Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[7-Fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.0 g) was stirred in acetic acid (20 ml) and fuming nitric acid (8 ml) was slowly added. Solution was stirred at ambient temperature for 1 hr and the clear solution was added to ice-water. Light yellow precipitate was separated by filtration to afford the title compound (0.95 g).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)C>Cl>[CH2:14]([CH:5]([CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4]([OH:21])=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(CSc1ccccn1)Cc1ccccc1
Agent: Cl
Product: O=C(O)C(CSc1ccccn1)Cc1ccccc1

Procedure:
903 mg of 2-benzyl-3-(2-pyridylthio)-propionic acid ethyl ester (Example 13c)) are boiled under reflux for 10 hours in 10 ml of 4N HCl. The reaction mixture is extracted with methylene chloride/methanol 10:1. The extracts are adjusted to pH 6 with NaHCO3 solution and subsequently washed with brine, dried with Na2SO4 and concentrated by evaporation. The residue is lyophilised from dioxan/water. Rf (I)=0.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][CH2:43][NH2:44])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:45][C:46]([CH3:48])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.COC(C)(C)C>[CH:46]([NH:44][CH2:43][CH2:42][C@@H:11]1[CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34])([CH3:48])[CH3:45]
Reactant: CC(C)=O
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCNC(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 2-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethylamine in 3 ml of ethanol are added 0.006 ml of acetone, 0.009 ml of acetic acid and 0.032 g of sodium cyano borohydride. The reaction mixture is stirred overnight at room temperature, diluted with tert-butyl methyl ether, washed with 1N sodium hydroxide and the organic phases are combined and dried over sodium sulfate. The crude product is obtained as a turbid yellow oil, which is used in the next step without any further purification. Rf=0.23 (EtOAc-heptane 2:1); Rt=4.59.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:29])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([Br:29])[C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:28][CH2:27][CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCOCC3)cc2)CC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCCC3)cc2)CC1

Procedure:
Same procedure as described for the preparation of compound 82, but using pyrrolidine in place of morpholine.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:25]=[C:26]([NH2:31])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:23][C:24]1[CH:25]=[C:26]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccc(F)c(F)c1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(F)c(F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3,4-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.05 (s, 3H), 2.32 (s, 3H), 4.70 (d, J=5.5 Hz, 2H), 5.87 (bs, 1H), 6.32 (bs, 1H), 6.95-7.05 (m, 2H), 7.16 (t, J=7.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.57-7.66 (m, 2H), 8.58 (d, J=3.6 Hz, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[N:15]([CH2:19][CH3:20])[CH:14]=[C:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2=[O:26].[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCCl>[CH2:19]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([NH:8][CH:28]3[CH2:27][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)=[CH:18][N:17]=2)[C:12](=[O:26])[C:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14]1)[CH3:20]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)c1cn(CC)c2ncc(N)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CC)c2ncc(NC3Cc4ccccc4C3)cc2c1=O
Temperature: 2.5 °C
Reaction time: 0.42 h

