Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:11][CH:12]=1
Reactant: COC(=O)C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(COc1ccc(CCCCN)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Compound 12 (505 mg, 1.00 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (100 mg) was added. The flask was evacuated, filled with hydrogen gas under balloon pressure and stirred overnight. Filtration through celite to remove the catalyst followed by removal of the solvent under reduced pressure provided compound 13 (366 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 7.08 (d, 2H), 6.80 (d, 2H), 5.51 (d, 1H), 4.66 (m, 1H), 4.38 (m, 1H), 4.17 (m, 1H), 3.78 (s, 3H), 2.73 (m, 2H), 2.58 (m, 2H), 1.90 (br s, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CCC=C2c3cc(OCCN4CCOCC4)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 5-{3-[4-(4-chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.15 g, 0.28 mmol) in DMF (1.5 mL) was added NaH (0.034 g, 0.84 mmol) and stirred for 20 min. at room temperature. 4-(2-Chloro-ethyl)-morpholine HCl (0.063 g, 0.34 mmol) was added and the solution was heated to 50° C. for 16 h. The reaction was quenched with water and extracted with ethyl acetate (3×). The organics were combined, dried over Mg2SO4, filtered and concentrated, then purified by Biotage flash chromatography (5-10% methanol/dichloromethane) to yield the title compound (0.050 g). 1H-NMR (MeOD) δ: 0.73 (3H, s), 0.85 (3H, s), 2.39-2.90 (11H, m), 3.29-3.31 (3H, m), 3.69-3.72 (4H, m), 4.1 (2H, t), 5.20 (2H, br s), 6.18 (1H, t), 6.74-6.79 (2H, m), 6.89 (1H, d), 7.27-7.30 (2H, m), 7.43-7.47 (3H, m), 7.79 (1H, dd), 8.46 (1H, dd). ESI-MS m/z: 604 (M), UV retention time: 1.20 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][C@H:39]2[CH2:44][NH:43][CH2:42][CH2:41][NH:40]2)[CH:34]=[CH:35][CH:36]=1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][C@@H:39]2[NH:40][CH2:41][CH2:42][N:43]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:44]2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc(CC[C@H]2CNCCN2)c1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)c1
Yield: 67.7 %

Procedure:
Using a method similar to Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)2-[2-(3-Methoxy-phenyl)-ethyl]-piperazine (0.65 g, 3.0 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (0.99 g): mass spectrum (APCI+, m/e): 488 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.73–8.49 (m, 2H), 7.21–7.15 (m, 1H), 6.99–6.88 (m, 3H), 6.79–6.69 (m, 4H), 4.25–3.98 (br. m, 2H), 3.70 (s, 3H), 3.38–3.17 (m, 3H), 3.14–2.97 (m, 2H), 2.74–2.52 (m, 2H), 1.90–1.80 (m, 2H).
Reaction SMILES: [C:1]([CH:3]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[N+:21]([O-])=O)C(OCC1C=CC=CC=1)=O)#N.O>[Pd].C(O)C>[CH3:20][C:17]1[CH:16]=[C:15]2[C:14]([CH:3]=[CH:1][NH:21]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1ccc2cc[nH]c2c1
Reaction time: 18 h
Yield: 74 %

Procedure:
a mixture of benzyl 2-cyano-2-(2-nitro-4-methylphenyl)ethanoate (13 mmol), 5% palladium (0.84 g), water (4 mL) and ethanol (40 mL) is hydrogenated under 50 psi for 18 hours at 25° C. The catalyst is eliminated by filtration on celite and the solid is washed with ethanol. The filtrate obtained is evaporated under vacuum and the residue is purified by chromatography on silica gel (eluent: CH2Cl2/pentane, 2/1) in order to produce 6-methylindole with a yield of 74%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[CH:3]=[C:4]([CH3:14])[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:7]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Nc2cc(C)nc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a mixture of 6-chloro-4-methyl-2-(2-pyridinyl)pyrimidine (115 mg, 0.56 mmol),p-anisidine (68 mg, 0.55 mmol) in water (10 mL) was added 2 N HCl (0.3 mL). The mixture was refluxed for 6 h, cooled to room temperature, and neutralized with 2N NaOH to pH 10. The resulting mixture was then extracted with 1:1 Hexane/EtOAc (50 mL). The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:1 Hexane/EtOAc) to yield the product as a tan solid (72 mg, 45%). 1H NMR (CDCl3): 8.80 (d, J=4.5 Hz, 1H), 8.45 (d, J=8.1 Hz, 1H), 7.81 (m, 1H), 7.35 (m, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.12 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.41 (s, 1H), 3.83 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCCCCCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added heptanoyl chloride (0.10 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.10 g (74%) of product as an off-white solid: mp 172-174° C.; 1H NMR (DMSO-d6) 11.05 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.77-2.43 (m, 5H), 2.08-2.03 (m, 1H), 1.90 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 172.12, 172.02, 168.74, 167.36, 136.41, 135.90, 131.20, 125.70, 117.71, 116.31, 58.81, 36.51, 30.93, 29.07, 28.54, 28.12, 24.69, 21.94, 20.98, 13.86; Anal. Calcd. For C21H25N3O5: C, 62.83; H, 6.33; N, 10.47 Found: C, 62.45; H, 6.18; N, 10.24+0.50H2O.
