl-3-((S)-1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine. (4.32 g, 11.72 mmoles, 80% yield) as a yellow/orange oil. 1H NMR (300 MHz, CDCl3) δ 7.34-7.2 (m, 5H), 7.10 (d, 1H, J=8.79 Hz), 6.49 (d, 1H, J=8.79), 4.17-4.07 (m, 1H), 3.88 (s, 3H), 3.68-3.50 (m, 2H), 2.78-2.67 (m, 2H), 2.61-2.48 (m, 1H), 2.48-2.38 (m, 1H), 2.37 (s, 3H), 2.33-2.24 (m, 1H), 2.00-1.50 (m, 5H), 1.44-1.30 (m, 1H), 0.885 (at, 6H, Ja=7.03 Hz, Jb=6.44 Hz). LC/MS=369.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:12]=1
Reactant: OCc1cccnc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1cccnc1
Yield: 78.5 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 3-pyridyl carbinol, the titled compound was obtained as a yellow solid. (Yield: 78.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][CH2:6][CH:7]([OH:14])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][CH2:6][CH:7]([O:14][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=1[Cl:19])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Product: Clc1ccc(COC(CNc2ccc(Cl)c(Cl)c2)Cn2ccnc2)c(Cl)c1

Procedure:
Reaction of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]-imidazole with 2,4-dichlorobenzyl chloride yields 1-[3-(3,4-dichloroanilino)-2-(2,4-dichlorobenzyloxy)propyl]-imidazole. The base, purified by recrystallization from isopropanol, melts at 116°-117° C.; the methanesulfonate salt melts at 141°-143° C.
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:26][O:27][C@@H:28]1[O:60][C@H:59]([CH2:61][O:62][C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:29]1[O:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:22]([O:24]C)=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I-].[Li+].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:20][CH:21]([CH2:26][O:27][C@@H:28]1[O:60][C@H:59]([CH2:61][O:62][C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([O:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@H:29]1[O:30][C:31](=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:22]([OH:24])=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)C(=O)O
Yield: 68.1 %

Procedure:
In 26 mL of pyridine was dissolved 1.4 g of methyl 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyloxy)propionate, 1.7 g of lithium iodide was added to the solution, and the resulting mixture was refluxed under nitrogen atmosphere for 4 hours. Chloroform was added to the reaction mixture, the resulting mixture was washed with 2 mol/L of hydrochloric acid, the chloroform layer was dried over anhydrous magnesium sulfate, and then, the solvent was removed under reduced pressure. The finally obtained residue was purified by silica gel chromatography (Eluent; chloroform: methanol=60:1) to obtain 940 mg of 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyloxy) propionic acid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>CO.C1COCC1>[NH2:3][CH2:12][CH:13]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)s1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1ccc(C(=O)NC(CN)Cc2ccccc2C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (74 mg, 0.14 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (86 μL, 2.75 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:12]1([CH2:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]3=[C:9]([C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:19]([CH3:20])[N:2]3[CH2:3][CH2:4]2)[CH:8]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: NN1CCc2cc(Cl)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c2cc(Cl)cc3c2n1CC3

Procedure:
A mixture of 13 g. (0.077 mole) of 1-amino-5-chloroindoline, 10 g. (0.073 mole) of phenylacetone and 10 g. of sodium acetate in 120 ml. of glacial acetic acid was heated on a steam bath for 1 hour. The mixture was cooled, filtered and the solid material washed with acetic acid and water. The product was recrystallized from benzene-isooctane; yield 12.7 g. (65%); m.p. 202°-204°C.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[B:11]([OH:13])O)=O.[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]=[C:21]2[NH:26][NH2:27])=[CH:17][CH:16]=1.NN>C(O)C.CC(O)=O>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]=[C:21]2[N:26]2[N:27]=[CH:1][C:3]3[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=3[B:11]2[OH:13])=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: NNC1=NCC(=O)N1Cc1ccc(Cl)cc1
Agent: NN
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C=NN(C1=NCC(=O)N1Cc1ccc(Cl)cc1)B2O

