Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1[C:20]2[C:15](=[C:16]([CH2:21][C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>>[CH:11]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]([NH:1][C:2]3[S:6][CH:5]=[N:4][C:3]=3[C:7]([O:9][CH3:10])=[O:8])=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: COC(=O)c1ncsc1N
Product: COC(=O)c1ncsc1NC(=O)Cc1cccc2cnccc12

Procedure:
Methyl 5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxylate was prepared from methyl 5-aminothiazole-4-carboxylate (0.132 g, 0.834 mmol) and 2-(isoquinolin-5-yl)acetic acid (0.163 g, 0.834 mmol) according to protocol A. Retention time (min)=2.400, method [3], MS(ESI) 328.0 (M+H).
Reaction SMILES: [K].C([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]CC)=O)[CH2:9]1)(OCC)=O.Cl.CCCCCC(=O)CC>C1(C)C=CC=CC=1.CCCCCC.C(O)C>[N:8]12[CH2:9][CH:10]([C:14](=[O:16])[CH2:7]1)[CH2:11][CH2:12][CH2:13]2
Reactant: CCOC(=O)CN1CCCC(C(=O)OCC)C1
Agent: CCCCCC(=O)CC
Agent: Cl
Agent: [K]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CN2CCCC1C2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of ethanol (9 ml) and toluene (10 ml) was added dropwise to a rapidly stirred suspension of potassium (6 g) in toluene (30 ml). at 120° C. After all the ethanol had been added the reaction mixture was stirred at 120° C. for 1 hr before adding a solution of 1-carboethoxymethyl-3-carboethoxy piperidine (15 g, 61.7 mmol) in toluene (40 ml) dropwise at 140° C. The reaction mixture was heated for 3 hr at 140° C. before adding concentrated hydrochloric acid (3×50 ml), and refluxing the aqueous phase for 16 hr. The solvent was removed in vacuo, water (100 ml) added and the solution neutralised with potassium carbonate. The solution was extracted with dichloromethane (3×150 ml, the combined extracts washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated. The crude product was chromatographed through slicia-gel, eluting with dichloromethane/methanol (90:10) to give 1-azabicyclo[3:2:1]octan-6-one as a crystalline solid (1.1 g): mp. 83°-87° (hexane): m/e 125 (M+): δ(360 MHz, CDCl3) 1.30-2.40 (5H, m, 2×CH2, and CH): 3.12 (2H, s, CH2 --N); 2.60-3.60 (4H, m, 2×CH2 --N).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[CH2:19]/2)=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C>CN(C=O)C>[NH2:27][CH2:26][CH2:25][N:17]1[C:18](=[O:20])[CH2:19]/[C:15](=[CH:14]\[C:13]2[CH:22]=[CH:23][C:10]([O:9][CH2:7][CH3:8])=[CH:11][CH:12]=2)/[C:16]1=[O:21]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOc1ccc(/C=C2\CC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(/C=C2\CC(=O)N(CCN)C2=O)cc1
Reaction time: 0.33 h

Procedure:
Potassium carbonate (180 mg, 1.30 mmol) was added to a solution of compound 12 (100 mg, 0.43 mmol) in 3 mL of anhydrous DMF at 0° C. After stirring the reaction mixture for 20 min, a solution of tert-butyl (2-bromoethyl)carbamate (96 mg, 0.43 mmol) in anhydrous DMF (1 mL) was added and then the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NH4Cl aqueous solution followed by water and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% ethyl acetate in hexanes) to afford 70 mg (43.2%) of Boc-protected 13 as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=O)([O-])=O.CC(O)=O>[Pd].CO>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:13][C:14](=[O:16])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)NC(=O)C2
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A solution of 2-(2,4-dinitrophenyl)acetic acid (1.0 g, 4.42 mmol), AcOH (10 mL), and MeOH (5 mL) was purged with Ar for 15 minutes at which time 10 wt. % Pd/C (100 mg) was added. The mixture was then purged briefly with H2 and then stirred under 1 atm of H2 overnight. The mixture was filtered through a pad of celite, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 90:10 CH2Cl2/MeOH) to give 462 mg, 71% of a brown solid. 1H NMR (400 MHz, CD3OD) δ 6.95 (d, J=7.7 Hz, 1H), 6.37 (d, J=7.8 Hz, 1H), 6.34 (s, 1H), 3.38 (s, 2H); MS ESI 149.0 [M+H]+, calcd for [C8H8N2O+H]+149.07.
Reaction SMILES: Cl[CH:2]([OH:5])[CH2:3][CH3:4].[N+:6]([C:9]1([N+:13]([O-:15])=[O:14])[CH2:12][NH:11][CH2:10]1)([O-:8])=[O:7].[OH-].[Na+]>>[CH2:4]([N:11]1[CH2:12][C:9]([N+:13]([O-:15])=[O:14])([N+:6]([O-:8])=[O:7])[CH2:10]1)[CH:3]1[O:5][CH2:2]1
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Reactant: CCC(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1([N+](=O)[O-])CN(CC2CO2)C1

