Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](=O)(ON1C(=O)CCC1=O)[O:23]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:18][C:22](=[O:23])[O:20][C:19]=2[CH:21]=1)[C:10]([OH:12])=[O:11])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2oc(=O)oc2c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Boc-L-DOPA (22.3 g, 75 mmol) and disuccinimidyl carbonate (DSC, 80% pure, 24 g, 75 mmol) were suspended in anhydrous dichloromethane (500 mL) and triethylamine (21 mL, 150 mmol) was added dropwise at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min. The suspension became a clear solution. HPLC indicated a completed reaction. The reaction mixture was washed with 10% citric acid (200 mL) and water (200 mL×5) to remove triethylamine and N-hydroxysuccinamide. The organic layer was collected, dried over MgSO4, and concentrated to provide the title compound (16) (22 g, 91% yield), 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 3.11 (dd, 1H, J=14, 6.8 Hz), 3.27 (dd, 1H, J=14, 6.8 Hz), 4.59 (dd, 1H, J=14, 6.8 Hz), 5.03 (d, 1H, NH, J=8.0 Hz), 7.05 (dd, 1H, J=8, 2 Hz), 7.11 (d, 1H, J=2 Hz), 7.18 (d, 1H, J=8 Hz). MS (ESI) m/z 321.9 (M−H)−.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[I:8][C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1.C1COCC1.CCOCC>O>[I:8][C:9]1[S:13][C:12]([CH:14]=[C:1]2[C:2](=[O:3])[CH2:4][O:5][C:6]2=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1COC(=O)C1
Reactant: O=Cc1ccc(I)s1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1COC(=O)C1=Cc1ccc(I)s1
Reaction time: 0.08 h

Procedure:
0.59 gm of tetronic acid (FW=100, 0.056 mole) and 3.65 gm of 5-iodo-2-thiophenecarboxaldehyde (FW=238, 15.3 mmole) were added to a 25 mL roundbottom flask and 2.5 mL of THF were added and the solution was stirred for five minutes. The sludge was allowed to react for 30 minutes, occasionally helping the stirring with a glass rod. The precipitate was then treated with 10 mL of ether and 10 mL of water and swirled. The yellow crystals were then collected on a buchner funnel, washing them with ether, water and ether again. The excess 5-iodo-2-thiophenecarboxaldehyde was then recovered by extracting to aqueous layer with ether and resublimed. The crude adduct was dissolved in hot CHCl3 (approximately 250 mL) and passed through a silica plug (approximately 5 cm). The crystals obtained after solvent evaporation were recrystallized from ethyl acetate/igroin and the yield was 0.85 gm (46%). The material melted at 211°-212° C. (dec.) C9H6IO3S: %C 33.77; %H 1.57; found %C 33.53; %H 1.83 NMR results: 1HNMR (d6DMSO,(H20)/TMS) 6 4.69 (2H, d, 4.8 Hz); 7.53 (1H, m); 8.08 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH:15]([O:16]C(=O)C3C=CC=CC=3)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([OH:30])([OH:29])=[O:28])[O:12]2)=[C:4](Br)[N:3]=1.[CH3:32][NH2:33]>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:30])[OH:29])[CH2:14][CH:15]2[OH:16])=[C:4]([NH:33][CH3:32])[N:3]=1
Reactant: Nc1nc(Br)c2ncn(C3OC(C=CP(=O)(O)O)CC3OC(=O)c3ccccc3)c2n1
Reactant: CN
Solvent: O
Product: CNc1nc(N)nc2c1ncn2C1OC(C=CP(=O)(O)O)CC1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
Compound 46.2 (250 mg, crude) was dissolved in 40 wt % methylamine in water and stirred at rt for 3 h. The solution was concentrated under reduced pressure and the residue was subjected to a reverse phase HPLC to give compound 46.3 (60 mg, 35% yield). 1H NMR (CDCl3, 300 MHz): δ 2.05-2.18 (m, 2H), 2.83 (s, 3H), 4.54-4.55 (m, 1H), 4.84 (s, 1H), 5.73 (d, 1H, J=1.5), 5.89-5.95 (m, 1H), 6.22 (m, 1H), 7.64 (s, 1H). 31PNMR: 10.23 ppm. LRMS [M−H]− C12H17N6O5P requires 355.1. Found 355.1.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 3-[{[4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1.20 g) synthesized in Example A48(1) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (470 mg, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (433 mg, 38%, 99.9% ee) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])[CH3:3].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C(Cl)Cl>[OH:5][CH2:4][C@H:2]([N:1]1[C:9](=[O:10])[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:11])[CH3:3]
Reactant: C[C@@H](N)CO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 85.3 %