Procedure:
A mixture of 1 (360 mg, 2.0 mmol) and 3-(4-chlorobenzyl)-2-hydrazino-3,5-dihydroimidazol-4-one (compound 16, commercially available from Maybridge Chemical Co., Ltd., Ryan Scientific #RF03409; 500 mg, 2.1 mmol) in 6 mL of absolute ethanol was treated with 1 drop of AcOH and was warmed on a steam bath until homogeneous. The mixture was allowed to stand at 23 ° C. overnight, whereupon the 137 mg of the starting hydrazine that had separated as crystals (mp 186-188° C.) was removed by suction filtration. The filtrate was rotary evaporated to dryness, and the residue was triturated with Et2O to give 528 mg (69%, 91% based on unrecovered hydrazine) of the methoxy precursor (compound 17) as a pale yellow powder: mp 135-145° C. (EtOH). 1H NMR ((CD3)2SO) δ 9.16 (s, exchanges with D2O, 1, OH), 7.62 (d, J=8.4 Hz, 1), 7.40 (d, J =8.5 Hz, 2, p-CICA), 7.32 (d, J=8.5 Hz, 2, p-ClC6H4), 7.12 (m, 3), 6.97 (d, J=8.0 Hz, 1), 6.85 (d, J =8.0 Hz, 1), 6.68 (s, 1), 4.23 (d, J=5.6 Hz, 2, benzyl-CH2), 3.67 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 383 (2%, MH+). Deprotection of 17 can be effected using conventional techniques to form 18.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:26])[CH:6]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:7]1[CH2:17][CH2:16][CH2:15][CH:8]12.B(Cl)(Cl)Cl>>[OH:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:26])[CH:6]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:7]1[CH2:17][CH2:16][CH2:15][CH:8]12
Reactant: COc1ccc(C2C(=O)c3c(OC)cc(OC)cc3C3CCCC32)cc1
Agent: ClB(Cl)Cl
Product: COc1ccc(C2C(=O)c3c(O)cc(OC)cc3C3CCCC32)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.7 %

Procedure:
Combine 6,8-Dimethoxy-4-(4-methoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[a]naphthalen-5-one (0.15 g, 0.43 mmol), boron trichloride (2.1 ml, 1.0M in methylene chloride), and Ch2Cl2 (10 ml). Stir 3.5 hours at r.t. Quench with methanol, add water and extract with ethyl acetate. Wash with water, dry and concentrate in vacuo to give the titled compound (0.148 g, 100%). MS m/z 339 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>CCOCC>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: OCCCCCCCC1=CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OCCCCCCCC1=CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 2.5 mmol of 1-(7-hydroxyheptyl)-cyclopropene in 5 ml of ether was cooled in an ice bath. Triethylamine (0.44 ml) and 0.21 g (2.7 mmol) of acetyl chloride were added, and the reaction mixture was stirred 1 hour at 5° C. Additional acetyl chloride (0.11 g), ether and triethylamine were added, and the reaction was stirred at 5° C. until GC analysis indicated 95% conversion. The reaction was worked up by adding more ether and washing the organic phase with water, dilute HCl solution (diluted 1M aqueous HCl), potassium carbonate solution (2×), water and brine. The ether phase was dried over magnesium sulfate and stripped. Hexane was added and the reaction was stripped again to give 1-(7-acetoxyheptyl)-cyclopropene.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:9]=1[C:58]([O:60][CH2:61][CH3:62])=[CH2:59]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(C(C)(C)O)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(OCC)c1c(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(C(C)(C)O)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (0.550 g, 0.672 mmol), tributyl[1-(ethyloxy)ethenyl]stannane (681 μL, 2.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) were placed in a 3-neck 25-mL round bottom flask equipped with a reflux condenser and rubber septa. Then, the flask was evacuated and back-filled with nitrogen three times before adding 1,4-dioxane (20 mL). The resulting solution was sparged with nitrogen for 15 minutes and then lowered into an oil bath that was heated at 100° C. and the resulting solution stirred overnight at the same temperature. Another portion of tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) was added after 14 h, and the reaction allowed to progress for another 24 h, at which point, analysis showed consumption of the starting material and formation of the desired product. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude dark oil was purified by flash chromatography (40 g silica gel, 0 to 8% methanol in chloroform) to afford the title compound (476 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1Cl>>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:9]1[N:11]=[C:12]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[N:14]=[C:15]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[N:8]=1
Reactant: COC(CN)OC
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: COC(CNc1nc(NCC(OC)OC)nc(NCC(OC)OC)n1)OC

