Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([F:32])[CH:34]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cncc(F)c1
Product: Cn1ncc(NC(=O)c2csc(-c3cncc(F)c3)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (5-fluoropyridin-3-yl)boronic acid gave 246. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.13 (t, J=1.7 Hz, 1H), 8.76 (d, J=2.8 Hz, 1H), 8.55 (s, 1H), 8.40-8.32 (m, 1H), 7.72 (s, 1H), 5.05-4.73 (m, 2H), 4.21-4.05 (m, 1H), 4.05-3.91 (m, 1H), 3.79 (s, 3H), 3.29-3.24 (m, 1H), 2.21-2.10 (m, 1H), 1.94-1.77 (m, 2H), 1.71-1.61 (m, 1H). LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[C:9]2([CH:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][NH:11][CH2:10]2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([N:11]1[CH2:12][CH:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]2([CH2:8][CH2:7][CH2:6]2)[CH2:10]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CNCC12CCC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(S(C)(=O)=O)CC12CCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added dropwise to a stirred solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.177 g, 0.783 mmol) in and triethylamine (0.436 ml, 3.13 mmol) in THF (9.78 mL) @ 0° C. under N2. Stirring @ 0° C. was continued for 1.5 hr. +/−MS after 1 hr 15 min looked the same as for 40 min, mostly desired product with a trace of sm. Additional methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added and stirring was continued for 50 minutes. +/−MS after 40 m indicated that the reaction had proceeded essentially to completion and no starting material was detected by mass spectrum analysis (m/e 303.4, M−H for desired product). The volatile solvents were removed under vacuum. Ethyl acetate and water were added, the organic layer was washed twice with water, followed by washing with brine, and the organic layer was separated, dried (Na2SO4), and concentrated under vacuum to yield 0.231 g of the crude product as a yellow viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 1:1 hexane:EtOAc yielded 0.197 g of the title compoud as a white solid. +/−MS: m/e 303.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.61 (br. s., 1H), 4.10 (br. s., 1H), 3.49 (dd, J=10.6, 5.3 Hz, 1H), 3.43-3.36 (m, 2H), 3.29 (dd, J=10.6, 3.1 Hz, 1H), 2.84 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.86 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[F:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][NH:9]3)=[CH:4][CH:3]=2)=[O:22])=[C:19]([CH3:18])[N:27]=1
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Reactant: Cc1nc(-c2cccc(F)c2F)ccc1C(=O)O
Product: Cc1nc(-c2cccc(F)c2F)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (48 mg, 0.20 mmol) and 2-methyl-6-(2,3-difluorophenyl)-nicotinic acid (D26) (54 mg, 0.22 mmol) as an off-white solid. MS(ES): MH+ 380, M-H+ 378.
Reaction SMILES: [H][H].[BrH:3].[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=2[OH:15])[C:6]1=[O:17]>O.[Pt](=O)=O>[BrH:3].[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=2[OH:15])[CH:6]1[OH:17]
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Br
Solvent: O
Product: NC1CCc2c(ccc(O)c2O)C1O

Procedure:
In 5 volume parts of water is dissolved 0.200 part of 3,4-dihydro-2-amino-5,6-dihydroxy-1(2H)-naphthalenone hydrobromide and, using 0.050 part of platinum dioxide, the catalytic reduction is carried out in a current of hydrogen gas until a substantially stoichiometric amount of hydrogen gas is absorbed. The catalyst in the reaction mixture is filtered off and to the filtrate is added a mixture of ethyl ether, methanol and water. The procedure gives white prisms of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 190° to 200° C.(decomp.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: Cc1ccc(C(C)C)c(Br)c1
Product: Cc1ccc(C(C)C)c(N2CCNCC2)c1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-5-methyl-2-isopropyl-benzene.
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:27])[C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=[CH:15][CH:14]=1.C[Mg]Cl>C1(C)C=CC=CC=1.O.ClCCCl>[CH3:11][N:12]([CH3:27])[C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH2:1])=[CH:15][CH:14]=1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: C[Mg]Cl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1ccc(N(C)C)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
10 ml of 1,2-dichloroethane and 1 ml (12.9 mmol) of N,N-dimethylformamide (DMF) were weighed and placed in a 100 ml reaction flask. To the mixture was gradually added dropwise 1.0 g (6.5 mmol) of phosphorus oxychloride while the mixture was cooled in ice-water. A bath was dismantled and the mixture was stirred for 10 minutes. Then, 5 ml of 1,2-dichloroethane containing 1.3 g (5.8 mmol) of 1-(p-dimethylaminophenyl)-1-phenylethylene (3a) which was synthesized from 4-dimethylaminobenzophenone (2a) and methylmagnesium chloride by using the method described in JP-B No. H7-21646 was added dropwise to the mixture. The resulting mixture was stirred for 3 hours at the same temperature and was then poured into water, which was then neutralized by addition of soda ash. The neutralized solution was heated at 80° C. to carry out a decomposition reaction and the resulting solution was subjected to separatory treatment. The water phase was subjected to an extraction treatment using toluene and the extract was combined with the organic phase. The resulting solution was washed with water and dried/concentrated using magnesium sulfate to obtain 1.4 g of a mixed product (6a) of a cis-isomer and a trans-isomer. The mixed product was recrystallized from a mixed solvent consisting of hexane and toluene to obtain 440 mg of 3-(p-dimethylaminophenyl)-3-phenylacrolein (7a). The yield was 29.3% and the melting point (mp) was 134-136° C. The ratio of trans-isomer measured by H-NMR was 0.98 (the ratio of trans-isomer are hereinafter indicated by a value measured by 1H-NMR). 1H-NMR (only peaks of trans-isomer are described) δ; 3.05 (s, 6H), 6.59(d, J=8.2 Hz, 1H), 6.67(d, J=9.1 Hz, 2H), 7.27(d, J=7.9 Hz, 2H), 7.47(m, 3H), 9.38(d, J=8.2 Hz, 1H). MS (m/z); 251, 234, 223, 207, 178, 165, 145, 121, 102, 91, 77, 42.