Procedure:
1,2-dichloroethane (118.8 L), sodium sulphate (19.3 kg) and ethyl 6-amino-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylate (3.6 kg) were added sequentially to the reactor at 25-30° C. under a nitrogen atmosphere and cooled to 0-5° C. 2-Indanone (1.80 kg) was added to the reaction mixture under stirring at 0-5° C., followed by slow addition of acetic acid (136.8 L) keeping temperature at 0-5° C. The reaction mixture was stirred at 0-5° C. for 10-15 minutes. 13.8 L of sodium triacetoxy borohydride solution (prepared at step 1) was added slowly in three installments of 4.6 L each at 0-5° C. and stirred at 0-5° C. for 2 h. Then, sodium sulphate (10.1 kg) and 2-indanone (878 g) were sequentially added to reaction mixture at 0-5° C. 8.0 L of the sodium triacetoxy borohydride solution (prepared at step 1) were slowly added to the reaction mixture at 0-5° C. and the reaction mixture was maintained at 0-5° C. for 10-12 h. The reaction progress was monitored by TLC for disappearance of starting material. After the completion of reaction (15 h), solvents were removed under vacuum below 60° C. and the reaction mass was cooled to 25-30° C. Dichloromethane (72.0 L) was added to reaction mixture with stirring at 25-30° C. and stirring was continued for 20-30 minutes. Then, reaction mixture pH was adjusted to 7-8 with aqueous sodium bicarbonate solution (prepared by dissolving 36 kg of sodium bicarbonate in 324 L of water) and the reaction mixture was stirred at 25-30° C. for 10-15 minutes. Two layers were allowed to separate over 15-20 minutes and then the organic layer was separated. Aqueous layer was washed with 36 L of dichloromethane twice and all organic layers were pooled, washed twice with water (2×36 L) and with aqueous sodium chloride solution (prepared by dissolving 7.2 kg of sodium chloride in 28.8 L of water); and finally dried over anhydrous sodium sulphate (1.8 kg) at 25-30° C. by stirring for 15-20 minutes. The solution was filtered through a Nutsche filter. The filtrate was transferred to a reactor and solvents were distilled under vacuum below 40° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]#[N:18])=[CH:11][C:10]=1[CH3:19]>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:16][C:17]#[N:18])[C:5](=[O:7])[CH3:6])=[CH:11][C:10]=1[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(NCC#N)ccc1Br
Product: CC(=O)N(CC#N)c1ccc(Br)c(C)c1
Temperature: 115 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Acetic anhydride (4.99 ml) was added to (4-bromo-3-methyl-phenylamino)-acetonitrile (594 mg, 2.64 mmol), and the mixture was heated with stirring at 115° C. for one hour. The reaction solution was cooled and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-(4-bromo-3-methyl-phenyl)-N-cyanomethyl-acetamide (697 mg, 99%).
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[CH:36]=[C:35](Cl)[CH:34]=[CH:33][C:7]=1[CH2:8][NH:9][C:10]([C:12]1[C:13](=[O:32])[NH:14][N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)[CH:17]=1)=[O:11]>CO.[OH-].[Pd+2].[OH-]>[CH2:8]([NH:9][C:10]([C:12]1[C:13](=[O:32])[NH:14][N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH:17]=1)=[O:11])[C:7]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:6]=1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(NCc1ccccc1)c1cc(-c2ccc(O)cc2)n[nH]c1=O
Yield: 8.2 %

Procedure:
0.525 g of ammonium formate and 0.022 g of palladium hydroxide were added to 0.4 g of N-(2,4-dichlorobenzyl)-3-oxo-6-[4-(benzyloxy)phenyl]-2,3-dihydropyridazine-4-carboxamide dissolved in 10 cm3 of methanol. The reaction medium was heated and maintained at reflux for 2 hours. After cooling, the reaction medium was suction-filtered through a sinter funnel and the insoluble material was rinsed again with three times 10 cm3 of hot methanol. The organic phase was evaporated under reduced pressure (2 kPa; 45° C.). The residue was recrystallized from methanol. After filtration through a sinter funnel, washing with twice 10 cm3 of methanol and oven-drying under reduced pressure (10 kPa; 50° C.), 0.022 g of N-benzyl-3-oxo-6-[4-(hydroxy)phenyl]-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a yellow solid melting at a temperature above 260° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[NH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1.CCCCCC>C(OCC)(=O)C>[Br:29][C:25]1[CH:24]=[C:23]([NH:22][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([NH:9][C:5](=[O:6])[CH2:4][C:2](=[CH2:3])[C:1]([OH:7])=[O:8])[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=C1CC(=O)OC1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
Itaconic anhydride (0.1 4 g, 1.25 mmol) was added portionwise to a solution of 0.1 g (0.30 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2 mL of ethyl acetate under N2. After stirring at room temperature overnight, the reaction solution was added into ice water and hexane. The product was collected, washed with water, ether and hexane, and dried in vacuo to give 0.09 g (68%) of yellowish brown solid; ESMS m/z 451.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][F:30])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][F:30])[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[S:14]2)[C@H:10]1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Yield: 66.8 %

