Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].Cl.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=1)#[N:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CNC(=NCc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and a solution of p-nitrobenzylamine hydrochloride (0.55 g, 2.9 mmol) and triethylamine (0.32 g, 3.2 mmol) in methanol (5 ml) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.70 g, 2.5 mmol, yield: 95%) as colorless powder.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=1.[C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)#[N:18].C(=O)([O-])[O-].[Na+].[Na+].COCCOC.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>[CH3:16][C:3]1[C:2]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]#[N:18])=[CH:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[N:4]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1-c1cccc(C#N)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
A mixture of 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2-dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130° C. (a liquid resulted, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt), filtered and was washed with water (×2) and dimethyl ether (DME) (×2) to give the product as a pale orange solid (15 mg, 44% yield).
Reaction SMILES: Br[C:2]1[C:11]([N:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:19][C:20]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:14]1([N:12]([CH3:13])[C:11]2[C:2]([CH:19]=[CH2:20])=[C:3]([CH:8]=[CH:9][CH:10]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cccc(N(C)C2CCCC2)c1Br
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1c(C(=O)OC)cccc1N(C)C1CCCC1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 2-bromo-3-(cyclopentyl(methyl)amino)benzoate (1 equiv.) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then, Pd(PPh3)4 (0.1 equiv.) was added and argon purged for 10 min. and the reaction mixture heated at 100° C. for 2 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired methyl 3-(cyclopentyl(methyl)amino)-2-vinylbenzoate.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:37])=[N:4][CH:5]=1)[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-(thiophen-2-yl)propanamide (40 mg, 0.096 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (11 mg). MS 434.3 (M+H); UV 204.2, 265.8, 298.4, 357.9 nm; t 0.453 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[F:21][C:17]1[CH:16]=[C:15]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[N:25][CH:26]=3)[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: COCCOCOc1ccc(-c2cccc(F)c2)cc1Br
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: COCCOC
Solvent: O
Product: COCCOCOc1ccc(-c2cccc(F)c2)cc1-c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Yield: 87.6 %

Procedure:
A mixture of 3-bromo-3′-fluoro-4-((2-methoxyethoxy)methoxy)-1,1′-biphenyl (1.56 g, 4.39 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (1.09 g, 5.709 mmol) and potassium carbonate (0.91 g, 6.59 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (253.8 mg, 0.22 mmol) was added and the reaction mixture heated at 80° C. in a sealed vial for 2 days. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 20% ethyl acetate (containing 2% methanol) in hexanes to give 5-(3′-fluoro-4-((2-methoxyethoxy)methoxy)-[1,1′-biphenyl]-3-yl)-2-(trifluoromethyl)pyridine (1.62 g, 88% yield) as a yellow syrup.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([O:22]C)=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1(C)C=CC=CC=1>[CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([OH:22])=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzooxazol-6-yl}oxy)benzoate (8.2 g) in methanol (300 mL) was added 8N aqueous sodium hydroxide solution (50 ml), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added 6N hydrochloric acid to adjust the pH to about 6.0, and the reaction mixture was concentrated under reduced pressure to about 100 mL. Ethyl acetate (200 mL) was added to the residue, and the mixture was washed with water (150 mL×2). The collected aqueous layer was extracted with ethyl acetate (100 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a brown amorphous substance. The obtained crude product was dissolved in toluene (150 mL) and 2-methylpropan-2-ol (100 mL), and the solvent was evaporated under reduced pressure. An azeotropic operation with toluene and 2-methylpropan-2-ol was further repeated twice to remove water from the crude product. The obtained brown amorphous substance (8.6 g) was used as the title compound in the next operation without a further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]1=[O:1])[CH2:23]2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC[C@@H](c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (4.43 g, 18.99 mmol; Example 91D) and 5-fluoroisoindoline hydrochloride (3.63 g, 20.89 mmol) in dichloromethane (30 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (5.04 mL, 28.5 mmol). After a few minutes, a dark brown solution resulted. The reaction was stirred overnight then poured into 1 N HCl (100 mL). The product was extracted into dichloromethane (3×100 mL). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in minimal dichloromethane and was loaded onto a GraceResolv™ 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes to provide the racemic title compound. Supercritical fluid chromatography using a ChiralPak® OD-H 21×250 mm column eluting using 10% to 50% methanol/CO2 over 20 minutes gave the title compound as the first eluting enantiomer. 1H NMR (300 MHz, CDCl3) δ 7.40-7.11 (m, 6H), 6.97 (dd, J=8.6, 18.0, 2H), 4.84 (dd, J=8.7, 19.3, 4H), 4.44 (dd, J=1.6, 15.7, 1H), 4.05 (d, J=15.7, 1H), 3.81-3.47 (m, 3H), 2.34-1.83 (m, 4H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:20][CH:21]([O:28][C:29]([NH:31][CH2:32][C:33]1([CH2:39][C:40]([O:42]CCC#N)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([O:20][CH:21]([O:28][C:29]([NH:31][CH2:32][C:33]1([CH2:39][C:40]([OH:42])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CCCOC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.7 %

