Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=[C:5]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[N:4]=1.[NH4+:27].[OH-].C([O-])(O)=O.[Na+]>C(O)C>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:10])[NH:27][CH2:2][C:3]=3[N:4]=2)[CH2:19][CH2:18]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21

Procedure:
Dissolved in 10 ml of ethanol was 2.25 g (6 mmol) of ethyl 4-chloromethyl-2-(4-benzylpiperazino)pyrimidine-5-carboxylate (Referential Example 41), followed by an addition of 10 ml (59 mmol) of a 30% aqueous NH4OH solution at 20° C. The resultant mixture was stirred for 12 hours. The reaction mixture was poured in a 10% aqueous NaHCO3 solution, followed by extraction with CHCl3. The solvent was then distilled off and the residue was recrystallized from toluene.
Reaction SMILES: Cl.[CH:2]1(NN)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])[N:25](CCO)[N:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:3]3[CH2:2][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4]3)[N:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: NNC1CCc2ccccc21
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3Cc4ccccc4C3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-indanylhydrazine hydrochloride as described for compound 35. Crystallized from methanol (2x). M.p. 163°-164° C.
Reaction SMILES: [CH3:1][C:2]1([OH:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][C:2]([CH3:1])([OH:17])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: CC1(O)CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(O)CCN(c2ccc(N)nc2)CC1

Procedure:
A solution of 4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol (807 mg, 3.67 mmol) in methanol (15 ml) was hydrogenated at 50 psi with 10% Pd/C (117 mg, 110 umol) overnight. The catalyst was filtered off and the resultant filtrate was concentrated in vacuo to afford 1-(6-aminopyridin-3-yl)-4-methylpiperidin-4-ol. The product was carried to next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH3:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1ccccc1N
Reactant: CSc1ncnc2cc(N)ncc12
Product: COc1ccccc1Nc1ncnc2cc(N)ncc12
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 46.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (227 mg, 1.18 mmole) and o-anisidine (1.00 mL, 8.87 mmol) is stirred under N2 at 180° C. for 2.5 h. The resulting product is chromatographed over silica gel (5% EtOH/EtOAc) to give 7-amino-4-(2-methoxyanilino)pyrido[4,3-d]pyrimidine (147 mg, 47%) as a yellow solid. 1H NMR (DMSO) δ 9.44 (1H, brs), 9.25 (1H, s), 8.22 (1H, s), 7.54 (1H, dd, J=7.7, 1.4 Hz), 7.24 (1H, ddd, J=8.1, 7.4, 1.5 Hz), 7.10 (1H, dd, J=8.2, 1.2 Hz), 6.98 (1H, dt, Jd =1.3 Hz, Jt =7.5 Hz), 6.52 (2H, brs), 6.41 (1H, s), 3.79 (3H, s).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:1]([C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:25]=[CH:24][O:23][C:22]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1occc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
(4-sulfamoylphenyl) boronic acid (1.76. gm, 8.77 mmol) and Potassium carbonate (2.52 gm, 18.26 mmol) were added to a stirred suspension of ethyl 3-bromofuran-2-carboxylate (Prepared according to the procedure reported in the literature EP1489077A1, 2004, 1.6 gm, 7.30 mmol) in a mixture of 80 ml of ethanol and 20 ml of toluene (80 ml:20 ml) under nitrogen atmosphere at room temperature (25° C.) in a tube. A nitrogen gas was purged to the suspension for 15 minute at room temperature (about 25° C.). To the reaction mixture was then added Tetrakis(triphenyl phosphine) Palladium(0) (0.422 gm, 0.365 mmol) at 25° C. and tube was sealed. The reaction mixture was then stirred at 100° C. for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2×100 ml). The combined organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (11.2 gm), which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.2 g, 55.60%)
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1B(O)O.C(O)(O)=O>C(#N)C.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>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:20]1[CH:19]=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[Cl:14])[C:3]([CH3:13])=[N:4]2
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1cc(F)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 1.0000 g, 4.693 mmol), 2-chloro-5-fluorophenylboronic acid (0.9002 g, 5.163 mmol), tetrakis(triphenylphosphine)palladium (0.2712 g, 0.2347 mmol), and sodium carbonate anhydrous (2.487 g, 23.47 mmol) in acetonitrile-water (3:1) (47.00 mL) was stirred at 100° C. After 3 hs, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline as a red syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1H, dd, J=8.4, 1.4 Hz), 8.03 (1H, dd, J=7.6, 1.4 Hz), 7.88 (1H, dd, J=8.4, 7.6 Hz), 7.75 (1H, dd, J=9.0, 5.1 Hz), 7.61 (1H, dd, J=8.6, 3.1 Hz), 7.46-7.53 (1H, m), 2.54 (3H, s); LC-MS (ESI) m/z 307.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[N:19]3[C:15]([S:16][C:17]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:18]=43)=[N:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:12]2[N:19]3[C:15]([S:16][C:17]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:18]=43)=[N:14][CH:13]=2)[OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(F)c1)c1cnc2sc3c(n12)CCCCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(CCc1cccc(F)c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
A suspension of 3-(3-fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-6, X=3-fluoro), 1.02 g, in THF (100 mL) at −78° was treated with LiAlH4 (0.27 g) and reacted for 18 hours. The mixture was then maintained at −20° for 24 hours and excess reagent was quenched. The mixture was filtered, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with saline, dried and evaporated. The residue (0.30 g) was crystallized from acetonitrile to yield pure α-[2-(3-fluorophenyl) ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol, 0.21 g (m.p. 141-144°), Formula N-7, X=3-fluoro.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:21]=2)[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=2)=[N:8][CH:9]=1)[CH3:3].S(O)(C(F)(F)F)(=O)=O.FC(C(O)=O)(F)F.[OH-].[Na+]>>[NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=2)[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=2)=[N:8][CH:9]=1)[CH3:3]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)N)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a 25 mL round-bottomed flask was added 4-(5-(1-aminoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (150 mg, 0.246 mmol) and 7% TfOH-TFA (5 mL).The solution was heated at 70° C. for minutes. The mixture was cooled to 0° C. and neutralized with 10N NaOH. The obtained suspension was filtered to provide 4-(5-(1-aminoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (80 mg, 88% yield) as a yellow solid. m/z (ESI positive ion): 371 (M+H)+. 1H NMR 400 MHz, DMSO-d6): 6 ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.26 Hz, 3H) 1.75 (br s, 2H) 2.23 (s, 3H) 3.81-3.86 (m, 1H) 7.60 (d, J=61.62 Hz, 2H) 8.09-8.25 (m, 3H) 8.61 (s, 1H) 11.68 (s, 1H).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:14]=[C:15]([CH2:18][C:19]#[N:20])[S:16][CH:17]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:14]=[C:15]([C:18]3([C:19]#[N:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:16][CH:17]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: BrCCOCCBr
Reactant: N#CCc1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: N#CC1(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CCOCC1
Yield: 32.8 %