Procedure:
A mixture of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (600 mg, 1.10 mmol), KHCO3 (495 mg, 4.95 mmol), TBAB (18 mg, 0.06 mmol) and TEMPO (9 mg, 0.06 mmol) in dichloromethane (17 mL) and water (2 mL) was treated with NBS (215 mg, 1.21 mmol) for 15 min at 10-15° C. The reaction mixture was quenched by saturated aqueous Na2SO3 (5 mL), extracted with dichloromethane (3×15 mL), dried over magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 20% ethyl acetate in petroleum ether to provide compound 72 as a yellow syrup (0.4 g, 67%). (ES, m/z) [M+H]+ 545.0; 1H NMR (300 MHz, CDCl3) δ 9.64 (s, 1H), 7.23-7.39 (m, 10H), 6.09-6.11 (d, J=6.3 Hz, 1H), 4.55-4.75 (m, 5H), 4.34-4.45 (m, 2H), 4.13-4.28 (m, 3H), 3.90-4.12 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8](=[O:40])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8](=[O:40])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][N:34]5[CH2:35][CH2:36][N:37]([C:2]([O:4][CH3:5])=[O:3])[CH2:38][CH2:39]5)[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl chloroformate (11 μL) is added to a solution of {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (60 mg) and triethylamine (68 μL) in dichloromethane (2 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature for 2 h. Water is added and the resulting mixture is extracted with dichloromethane. The combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on reversed phase (HPLC; acetonitrile/water) to give the title compound. LC (method 4): tR=0.99 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]([O:30][P:31]([CH:34]([NH:38][C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]([CH3:37])[CH3:36])([OH:33])=[O:32])([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[CH2:16][CH2:15]1)=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]([O:30][P:31]([CH:34]([NH:38][C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]([CH3:36])[CH3:37])([OH:33])=[O:32])([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)OC1(C(=O)OCc2ccccc2)CCN(CCNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)OC1(C(=O)O)CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The benzyl 1-(2-benzyloxycarbonylaminoethyl)-4-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylate (56 mg) obtained in the above step (f) was dissolved in a mixed solvent of dioxane (1.5 ml) and water (0.5 ml), and then the solution was added with palladium hydroxide (13 mg). The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered with celite, and then the solvent was evaporated. The residue was purified with HP-20 (Diaion, 40 cc, methanol:water=1:1 to acetone:water=1:4)) to obtain the title compound:1-(2-aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid (32 mg, 84%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][C:17]([F:20])([F:19])[C:11]2(SCCCS2)[C:10]([F:22])([F:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni]>[CH2:1]([N:8]1[CH2:9][C:10]([F:21])([F:22])[CH2:11][C:17]([F:20])([F:19])[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC1(F)CN(Cc2ccccc2)CC(F)(F)C12SCCCS2
Agent: [Ni]
Product: FC1(F)CN(Cc2ccccc2)CC(F)(F)C1