Reaction SMILES: [Na+].[OH:2][C@H:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][C@H:4]1[C:16]([O-:18])=O.O[N:20]1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[NH4+]>CN(C)C=O>[OH:2][C@H:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][C@H:4]1[C:16]([NH2:20])=[O:18]
Reactant: On1nnc2cccnc21
Reactant: O=C([O-])[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.6 %

Procedure:
To a solution of (cis)-4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxylic acid sodium salt (17 g) and 1-hydroxy-7-azabenzotriazole (5 g, 37 mmol) in N,N-dimethylformamide was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (14.1 g, 73.4 mmol), followed by ammonium bicarbonate (21 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was then removed under reduced pressure and the residue was treated with aqueous sodium bicarbonate solution. The aqueous phase was extracted with 9:1 dichloromethane:methanol mixture. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a methanol and dichloromethane gradient (0-20% methanol/dichloromethane). This provided the desired compound (9.5 g, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2ccnc(C(C)(C)O)n2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1c(-c2cc(Nc3ccnc(C(C)(C)O)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 264b (170 mg, 0.50 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (200 mg, 0.50 mmol), Pd(dppf)Cl2 (40 mg, 0.050 mmol), K3PO4 (212 mg, 1.0 mmol), water (0.5 mL), and tetrahydrofuran (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 264c as brown solid (200 mg, 54%). MS-ESI: [M+H]+ 612.3
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1([F:12])[CH2:9][CH:8]1[CH2:10][OH:11].C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([O:11][CH2:10][CH:8]1[CH2:9][C:7]1([F:12])[F:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC1(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (1.43 mL) was added to a solution of (2,2-difluorocyclopropyl)methanol (1.00 g) and triethylamine (2.58 mL) in THF (10 mL) dropwise at 0° C. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.47 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][NH2:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NN
Solvent: O
Solvent: OCCO
Product: COc1ccc(C(=NN)c2sccc2Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture prepared form 18 g of (3-bromothien-2-yl) (4-methoxyphenyl)methanone, 12 ml of hydrazine hydrate (99%) and 120 ml of ethylene glycol was stirred at 120° for 2 hours. Thereafter, the mixture was cooled and diluted with 1000 g of ice water and quickly extracted with ether (3×500 ml). The combined ether solution was washed four times with water to remove unreacted hydrazine and dried over anhydrous magnesium sulfate overnight.
Reaction SMILES: [CH:1]([C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=2)=[N:5][N:4]=1)=O.Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].C([O-])(=O)C.[Na+].C(O)C>CC(C)=O.O>[CH3:26][C:19]1[CH:18]=[C:17]([C:6]2[C:7]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:8]=3[CH2:9][C:3]([CH:1]=[N:28][NH:29][C:30]([NH2:32])=[O:31])=[N:4][N:5]=2)[CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24]
Reactant: NNC(N)=O
Reactant: Cc1cc(C2=NN=C(C=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1cc(C2=NN=C(C=NNC(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of 3.51 g (10.0 millimoles) of 8-formyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine, 1.34 g (12.0 millimoles) of semicarbazide hydrochloride, 1.01 g (12.0 millimoles) of anhydrous sodium acetate and 100 ml of anhydrous ethanol is stirred under boiling for 6 hours. The reaction mixture is evaporated in vacuo, the residue is suspended in 100 ml of water, stirred at room temperature for half an hour, filtered and washed with 25 ml of water. The crude product thus obtained is heated to boiling in 75 ml of acetone for half an hour, cooled with icecold water, the precipitated product is filtered and washed with 10 ml of cold acetone. Thus 3.34 g of the desired compound are obtained, yield 81%, mp.: 260–264° C.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([F:18])[CH:4]([P:6](C(OCC)OCC)(=[O:10])[O:7]CC)[CH3:5].B.C1COCC1.Cl>C1COCC1>[NH2:1][CH2:2][CH:3]([F:18])[CH:4]([PH:6](=[O:7])[OH:10])[CH3:5]
Reactant: CCOC(OCC)P(=O)(OCC)C(C)C(F)C(N)=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C(F)CN)[PH](=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