Procedure:
D-Alaninol (3.90 ml, 50 mmol) and phthalic anhydride (7.41 g, 50 mmol) were heated at 160° C. for 30 min. To cooled reaction mixture was added ice water and DCM. Organic phase was collected and the water phase was extracted with DCM. Combined organic phases were dried over Na2SO4 and evaporated to obtain 8.75 g (85%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.32 (d, 3H), 3.54 (m, 1H), 3.84 (m, 1H), 4.26 (m, 1H), 4.91 (m, 1H), 7.84 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH:11]3[C:13](=[O:14])[CH:8]([CH2:9][CH2:10]3)[CH2:7][C:6]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH:11]3[C:13](=[O:14])[CH:8]([CH2:9][CH2:10]3)[CH2:7][C:6]=2[CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CCC1Cc1cc(OCc3ccccc3)ccc1C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one (15 g; J. Org. Chem 1982, 47, 4329), K2CO3 (20.5 g) and benzyl bromide (10.6 ml) in DMF (100 ml) was stirred for 48 hrs at room temperature. The reaction was diluted with water (500 ml) and extracted with EtOAc (3×150 ml). The combined organic phases were washed with water (2×300 ml), brine (150 ml), dried and concentrated to give a gummy oil which crystallized on standing and after trituration with ether the title benzyl ether (19.5 g, 90%) as a white solid (360 MHz 1H, δ-CDCl3) 1.32 (2H, m), 1.85 (2H, m), 2.57 (2H, m), 2.87 (4H, m), 5.05 (2H, s), 6.82 (2H, m), 7.11 (1H, d, J=8.2), 7.37 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[SH:11].Cl[CH2:14][C:15](=[O:17])[CH3:16].[CH2:18](N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]([CH3:18])[CH:7]1[S:11][CH2:14][C:15](=[O:17])[CH3:16]
Reactant: CCN(CC)CC
Reactant: CC(=O)CCl
Reactant: COC(=O)CCn1ccnc1S
Product: COC(=O)CCN1C=CN(C)C1SCC(C)=O