Procedure:
DBU (79.2 mg, 78 μL, 0.520 mmol) was added to a solution of 2-cyanoethyl 1-{[(α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate (11) (166 mg, 0.347 mmol) in 10 mL of CH2Cl2 at −10° C. The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature, stirred for two hours and cooled to 0° C. Another 78 μL of DBU was added, the reaction mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, washed with citric acid and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by reversed phase HPLC to afford 7 mg (4.7%) of the title compound. M.p. 75.5-76.0° C. 1H NMR (CDCl3): δ 8.08 (2H, dd, J=8.8, 1.2 Hz); 7.89 (1H, s); 7.63-7.55 (3H, m); 7.46-7.26 (5H, m); 5.38 (1H, t, J=6.8 Hz); 3.26 (2H, dd, J=6.8, 0.8 Hz); 2.34 (2H, s); 1.58-1.35 (10 H, m). MS (ESI) m/z 424 (M−H31 ).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:36]4[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: OC1CCNCC1
Product: OC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 4-hydroxypiperidine (49.1 mg; 0.48 mmol) to give Example 141 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.6 Hz), 7.52 (4H, t, J=8.4 Hz), 4.57 (1H, d, J=4.1 Hz), 3.56-3.43 (3H, m), 2.70 (2H, d, J=10.5 Hz), 2.13-2.04 (2H, m), 1.74 (2H, d, J=12.0 Hz), 1.48-1.37 (2H, m). LC/MS (Method C): 498 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 99.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1>C(OCC)(=O)C.[Pt]>[F:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:2]([F:1])=[CH:7][C:6]=1[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(OCc2cccc(F)c2)cc1F
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 95.5 %

Procedure:
A solution of 2.63 g (9.3 mmol) of 1,4-difluoro-2-(3-fluoro-benzyloxy)-5-nitrobenzene in 25 ml of ethyl acetate is hydrogenated with Pt/C (5%) as the catalyst under normal pressure during 3 hours. For the working-up, the catalyst was filtered over a Dicalit layer and the solution evaporated under reduced pressure. There are obtained 2.25 g (95% of theory) of 2,5-difluoro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid; MS: m/e=253 (M)+. The crude product is engaged in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13].[BH4-].[Na+]>C(O)C.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C[C@@H](CO)NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Chloro-benzaldehyde (1.4 g, 0.01 mol) was dissolved in dry ethanol (30 mL) and (S)-(+)-2-amino-1-propanol (0.75 g, 0.01 mol) was added. The reaction mixture was stirred overnight at 60° C. The ethanol was evaporated under reduced pressure to give a colorless oil. The oil was then dissolved in dry methanol (30 mL) and cooled in ice. NaBH4 (0.57 g, 0.015 mol) was added slowly in portions, and the resulting solution was left overnight at room temperature. The solvent was evaporated in vacuo, and the residue was dissolved in water, and extracted with CH2Cl2 (3×20 mL). The organic layers were combined and dried with Na2SO4, filtered and evaporated in vacuo to give colorless oily residue, which was purified by column chromatography (silica gel, CH2Cl2:MeOH, 9:1) to afford colorless oil (III-1, 1.85 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=2)[N:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:19]2[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=3)[N:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 6-(tert-butoxycarbonylamino)pyridin-3-ylboronic acid (316.0 mg, 1.33 mmol) in dioxane (5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (130.0 mg, 0.44 mmol), K3PO4 (280.0 mg, 1.33 mmol) and Pd(PPh3)4 (25.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (160 mg, 80%).
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[CH2:9]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([OH:27])=[O:26])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([O:27][CH3:3])=[O:26])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodomethane (2.0 mL), K2CO3 (5.60 g), (S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (1) (NovaBiochem, A29340), and anhydrous DMF (20 mL) were combined and stirred at ambient temperature for 2 hours. The reaction mixture was subjected to an aqueous work-up, affording (S)-methyl 6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoate (TU3000-090) as clear oil. MS (ESI+): calcd. 417.20. found 417.20 (MNa+), calcd. 295.16. found 295.209((M-Boc)H+). H-NMR (400 MHz, CDCl3):1.372 (2H, m), 1.425 (9H, s), 1.515 (2H, m), 1.623 (1H, m), 1.785 (1H, br.s), 3.175(2H, m), 3.723 (3H, s), 4.284 (1H, m), 4.848 (1H, br.s), 5.084 (3H, overlapping br.s and s), 7.344 (5H, m). C-NMR (100 MHz, CDCl3): 22.340, 28.268, 29.307, 32.313, 40.569, 52.272, 53.099, 66.597, 79.897, 128.061, 128.100, 128.471, 136.519, 155.435, 156.426, 173.230.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][OH:12]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: COC(=O)c1ccc(C)cc1