To an ice bath cooled solution of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxymethyl)phosphinate (1.6 g, 5.3 mmol) in THF (15 ml) was added 1 M BH3-THF (12.3 mL, 12.3 mmol) while under an argon atmosphere. After 10 minutes, the solution was heated to reflux for 3 h. The solution was cooled to room temperature and 6 N HCl (100 mL) was added dropwise. The THF was removed by rotovap and another portion of 6 N HCl (100 mL) was added. The mixture was refluxed for 3 h. The solution was cooled, evaporated, co-evaporated with water and then with etanol. The residue was purified ion exchange chromatography (DOWEX® 50WX-8-200, H+ form, 3.5×4.0 cm). The ion exchange resin was prewashed with 2:1 methanol/water. The crude product dissolved in 1:1 methanol/water was loaded onto the column and washed with 1:1 methanol/water. The eluent was changed to 3:1 methanol/concentrated ammonium hydroxide. The appropriate fractions were combined and evaporated to give 150 mg (15%) of a diastereomeric mixture of (3-amino-2-fluoro-1-methylpropyl)phosphinic acid as an oil. Data: 1H NMR (400 MHz, D2O) δ 6.2-7.8 (m, 1H), 4.8-5.2 (m, 1H), 3.2-3.5 (m, 2H), 1.8-2.2 (m, 1H), 1.0-1.2 (m, 3H); MS: m/z=156 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35](O)=[O:36])[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[C:24]([C:21]1[N:20]=[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[C:18]([C:16]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C@H:10]([C:35](=[O:36])[NH:45][CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])=[CH:23][N:22]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: NCc1ccccn1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[(tert-Butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alanine (40 mg), 1-pyridin-2-ylmethanamine (157 μl) and diisopropylethylamine (330 μl) were dissolved in 1,2-dichloroethane (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (200 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, 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 subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (19 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33](O)=[O:34])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1.Cl.CCOCC>C1COCC1.CN(C=O)C.C(Cl)Cl>[OH:46][NH:45][C:33](=[O:34])/[CH:32]=[CH:31]/[C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][CH:12]3[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]3)=[CH:21][CH:20]=2)=[O:36])=[CH:26][CH:27]=1
Reactant: CN1CCC(Nc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(Nc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-ylamino)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid trifluoroacetate (126 mg, 0.25 mmol), HOBT (40 mg, 0.30 mmol), EDC (58 mg, 0.30 mmol), TEA (0.10 ml, 0.75 mmol) and NH2OTHP (30 mg, 0.25 mmol) in THF (5 ml) and DMF (1 ml), was stirred at room temperature overnight and then partitioned between water and AcOEt. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude product was triturated in CH3CN/MeOH 9:1 and filtered to give a brown powder that was dissolved in DCM and treated with HCl/Et2O for 2 h. The precipitate was filtered off to give 65 mg of (E)-N-hydroxy-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-ylamino)-phenyl]-3-oxo-propenyl}-phenyl)-acrylamide as its hydrochloride salt.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[OH:22].[CH2:23]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH2:29]Br)[CH3:24]>CS(C)=O>[Cl:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:22][CH2:29][CH2:28][O:27][C:26]([NH:25][CH2:23][CH3:24])=[O:31]
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1Cl
Reactant: CCNC(=O)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)OCCOc1ccc(Oc2ccc(F)cc2)cc1Cl
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 1.41 g of potassium tert-butylate in 20 ml of dimethyl sulfoxide is added dropwise with stirring at 10°-15° C. to 2.86 g of 2-chloro-4-(4-fluorophenoxy)phenol in 10 ml of dimethyl sulfoxide. 2.92 g of 2-bromoethyl ethylcarbamate in 10 ml of dimethyl sulfoxide are subsequently added dropwise at room temperature and the mixture is then stirred for 18 hours at 40° C. The reaction mixture is then poured into 300 ml of ice-water and extracted several times using ether. The combined ether phases are washed to neutrality using a small amount of water and dried over sodium sulfate and the solvent is evaporated in vacuo. The crude product is purified on silica gel using diethyl ether/hexane (1:9) as eluent. This gives the title compound of melting point 42°-43° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NC(C)(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-tert-butyl-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:19]([O:21][C:22](=[O:35])[C@@H:23]([O:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[CH2:19]([O:21][C:22](=[O:35])[C@@H:23]([O:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Yield: 151 %

Procedure:
A solution of 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (described in Example 1a) (2.41 g; 8.14 mmole) in acetonitrile (11.8 ml) was added to a mixture of (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoic acid ethyl ester (1.3 g; 5.46 mmole), potassium carbonate (2.26 g; 16.4 mmole) and magnesium sulfate (1 g) in acetonitrile (50 ml). The reaction mixture was refluxed for 19 hours. More of 2-(4-methanesulfonyloxyphenyl)ethyl-methanesulfonate (0.8 g; 2.73 mmole) was added and the reaction mixture was refluxed for another 25 hours. Solid material was filtered off and the solvent was evaporated in vacuo to give 3.6 g of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]-propanoic acid ethyl ester.