Procedure:
In operations carried out in a manner similar to that described in Example I, 1-(3-methoxy-3-oxopropyl)imidazol-2-thiol was reacted first with chloroacetone and triethylamine to obtain 1-(3-methoxy-3-oxopropyl)-3-methyl-2-[(2-oxopropyl)thio]-1H-imidazole, which then was reacted with methyl trifluoromethanesulfonate to obtain 1-(3-methoxy-3-oxopropyl)-3-methyl-2-[(2-oxopropyl)thio]-1H-imidazolium trifluoromethanesulfonate, which in turn was passed through a Dowex-1 (Cl-) ion exchange column to obtain 1-(3-methoxy-3-oxopropyl)-3-methyl-2-[(2-oxopropyl)thio]-1H-imidazolium chloride having m.p. 121°-124° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3 g (0.014 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 30 ml of dichloromethane, are added dropwise at 15 to −20° C. to a solution of 2.65 ml (0.013 mol) of 4-amino-1-benzyl-piperidine and 6 ml (0.043 mol) of triethylamine in 100 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is extracted with a mixture of I molar sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml of ethanol.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[N-:22]=[N+]=[N-].[Na+]>ClCCl>[CH:6]1[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:21])[NH:22][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of concentrated sulfuric acid (25.2 mL) and DCM (dichloromethane) (8.4 mL) was cooled to 0° C., anthraquinone (1) (5 g, 24 mmol) was added, then sodium azide (1.84 g, 28.3 mmol) was added in small portions over a 1 h period at 0-5° C. The reaction mixture stirred overnight at room temperature and then poured into ice water (300 mL). The product was filtered off, washed with water till acid-free and dried to give 5H-dibenzo[b,e]azepine-6,11-dione (2) as a white solid (5.3 g, 100%). Data: (m/z)=224 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]([CH3:10])[CH2:5][C:6]([CH3:9])([CH3:8])[N:7]=1.C([Li])CCC.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.Cl>O1CCCC1.CCCCCC.O>[CH3:8][C:6]1([CH3:9])[CH2:5][CH:4]([CH3:10])[O:3][C:2]([CH2:1][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)=[N:7]1
Reactant: Fc1ccc(CCl)cc1
Reactant: CC1=NC(C)(C)CC(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC1CC(C)(C)N=C(CCc2ccc(F)cc2)O1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
5,6-Dihydro-2,4,4,6-tetramethyl-4H-1,3-oxazine (10.98 g) in anhydrous tetrahydrofuran (80 ml) was cooled to -70° under nitrogen. n-Butyllithium in hexane (44 ml) was added dropwise to the stirred solution over approximately 1 hr and the mixture was stirred for a further hour. 4-Fluorobenzyl chloride (12.38 g) in anhydrous tetrahydrofuran (20 ml) was added to the mixture over 30 min and the stirred reaction mixture was allowed to warm to room temperature overnight. The mixture was poured into iced water (100 ml) and adjusted to pH 2-3 with 9 M hydrochloric acid. The solution was extracted with pentane (3×75 ml), then adjusted to pH 14 with 10 M sodium hydroxide, and the resulting oil was extracted with ether (3×75 ml). The solvent was evaporated to give crude 5,6-dihydro-4,4,6-trimethyl-2-[2-(4-fluorophenyl)ethyl]-4H-1,3-oxazine (13.87 g).
Reaction SMILES: O=[C:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.N12CCCCC1C=NCCC2.C([O:35]CC)C>>[C:11]1([CH:10]=[CH:9][C:2]([Si:18]([CH3:21])([CH3:20])[CH3:17])=[CH:3][CH:4]([OH:35])[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)CCC(=O)/C=C/c1ccccc1
Reactant: CCOCC
Agent: C1=NCCCN2CCCCC12
Product: COC(=O)C(O)C=C(C=Cc1ccccc1)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of the product of Step B , 45 ml of diethyl ether and 2.2 ml of trimethylchlorosilane were mixed together and after the mixture was cooled to 0° C., then 2.5 ml of 1,5-diaza-5-bicyclo-[5,4,0]-undecene (DBU) and 20 ml of diethyl ether were added. The mixture was stirred while allowing the temperature to rise to 20° to 21° C. for one hour. After filtration, the ether was evaporated off to obtain 4.2 g of the desired product which was used as is in the following step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][O:12][CH3:13])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>O1CCCC1.O>[OH:4][C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:2]([NH:1][CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:11][O:12][CH3:13]
Reactant: O=S1(=O)CCCO1
Reactant: COC[C@H](N)[C@@H](O)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H](NCCCS(=O)(=O)O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (1S,2S)-2-amino-3-methoxy-1-phenyl-1-propanol (1.0 g, 5.5 mmol) in tetrahydrofuran (10 mL) was slowly added 1,3-propane sultone (662 mg, 5.3 mmol). The mixture was stirred at reflux for 2.5 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration and dried in a vacuum oven (50° C.), to afford compound EG (1.0 g, 63%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.77 (d, 1H, J=9.8 Hz), 3.53 (m, 1H), 3.37 (m, 1H). 3.26 (m, 1H), 3.17 (m, 6H), 2.91 (t, 2H, J=7.3 Hz), 2.07 (m, 2H). 13C NMR (D2O, 125 MHz) δ ppm 139.09, 129.33, 129.27, 127.11, 70.85, 66.29, 62.62, 58.76, 48.14, 44.24, 21.47. [α]D=+42.6° (c=0.00091 in water), ES-MS 302 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[N:40]=[C:41]=[O:42]>C(N(CC)C(C)C)(C)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[NH:40][C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:18])[S:10][N:9]=2)=[CH:6][CH:7]=1)=[O:42]
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)nsc1NC(=O)NCCCN1CCOCC1
Yield: 60.1 %