Reaction SMILES: [C@H:1]12[CH2:22][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[C:17](Br)[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2.CC1(C)C(C)(C)OB([C:31]2[O:35][C:34]([Si](C(C)C)(C(C)C)C(C)C)=[N:33][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.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>[C@H:1]12[CH2:22][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[C:17]([C:31]5[O:35][CH:34]=[N:33][CH:32]=5)[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2
Reactant: CC(=O)c1cc(Br)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cc(-c2cnco2)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of the obtained 1-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-8-bromoimidazo[1,2-a]pyridin-6-yl)ethanone obtained in Step E of Example 155, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (80 mg), tetrakis(triphenylphosphine)palladium(0) (25 mg) and potassium carbonate (61 mg) in DME/water (2/0.5 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (3 mL), and 1N hydrochloric acid (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:4][CH:3]=1
Reactant: COc1cccc(Cc2ncc(Cl)cc2C(=O)O)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(OC)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-methoxybenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.15 (1H, d, J=7.5 Hz), 8.63 (1H, d, J=2.4 Hz), 7.94–7.90 (3H, m), 7.49 (2H, d, J=8.4 Hz), 7.09 (1H, t, J=7.8 Hz), 6.74–6.63 (3H, m), 5.18–5.08 (1H, m), 4.17 (1H, d, J=13.8 Hz), 4.09 (1H, d, J=13.8 Hz), 3.85 (3H, s), 3.66 (3H, s), 1.41 (3H, d, J=7.0 Hz); MS (ESI) m/z 439 (M+H)+, 437 (M−H)−.
Reaction SMILES: CCN(CC)CC.Cl.Cl.[N:10]1([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:25]([O:29][C:30]([NH:32][CH2:33][C@H:34]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:35](O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C@H:34]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:35](=[O:36])[N:13]1[CH2:12][CH2:11][N:10]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: c1nc(N2CCNCC2)c2cc[nH]c2n1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NEt3 (150 μL, 1.1 mmol) was added to a stirred suspension of 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (100 mg, 0.36 mmol), (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (130 mg, 0.40 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) in DMF (15 mL) at RT. Stirred at RT overnight. Poured into EtOAc (100 mL), washed with water (100 mL), 1N NaOH (50 mL), dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica (100% EtOAc) to give (S)-{2-(4-Chlorobenzyl)-3-oxo-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propyl}-carbamic acid tert-butyl ester. LCMS (APCI+) m/z 499 [M+H]+; Rt: 2.70 minutes. This was taken up into DCM (50 mL) and stirred with TFA (5 mL) overnight. Poured into EtOAc (100 mL) and washed with 1N NaOH (2×100 mL), dried over Na2SO4 and concentrated in vacuo. Formed HCl salt (Et2O.HCl, 2M in diethyl ether) to give (S)-2-Aminomethyl-3-(4-chlorophenyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride (100 mg, 59%.) LCMS (APCI+) m/z 399 [M+H]+; Rt: 1.82 min. [Free base: 1H NMR (CDCl3, 400 MHz) δ 9.97 (1H, br.s), 8.32 (1H, s), 7.24 (2H, d, J 7.4 Hz), 7.13 (2H, d, J 7.4 Hz), 7.09 (1H, d, J 2.4 Hz), 6.45 (1H, d, J 2.3 Hz), 4.00-3.68 (5H, m), 3.60-3.53 (1H, m), 3.46-3.40 (1H, m), 3.33-3.27 (1H, m), 3.16-3.05 (2H, m), 2.92-2.83 (2H, m), 2.77 (1H, dd, J 13.3 and 5.5 Hz.)]