Procedure:
The procedure of Example 1 was repeated with the exception that aminoacetaldehyde dimethyl acetal (6.3 g, 0.060 mole) and cyanuric chloride (3.68 g, 0.02 mole) were used to give 2,4,6-tris-(2,2-dimethoxyethylamino)-1,3,5-triazine as an oily product in 80.8% isolated yield (6.3g). The structure was analyzed by infrared (IR) spectroscopy, and confirmed by NMR spectroscopy 1H NMR (δ): 4.2 (t, 1H), 3.6-3.2 (m, 2H), 3.4 (s, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:14](=O)[CH3:15])[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl>C1COCC1>[CH2:14]([N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:15]
Reactant: CC(=O)N1CCCNCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN1CCCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
Lithium aluminum hydride (38.2 ml, 38.19 mmol) was added to 1-(1,4-diazepan-1-yl)ethanone (1.697 g, 11.93 mmol) in THF (59.7 ml) at 0° C. under nitrogen. The resulting solution was stirred at ambient temperature for 1 h and then at 60° C. for 1 h. The cooled reaction mixture was poured onto ice (500 mL), acidified with HCl (2M aqueous solution) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford 1-ethyl-1,4-diazepane (0.610 g, 40%) as a yellow liquid. This was used directly with no further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH3:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
2-Bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (0.279 g, 1.321) was dissolved in DMF (5 mL) and cooled down to 0° C. NaH (60%, 63 mg, 1.58 mmol) was added slowly. After the addition was complete stirring was continued for 30 minutes at 0° C. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.28 mL, 1.58 mmol) was added and the reaction mixture was allowed to warm up overnight. The reaction was quenched with H2O. The aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (24 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 340 mg of 2-bromo-7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a yellow liquid (77% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:49]=[CH:48][C:11]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:47]=[CH:46][C:27]([C:28]([NH:30][C:31]5[CH:32]=[C:33]6[C:37](=[CH:38][CH:39]=5)[N:36]([CH2:40][C:41]([O:43]CC)=O)[CH:35]=[CH:34]6)=[O:29])=[CH:26][CH:25]=3)[CH:19]=[CH:18]4)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:50]1([NH2:53])[CH2:52][CH2:51]1>>[CH:50]1([NH:53][C:41](=[O:43])[CH2:40][N:36]2[C:37]3[C:33](=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:26]=[CH:25][C:24]([N:20]5[C:21]6[C:17](=[CH:16][C:15]([NH:14][C:12](=[O:13])[C:11]7[CH:48]=[CH:49][C:8]([N:5]8[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]8)=[CH:9][CH:10]=7)=[CH:23][CH:22]=6)[CH:18]=[CH:19]5)=[CH:47][CH:46]=4)=[CH:39][CH:38]=3)[CH:34]=[CH:35]2)[CH2:52][CH2:51]1
Reactant: NC1CC1
Reactant: CCOC(=O)Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21
Product: O=C(Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21)NC1CC1

Procedure:
Compound 969 was prepared by treatment of Compound 962 with cyclopropylamine. [M+H]+ calcd for C40H38N6O4: 667.30; found 667.31.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[Li+].[OH-].Cl>O1CCCC1.CO>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cscc1NC(=O)CCCCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCc1ccccc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 4-(5-phenyl-pentanoylamino)-thiophene-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) in tetrahydrofuran/methanol 2/1 (1.5 ml) was added a 1 N aqueous LiOH solution (0.95 ml, 0.95 mmol). The reaction mixture was stirred at room temperature for 2 h, acidified with 1 N HCl and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by thin layer chromatography (SiO2, dichloromethane) to give the title compound as colorless oil (20 mg, 0.07 mmol, 42%).