Procedure:
In a manner similar to that described for Example 3 (, 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (12 mg, 0.030 mmol), 3 drops N,N-diisopropylethylamine, and 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0087 mL, 0.060 mmol) was used to give the title compound as a white solid (11 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.C(OCC)(=O)C>C1COCC1>[OH:22][CH2:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:14]#[C:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=1
Reactant: COc1cc(C#Cc2cc(C(=O)O)ccn2)cc(OC)c1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C#Cc2cc(CO)ccn2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
2-(3,4,5-Trimethoxyphenylethynyl)pyridine-4-carboxylic acid (90 mg) was dissolved in THF (6 mL), and to the solution triethylamine (35 mg) was added at 0° C. under an argon atmosphere. Ethyl chloroformate (34 mg) was then added to the mixture, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture, the residue was dissolved in THF (2 mL), and to the solution an aqueous solution (1 mL) of sodium borohydride (16 mg) was added at 0° C., and the resultant mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to ethyl acetate) to obtain the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32](=[O:44])[C@@H:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:44])[C@@H:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][I:20])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CI)C(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a suspension of PPh3-resin (5 g, 6.5 mmol) in methylene chloride (50 mL) at 0° C. is added iodine (1.65 g, 6.5 mmol) and imidazole (0.485 g, 7.12 mmol) then stirring is continued at 0° C. for 45 min. To this is added (S)-2-tert-butoxycarbonylamino-3-hydroxypropionic acid tert-butyl ester (0.81 g, 3.1 mmol) and the suspension is refluxed for 45 min. The suspension is filtered and the organic layer is washed with a saturated sodium bisulfite solution, water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])OC1C=CC([N+]([O-])=O)=CC=1.[CH3:20][N:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:22].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:20][N:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:22][C:8](=[O:19])[NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CN(C)N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(C)NC(=O)NCc1cccs1
Reaction time: 4.5 h
Yield: 46.2 %

Procedure:
To the solution of 4-nitrophenyl thiophen-2-ylmethylcarbamate (Compound XII-1) 3.14 g (11 mmol) in dichloromethane 20 ml, ethyl 2-(1-methylhydrazinyl)acetate (Compound XV-2) 2.98 g (22.6 mmol) and triethylamine 2.36 ml (17 mmol) was added at 0° C. and stirred at additional 4.5 hours. The reaction mixture was diluted with ethyl acetate 100 ml and washed with water 10 ml and brine 75 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was submitted to silcagel chromatography to obtain the title compound 1.38 g (45%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(Cl)(Cl)Cl.C(O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:3]=1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)nc(Cl)c1C#N
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A solution of 2,6-dichloro-3-cyano-4-methylpyridine (5.6 g) and imidazole (2.04 g) in dimethylformamide (10 mL) was heated at 130° C. for 1.25 hours. After cooling to room temperature the mixture was fractionated directly on silica gel with chloroform/ethanol gradient) to give 1.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]([CH2:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[F:18])=[O:8])[NH:5]C=1.[C:24]([NH:31][C@:32]([C:36]([OH:38])=O)([CH3:35])[CH2:33][CH3:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C1CCC([N:45]=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(OCC)(=O)C>[C:24]([NH:31][C@@:32]([CH3:35])([CH2:33][CH3:34])[C:36]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23]2)[C:7]([C:4]2[NH:5][N:45]=[C:2]([Cl:1])[CH:3]=2)=[O:8])=[C:12]([F:18])[CH:13]=1)=[O:38])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(c1cc(Cl)c[nH]1)N(Cc1ccc(O)cc1F)CC1CCC1
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(CN(CC2CCC2)C(=O)c2cc(Cl)n[nH]2)c(F)c1
Yield: 0 %

Procedure:
To a solution of 4-chloro-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrrole-2-carboxamide (0.040 g, 0.118 mmol) in 3 mL ethyl acetate was added Boc-iso-Valine (0.026 g, 0.118 mmol), DCC (0.037 g, 0.178 mmol) and pyridine 0.5 mL. The reaction mixture was added at r.t. for overnight. After removal of all the solvent, the residue was purified by chromatography. (0-30% methanol/DCM) (S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl 2-(Boc-amino)-2-methylbutanoate was obtained (0.030 g, 0.056 mmol, 47% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1cccnc1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cccnc2)cc1C=O
Yield: 32 %

Procedure:
N1 is prepared according to a method similar to Method A. Commercially available 3-formyl-4-methoxyphenylboronic acid (1.66 g, 9.22 mmol) is dissolved in 56 mL toluene and 14 mL ethanol. 3-Bromopyridine (0.98 mL, 10.2 mmol) is added followed by cesium carbonate (3.0 g, 9.21 mmol). Nitrogen is bubbled through the mixture for 10 minutes, then palladium tetrakistriphenylphosphine (0.53 g, 0.46 mmol) is added and nitrogen bubbling is resumed for another ten minutes. The mixture is heated to reflux for 5 hours. The mixture is allowed to cool and is filtered through Celite. The Celite pad is washed with ethyl acetate and methylene chloride. The filtrate is pumped dry and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. 2-Methoxy-5-pyridin-3-yl-benzaldehyde (N1) is obtained (0.635 g, 2.98 mmol; 32% yield).