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a cold solution of 4-fluorobenzoic acid (50.0 g, 0.36 mol, 1.0 equiv) in concentrated H2SO4 (180 ml) was added portionwise potassium nitrate (39.7 g, 0.39 mol, 1.1 equiv). The reaction mixture was stirred overnight at rt and then poured on crushed ice (800 g) with constant stirring. The resulting mixture was kept overnight at rt, filtered and washed thoroughly with water, and finally dried by making an azeotrope with toluene to yield 59.5 g (90%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO): δ7.69-7.74 (m, 1H), 8.29-8.32 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 13.75 (br s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.[H][H]>[Ni].C(O)C>[CH3:1][NH:2][CH:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1
Reactant: CNC1=CC(=O)c2ccccc2OC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CNC1COc2ccccc2C(O)C1

Procedure:
18.8 g (0.1 mole) 3-methylamino-1-benzoxepin-5(2H)-one is stirred with 40 g Raney Nickel in 400 ml ethanol for five hours at an hydrogen pressure of 55 bar. Subsequently, the catalyst is filtered out, the solvent is distilled off and one obtains 7.7 g (40% of the theoretical yield) racemic-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol as an oil. The compound can be further separated as described earlier and further identified.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(/C=N/O)n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(CN)n1
Reaction time: 0.5 h

Procedure:
To (E)-6-methylpicolinaldehyde oxime (0.635 g, 4.66 mmol)/acetic acid (267 μL, 4.66 mmol)/ethanol (10 mL) solution was added portionwise zinc dust (5.19 g, 79 mmol) over 30 min. The resulting mixture was stirred for additional 30 min. LCMS of reaction aliquot indicated reaction was completed. The zinc precipitates in reaction mixture was removed by filtration, and the filtrate was concentrated. The residue was basified to pH>12 with excess sat. KOH (˜7 mL), and stirred with Et2O (30 mL). The Et2O layer was collected, dried over Na2SO4, and concentrated. The residue was redissolved in EtOAc(15 mL), dried over Na2SO4, and concentrated. (6-Methylpyridin-2-yl)methanamine was obtained as a colorless oil (385 mg, 3.15 mmol, 67.6%). LCMS (m/z) 123.2 (MH+) 0.15 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN(C)C=O>C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Tert-butyl-4-oxo-1-piperidinecarboxylate (10 g, 50 mmol) and N,N-dimethylformamide dimethyl acetal (7.3 mL, 55 mmol) were added to N,N-dimethylformamide (75 mL) under nitrogen gas and the mixture heated at 90° C. for 8 hours and then stirred for a further 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate (200 mL) and brine (200 mL). The aqueous phase was re-extracted with ethyl acetate (200 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a brown oil that solidified on standing. Trituration with cyclohexane (20 mL) gave the title compound as a light brown solid (8.5 g, 67%).
Reaction SMILES: B(F)(F)F.[N:5]1[O:6][CH2:7][CH:8]2[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:10][C:9]=12.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:23]1([C:9]23[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:12][CH:8]2[CH2:7][O:6][NH:5]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Agent: FB(F)F
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Boron trifluoride (30.8 mL, 244 mmol) is added to a −50° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (40 g, 162 mmol) in tetrahydrofuran (200 mL). The mixture is stirred for 10 minutes and the solution is added to phenyl magnesium bromide (325 mL, 325 mmol, 1 M in tetrahydrofuran) at −50° C., warmed to 0° C., and stirred for 4 hours. The reaction is quenched with saturated ammonium chloride (200 mL) and the aqueous layer is separated. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel using a 5 to 50% ethyl acetate/hexanes gradient to give the title compound (31 g, 59%). ES/MS (m/e): 325 (M+H).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([SH:12])=[N:9][N:8]=1)(=O)C.[ClH:13]>O1CCOCC1>[ClH:13].[NH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([SH:12])=[N:9][N:8]=1
Reactant: CC(=O)NCCc1nnc(S)s1
Agent: Cl
Solvent: C1COCCO1
Product: NCCc1nnc(S)s1

Procedure:
Thus obtained 5-(2-acetamidoethyl)-1,3,4-thiadiazole-2-thiol f(0.86 g) was dissolved in a mixture of 6 N hydrochloric acid (9 ml) and dioxane (5 ml) and the solution was heated to reflux for 2.5 hours. The solvent was distilled off and the residue was washed with ethanol to give 5-(2-aminoethyl)-1,3,4-thiadiazole-2-thiol hydrochloride (700 mg). m.p. 218° to 220° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:57]([NH:59][C@H:60]([C:62](O)=[O:63])[CH3:61])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>O1CCCC1>[C:44]([NH:54][C@H:55]([C:57]([NH:59][C@H:60]([C:62]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:63])[CH3:61])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 70 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-alanyl-L-alanine. Yield 70%. [α]D =+10.3° (c=0.92, tetrahydrofuran). m.p. 99-100°.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:10][C:9](=[O:11])[CH:8]([O:7][C:6]2[CH:14]=[CH:15][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:12][CH3:13])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCc1ccc(OC(CC)C(=O)O)cc1
Product: CCc1ccc(OC(CC)C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)cc1
Yield: 114.7 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 416 mg of (2RS)-2-(4-ethylphenoxy)butyric acid and 551 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 850 mg of the title compound as a colorless foam.