Procedure:
React 4.0 mmol of the product of Example 29 with Raney nickel according to the general procedure set forth in Example 23 and purify by silica gel chromatography using methylene chloride/methanol/saturated NH4OH as eluant to yield the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C[O-].[Na+].[C:19](#[N:22])[CH:20]=[CH2:21]>N1C=CC=CC=1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH:15][CH2:21][CH2:20][C:19]#[N:22])=[N:12][O:13][N:14]=1
Reactant: C=CC#N
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To an ice-cooled, stirred solution of 18.2 g of 4-(1H-benzoimidazol-2-yl)-furazan-3-ylamine (90.5 mmol, 1 eq) in 240 ml of pyridine are added 30 ml of sodium methoxide solution (30% in MeOH) (163 mmol, 1.8 eq) and subsequently 6 ml of acrylonitrile (90.5 mmol, 1 eq). The reaction mixture is stirred at room temperature overnight, before it is concentrated under reduced pressure. The residue is suspended in 250 ml of water and extracted with 4×400 ml of ethyl acetate. The combined organic layers are washed with 2×500 ml of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is dissolved in about 1000 ml of refluxing ethyl acetate. Then 1700 ml of n-hexane are added to the solution. The resulting turbid mixture is allowed to stand at room temperature overnight and the formed precipitate is filtered to provide 11.1 g of the product as light yellow solid. The filtrate is concentrated to dryness under reduced pressure and the residue is suspended in 100 ml of a 1/1 mixture of n-hexane/ethyl acetate. The suspension is filtered to provide 4.7 g additional product.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 62a, a mixture of acryloyl chloride (58.2 g) was added to 1-(4-chlorophenyl)ethylamine (100 g) and triethylamine (65.2 g) in dichloromethane (400 ml) to give N-[1-(4-chlorophenyl)ethyl]acrylamide, m.p. 103°-104° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(CC)CC.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 75.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (4.43 g, 20 mmol) and Et3N (3 mL, 22 mmol) in THF (100 mL), chloroacetyl chloride (1.6 mL, 20 mmol) was added dropwise with stirring. The solvent was evaporated in vacuo. The residue was slurred with water, filtered, and dried. The solid was dissolved in hot toluene (300 mL), treated with silica gel, filtered and left to recrystallize to afford 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (4.5 g, 76% yield). LCMS calculated for C16H12ClN3O (M+H): 298.75. found 298.06. 1H-NMR (400 MHz, DMSO-d6) δH: 10.6 (1H, br. s), 9.52 (1H, s), 8.54 (1H, m), 8.20-8.05 (3H, m), 7.90-7.70 (3H, m), 7.62-7.51 (1H, m), 4.31 (2H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[S:13][CH:14]=[CH:15][N:16]=3)O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccc2occc2c1)c1nccs1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: c1csc(Cc2ccc3occc3c2)n1

Procedure:
Under argon at 24° C., crude benzofuran-5-yl(thiazol-2-yl)methanol (2.50 g, 10.8 mmol) was dissolved in 1,2-dichloroethane (40 mL), treated with triethylsilane (3.14 g, 27.0 mmol) and trifluoroacetic acid (1.25 mL, 16.2 mmol), and heated to reflux for 20 h. The mixture was diluted with EtOAc and ice, washed 1× with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated. Purification by flash chromatography (hexanes to hexanes/EtOAc=3:2) gave 2-(benzofuran-5-ylmethyl)thiazole as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=3.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.55 (br. s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.27-7.24 (m, 1H), 7.19 (d, J=3.3 Hz, 1H), 6.74-6.73 (m, 1H), 4.44 (s, 2H). MS (ESI) m/z: Calculated: 215.0; Observed: 216.1 (M++1).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C:8]#[C:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:5]1=[O:17])[CH3:3].FC(F)(F)C(O)=[O:21].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:21])[NH:6][C:5]1=[O:17])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1C#CSc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution of 718 mg of (3S, 4S)-3-[(R)-1-hydroxyethyl]-4-[(phenylthio)ethynyl]-2-azetidinone in 8 ml of anhydrous methylene chloride was added, under an atmosphere of nitrogen gas, 1.1 ml of trifluoroacetic acid, with stirring and ice-cooling. The mixture was then stirred for 30 minutes under ice-cooling and for a further 1.5 hours at room temperature. The reaction mixture was then poured into a mixture of 2.44 g of sodium bicarbonate, 15 ml of water and 30 ml of ethyl acetate. The mixture was saturated with sodium chloride and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer and the ethyl acetate extracts were combined, and the combined solution was washed successively with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography through silica gel, eluted with a 1:3 by volume mixture of cyclohexane and ethyl acetate, to give 281 mg (yield 36.5%) of the title thioester compound, which was recrystallized from a mixture of ethyl acetate and hexane to give crystals melting at 121.5-123.5° C.