Procedure:
To 200 ml of methanol at 0° was added, with stirring, 48.4 g (0.312 mole) of 4-methylbenzoyl chloride over 20 minutes. Following the addition, the reaction mixture was stirred at room temperature for one hour. The methanol was evaporated and the residue was distilled to give 43 g of the title compound as a colorless liquid: boiling point 103°-108° C. at 20 mm of Hg.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])=[CH2:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@@H:4]([C:1]([CH3:3])=[CH2:2])[CH2:5][CH2:6]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)[C@H]1CC[C@@H](CO)CC1
Solvent: c1ccncc1
Product: C=C(C)[C@H]1CC[C@@H](COC(C)=O)CC1

Procedure:
3.9 g of cis-4-isopropenyl-cyclohexylmethanol, 50 ml of acetic anhydride and 20 ml of pyridine were kept overnight at room temperature. The reaction mixture was then poured onto crushed ice and extracted with ether. The organic layer was successively washed with a 2N solution of Na2CO3, HCl at 10% in water and finally with a saturated aqueous NaCl solution. After the usual treatments of drying and evaporation, the fractional distillation of the obtained residue yielded 3.2 g (65%) of cis-4-isopropenyl-cyclohexylmethyl acetate, bp 105° - 108°/10 Torr.
Reaction SMILES: [CH3:1][CH:2]([C@@:4]1([NH:26][C:27]([C@H:29]2[CH:44]=[C:43]3[C@@H:32]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][C:41]=53)[NH:36][CH:35]=4)[N:31]([CH3:45])[CH2:30]2)=[O:28])[O:17][C@:16]2([OH:18])[N:7]([C@@H:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]([N:11]3[C@H:15]2[CH2:14][CH2:13][CH2:12]3)=[O:10])[C:5]1=[O:6])[CH3:3].[CH3:46][S:47]([OH:50])(=[O:49])=[O:48].C(OCC)C>C(O)C>[CH3:3][CH:2]([C@@:4]1([NH:26][C:27]([C@@H:29]2[CH:44]=[C:43]3[C@H:32]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][C:41]=53)[NH:36][CH:35]=4)[N:31]([CH3:45])[CH2:30]2)=[O:28])[O:17][C@:16]2([OH:18])[N:7]([C@H:8]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:9]([N:11]3[C@H:15]2[CH2:14][CH2:13][CH2:12]3)=[O:10])[C:5]1=[O:6])[CH3:1].[CH3:46][S:47]([OH:50])(=[O:49])=[O:48]
Reactant: CC(C)[C@@]1(NC(=O)[C@H]2C=C3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)O[C@@]2(O)[C@@H]3CCCN3C(=O)[C@H](Cc3ccccc3)N2C1=O
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)[C@@]1(NC(=O)[C@@H]2C=C3c4cccc5[nH]cc(c45)C[C@@H]3N(C)C2)O[C@@]2(O)[C@@H]3CCCN3C(=O)[C@@H](Cc3ccccc3)N2C1=O

Procedure:
Ergocristinine (1.25 g; 0.05 mmoles) was dissolved in absolute ethanol (25 ml), containing methanesulfonic acid (0.15 ml; 2.31 mmoles). After clarifying, the solution was slowly poured into absolute diethylether (350 ml) while stirring. The precipitated salt was filtered off and dried in vacuo. Ergocristinine methanesulfonate (1.40 g; 96.4% of the theory) with a melting point of 170°-180° C. was obtained.