Procedure:
cis-[4-(Octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-acetonitrile (0.049 g, 0.17 mmol) and 1-bromo-2-(2-bromo-ethoxy)-ethane (0.04 g, 0.17 mmol) and caesium carbonate (1.0 mmol) in DMSO (2 mL) was stirred for 12 hr at room temperature. The mixture was diluted with water (5 mL) and DCM (5 mL). The organic layer was filtered and then evaporated to give an oil which was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.02 g). LCMS m/z 359.24 [M+H]+ RT=10.70 min (Analytical Method 2).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]C(=O)C2C=CC=CC=2)=[O:9])=[CH:5][C:4]([CH3:25])=[N:3]1.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[SH:16])=[CH:5][C:4]([CH3:25])=[N:3]1
Reactant: Cc1cc(NC(=O)c2ccccc2SC(=O)c2ccccc2)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2ccccc2S)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
The thiobenzoic acid S-[2-(2,5-dimethyl-2H-pyrazol-3-ylcarbamoyl)-phenyl]ester (as prepared in step 2 above; 0.966 g, 2.75 mmol) was dissolved in THF (50 mL) and MeOH (100 mL). Under N2(g), a 0.2M solution of NaOH (80 mL) was added and the mixture was stirred for 1.5 h at rt. A saturated solution of NaHCO3(aq) (100 mL) was added and the aqueous layer was extracted with CHCl3 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. The crude mixture was then purified over silica (5% MeOH/CHCl3) to give the title compound in 67% yield (0.455 g, 1.84 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:13].[OH-].[K+].OO.C(OCC)(=[O:20])C>CO>[NH2:7][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[C:5]([OH:13])=[O:20]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Cl)cc2c1NC(=O)C2=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cl)cc(C(=O)O)c1N
Reaction time: 16 h

Procedure:
The 5-chloro-7-methyl-1H-indole-2,3-dione (25.0 g, 0.13 mol), potassium hydroxide (8.4 g, 0.15 mmol) and 30% hydrogen peroxide (21.6 g, 0.18 mol) were mixed together in methanol (300 mL) at 0° C. for 2 h followed by 16 h at room temperature. The solution was poured into ethyl acetate (500 mL) and extracted with I N hydrochloric acid (3×200 mL) followed by brine (1×50 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 2-amino-5-chloro-3-methylbenzoic acid (18.0 g, 0.10 mmol) was isolated as a yellow solid (75% yield). HRMS m/z 185.0238; calcd 185.0244.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH:13]([CH3:14])[C:12]([CH:11]=[O:15])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: C/C=C/C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1Oc2ccc(O)cc2C=C1C=O