Procedure:
reacting 1-chloropropanol-3,3-dinitroazetidine of Formula IV prepared in step (1) with aqueous solution of NaOH to obtain 1-glycidyl-3,3-dinitroazetidine of Formula I, as shown in the following reaction scheme 2-2.
Reaction SMILES: Br[C@@H:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:3]C.[C-:13]#[N:14].[K+].[CH3:16]S(C)=O>>[F:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C@H:2]([CH3:3])[CH2:16][C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: [C-]#N
Reactant: CS(C)=O
Reactant: CC[C@@H](Br)Oc1ccc(F)cc1
Agent: [K+]
Product: C[C@H](CC#N)Oc1ccc(F)cc1
Yield: 54.6 %

Procedure:
To a stirred solution of the bromide 5 (12.82 g, 55 mmol) dissolved in DMSO (60 mL) was added dry KCN (1.95 g, 30 mmol), and the reaction mixture was stirred at 40° C. for 3.5 hours until the KCN powder had disappeared. The reaction was quenched with saturated aqueous NH4Cl solution (150 mL). After extraction with ethyl acetate, the combined organic layers were washed with 1N NaOH, water, and brine. After drying over Na2SO4, the organic layer was filtered and ethyl acetate was evaporated in vacuo. The residue was then vacuum distilled at 130-135° C. at 1.0 mm Hg to give 5.35 g (54.6%) of product as a colorless oil. Further distillation yielded 5.8 g (45.2%) of recovered bromide 5. 1H NMR (CDCl3) δ 7.01-6.98 (m, 2H), 6.90-6.87 (m, 2H), 4.55-4.52 (m, 1H), 2.68 (d, J=5.5 Hz, 2H), 1.48 (d, J=6.5 Hz, 3H). EI-MS (m/z) 179 (M++1). The reaction is shown as follows.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:23])=[O:22]
Reactant: OCCCCc1cccc(I)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CS(=O)(=O)OCCCCc1cccc(I)c1

Procedure:
4-(3-Iodophenyl)butan-1-ol (1.7 g) was stirred with diisopropylamine (1.74 ml) and methanesulfonyl chloride (0.66 ml) in dichloromethane (50 ml) at 21° for 2 h. The solution was washed successively with sodium bicarbonate solution, water, water acidified with a few drops of 2M HCl and water, each time back extracting with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to give the title compound (2.23 g), tlc Rf=0.28 (1:3 ethyl acetate in cyclohexane)
Reaction SMILES: C(OCC)(=O)C.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[CH3:15][N:16]([CH3:18])[CH3:17]>>[Br-:7].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: BrCCCCCCBr
Reactant: CN(C)C
Solvent: CCOC(C)=O
Product: C[N+](C)(C)CCCCCCBr
Product: [Br-]
Temperature: 60 °C

Procedure:
494 kg (5606 mol) of ethyl acetate and 244 kg (1000 mol) of 1,6-dibromohexane were charged into a reactor with stirring and simultaneous heating to 60° C. 64 kg (1080 mol) of trimethylamine were metered in at 1 bar in the course of 3 hours. After an after-reaction time of a further 3 h, the reaction mixture was cooled and filtered through a suction filter and the crystallizate obtained was washed with ethyl acetate. After drying had taken place, 288 kg (95.1%) of (6-bromohexyl)trimethylammonium bromide of 99.8% purity were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13](Cl)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13]([N:21]([CH3:20])[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18]
Reactant: CNCCN(C)C
Reactant: Cn1c(-c2nnc3ccc(Cl)nn23)cnc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc2nnc(-c3cnc([N+](=O)[O-])n3C)n2n1