Procedure:
The starting material is prepared as follows: A mixture of 2,5-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), crotonaldehyde (3.8 g, 54.3 mmol), and potassium carbonate (10.0 g, 72.4 mmol) in 75 ml of 1,4-dioxane is heated at reflux for 6 hours. The mixture is cooled and poured into water. This is extracted (3×) with dichloromethane, and the combined organic layers are dried (MgSO4) and concentrated to dryness to give 6-hydroxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde as a colored solid. Such is converted to 6-benzyloxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde, m.p. 107°-109° C., which is in turn converted to 3-(N-hydroxyaminomethyl)-6-benzyloxy-2-methyl-2H-1-benzopyran as described above.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>ClC(Cl)C.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@@H]4CO4)c3)noc2c1
Reactant: NCc1cccs1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@@H](CNCc1cccs1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-thiophenemethylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=96%, [M+H]+=399.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C[O:26][CH2:25][CH2:24]1.BrCCO>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:24][CH2:25][OH:26])[CH:17]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1
Agent: OCCBr
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCCO)c2)cc1
Temperature: 25 °C

Procedure:
To a round-bottomed flask, equipped with magnetic stirring and reflux condenser, was added (2E)-3-[4-(tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, Example 23, (200 mg, 0.68 mmol), THF (10 mL), 2-bromoethanol (200 uL, 2.80 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at reflux for 5 h. After allowing to cool to 25° C., the mixture was extracted with EtOAc (20 mL). The organic extract was washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (2:1 hexane:EtOAc) provided the title product as a colorless oil. MS (ESI, pos. ion) m/z: 340 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[C:19]=1[CH3:20])[O:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.O=[C:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28][CH2:27]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:35]([O:34][C:33]([NH:32][CH:29]1[CH2:30][CH2:31][CH:26]([NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[C:19]=2[CH3:20])[O:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:27][CH2:28]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(N)c1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a stirred solution of tert-butyl 3-(3-amino-5-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (0.90 g, 2.67 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (0.741 g, 3.47 mmol) in dichloroethane (10 mL) was added acetic acid (0.96 g, 16.1 mmol) and the mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (1.7 g, 8.0 mmol) was added at 0° C. and the reaction stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure and the crude material purified by column chromatography to afford the title compound (0.9 g, 63%) as a mixture of cis/trans isomers.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:12])[CH3:10].C(N(CC)CC)C.[OH:26][C:27]1[C:28]([C:33](OC)=[O:34])=[N:29][CH:30]=[CH:31][N:32]=1>CS(C)=O>[O:26]=[C:27]1[NH:32][CH:31]=[CH:30][N:29]=[C:28]1[C:33]([NH:8][C@@H:9]([CH3:10])[C:11]([NH:13][C@@H:14]([CH3:15])[C:16]([OH:18])=[O:17])=[O:12])=[O:34]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)c1nccnc1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)c1ncc[nH]c1=O)C(=O)O
Temperature: 40 °C
Reaction time: 17 h
Yield: 8.1 %

Procedure:
In 5 mL of dimethyl sulfoxide is dissolved 0.42 g of L-alanyl-L-alanine trifluoroacetate. Then, 1.07 mL of triethylamine and 0.71 g of methyl 3-hydroxy-2-pyrazinecarboxylate are successively added to the solution, which is then stirred at 40° C. for 17 hours. The solvent is distilled off under reduced pressure, and 2 mL of water was added to the residue thus obtained. The deposited product is collected by filtration and purified by column chromatography [eluent: chloroform:methanol=30:1) to obtain 0.035 g of (2S)-2-[((2S)-2-{[(3-oxo-3,4-dihydro-2-pyrazinyl) carbonyl]amino}-propanoyl)amino]propanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2NCCc3ccccc32)cc1F
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.1019 g, 0.415 mmol) in 3 mL of DCM, 4-fluorophenyl isocyanate (0.0550 mL, 0.484 mmol) was added. The clear solution was stirred for 1 h. The solvent was evaporated and residue was taken into small amount of DCM. The resulting precipitate was collected to yield the title compound as a white solid. The filtrate was concentrated and purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford another batch of the title compound as a white solid. MS (ESI pos. ion) m/z: 383 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.16-7.37 (m, 6H) 6.93-7.13 (m, 5H) 6.54 (s, 1H) 6.40 (s, 1H) 3.66 (t, J=6.28 Hz, 2H) 2.77-3.08 (m, 2H).
Reaction SMILES: CC([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])(C)C.[H-].[Na+]>CN(C)C=O>[C:23]1([CH2:22][C:21]2([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]3[C:6](=[O:5])[O:7]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(O)(Cc2ccccc2)Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC(Cc3ccccc3)(Cc3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.8 %

Procedure:
Bis(1,1-dimethylethyl)2-[1-hydroxy-2-phenyl-1-(phenylmethyl)ethyl]-1,4-piperazinedicarboxylate (2.0 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (20 mL). 60% Sodium hydride (0.19 g, 4.8 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours. The resulting mixture was extracted with ethyl acetate, washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added diisopropyl ether, and the obtained crystals were collected by filtration and washed with diisopropyl ether to obtain the title compound (1.4 g, yield 82%).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([Cl:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: NCc1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)F)c(Cl)c1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (300 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (250 mg, 0.90 mmol, Amine-54) in a similar manner to Intermediate-2.