Procedure:
0.65 g. 3-(1-methyl-2-nitro-5-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were reacted in 13 ml. dimethyl formamide with 0.5 g. trimethylethylenediamine at 60° C. for 15 minutes. After working up the reaction mixture in a manner analogous to that described in Example 47, there was obtained 0.6 g. (75 percent of theory) of the desired 3-(1-methyl-2-nitro-5 -imidazolyl)-6-[N-methyl-N-(β-dimethyl-aminoethyl)-amino] -s-triazolo[4,3-b]pyridazine in the form of yellow crystals which have a melting point of 196° - 198° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]([NH:23][C:24]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)[CH2:27]3)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24]([NH:23][CH:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=4)[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])=[O:25])[CH2:27]2)=[O:48])[CH2:36][CH2:37]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(OCCF)cc2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cncc(-c4ccc(OCCF)cc4)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
76 mg (0.11 mmol) tert-butyl 4-(3-{(3R)-3-[(1-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate were dissolved in 14 ml methanol. 358.5 mg (1.14 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 20 hours and then concentrated to give 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:5][C:4]=1F)#[N:2].Cl.[NH2:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1.[H-].[Na+].CC(O)=O>CS(C)=O>[C:1]([C:3]1[C:4]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)=[CH:5][C:6]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1cc(N)sn1
Reactant: CC(C)C[C@@H](Nc1cc(F)c(C#N)c(F)c1)C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C#N)sn1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of (R)-2-(4-cyano-3,5-difluorophenylamino)-4-methylpentanamide (92 mg, 0.34 mmol) and 5-amino-3-methylisothiazole hydrochloride (70 mg, 0.46 mmol) in DMSO (2 mL), NaH (60% in mineral oil, 80 mg, 2.00 mmol) was added. H2 gas evolved. The mixture was stirred at 130 C for 1 h. After being acidified with HOAc (1.0 mL), the mixture was purified by HPLC to give (R)-2-(4-cyano-3-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (38 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:13]([OH:15])C.Cl.C[NH:18]O.N1C=CC=CC=1>C(#N)C>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[N:18][O:15][CH3:13])[C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH3:10]
Reactant: CCO
Reactant: CNO
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)C(=NOC)C(=O)OCC
Temperature: 78 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
Combine diethylketomalonate (50 g, 0.287 mol) in 3A ethanol (250 mL) and add N-methylhydroxylamine-HCl (23.9 g, 0.287 mol). Add pyridine (22.7 g, 0.287 mol) and heat to reflux (78° C.) the colorless homogeneous solution with stirring under nitrogen for approximately 2.5 hours before cooling to ambient temperature. Stir at ambient temperature for approximately 48 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Concentrate the reaction mixture in vacuo to a wet, waxy white solid and partition between 100 mL of EtOAc and 100 mL of H2O. Extract the aqueous layer with 3×100 mL portions of EtOAc. Combine the EtOAc layers, wash with 100 mL of brine, dry over MgSO4, filter, and evaporate down to a yellow oil. Absorb the crude product onto silica gel 60 (Merck, 230-400 mesh) and elute with 4 L of a 9:1 hexanes:EtOAc solution as eluent. Evaporate the eluent in vacuo to afford 56.3 g (96.6% yield) of the title compound as a pale yellow homogeneous oil; 1H NMR (300 MHz, CDCl3) δ 4.29 (m, 4H), 4.05 (s, 3H), 1.259 (t, 6H, J=7.32 Hz); 13C NMR (75 MHz, CDCl3) δ 159.9, 158.9, 143.3, 64.2, 62.3, 62.1, 13.7; IR (CHCl3) 3029, 2986, 2944, 1744, 1605, 1329, 1301, 1264, 1237, 1103, 1043 cm−1; UV (EtOH) λmax 231 nm (ε 8582); HRMS (ES) exact mass calc'd for C8H13NO5 203.0794, Found 203.0797. Anal. calc'd for C8H13NO5: C, 47.29; H, 6.45; N, 6.89. Found: C, 46.28; H, 6.36; N, 4.86.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1c(F)cccc1F
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1c(F)cccc1F
Temperature: 4 °C
Yield: 48.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (12.1 g), N,N'-carbonyldiimidazole (12.3 g) and 2-amino-7-chloro-1,8-naphthyridine (8.5 g). The product produced by precipitation in water (6.8 g; m.p. 215° C.) is dissolved in boiling ethanol (450 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration washed with ethanol (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-2,6-difluorobenzamide (7.3 g) is produced, m.p. 242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11].C1C=C(O[C:19](OC2N=CC=CC=2)=[S:20])N=CC=1>ClCCl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11])=[C:19]=[S:20]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2ocnc12
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2ocnc12
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of 5-amino-4-methylbenzoxazole (0.59 g, 3.98 mmol) in dichloromethane (100 mL) is treated with di-2-pyridyl thionocarbonate (1.02 g, 4.39 mmol). The mixture is stirred for two hours. The reaction mixture is concentrated under reduced pressure to yield a brown residue. This material is purified by chromatography (silica-gel, 20% ethyl acetate/hexanes) to afford 0.68 g of 5-isothiocyanato-4-methylbenzoxazole as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+]>C1COCC1.O>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:4]([C:3]([OH:30])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N)cc3)C(=O)O)CCCC2)cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (280 mg, 0.68 mmol) in THF (12 mL) was treated with a solution of lithium hydroxide hydrate (100 mg, 2.4 mmol) in water (2 mL) and the mixture was stirred for 3 hr. The mixture was concentrated and the residue was acidified with 6 H HCl to give a white sticky solid. Trituration with water and drying under high vacuum afforded crude 4-amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (200 mg) suitable for use in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22]C)[CH3:20].ClC(OC1C=CC=CC=1)=[O:28].N1CCCC1>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:22]([N:21]2[CH2:24][CH2:25][CH2:20][CH2:19]2)=[O:28])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Yield: 70.7 %

Procedure:
To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylamine (1.00 g) in tetrahydrofuran (50 ml) was added triethylamine (1.14 ml), and then phenyl chloroformate (0.768 ml) was added dropwise thereto while stirring in an ice bath, followed by stirring for 1.5 hrs. Phenyl chloroformate (0.252 ml) was further added thereto while stirring in an ice bath, followed by stirring for 0.5 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (20 ml) and pyrrolidine (1.36 ml) were added, followed by stirring at room temperature for 0.5 hr. The reaction mixture was partitioned between ethyl acetate (150 ml) and water (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=2:1 to 1:1, then ethyl acetate) to provide the titled compound (988 mg, 70.7%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:7].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Product: [Br-]

Procedure:
The 3,5-dimethoxybenzyl triphenylphosphonium bromide is prepared by refluxing a mixture of 3,5-dimethoxybenzyl bromide (12 g.) and triphenylphosphine (14.2 g.) in acetonitrile (200 ml.) for one hour. The reaction mixture is then cooled and the crystalline product recovered by filtration, washed with ether and dried (20 g.); m.p. 269°-270° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[O:11]=[C:10]1[NH:6][CH2:7][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:9]1
Reactant: COc1ccc(CN2C[C@@H](C(=O)O)CC2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C[C@H](C(=O)O)CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (5.3 g) were added anisole (3.1 ml) and trifluoroacetic acid (26.5 ml) at room temperature, and the mixture was stirred for 4 hours at reflux. This reaction solution was cooled to room temperature, concentrated under reduced pressure, azeotropic-dried with toluene. To the resulting residue was added diisopropyl ether (53 ml), and the mixture was stirred at room temperature. A solid was collected from this suspension by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the titled compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cc(F)cc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cc(F)cc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3,5-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: CO[C:3]1[CH:4]([CH3:10])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH3:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:3]1=[NH:12]
Reactant: COC1=NCCCCC1C
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: CC1CCCCNC1=N
Product: Cl
Yield: 79.9 %

Procedure:
The product of EXAMPLE 44 (294 mg, 2.1 mmol) in 14.5 mL of MeOH was reacted with ammonium chloride (103 mg, 2.0 mmol) by the method of EXAMPLE 27 to yield 260 mg (77%) of the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8]C2CCNCC2)=[CH:4][C:3]=1[N+:17]([O-])=O.O.O.[Sn](Cl)Cl.[CH3:25][CH2:26]O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:17]2[CH2:26][CH2:25][CH2:16][CH2:2][CH2:3]2)=[CH:4][C:3]=1[NH2:17]
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(OCCC2CCNCC2)ccc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 19 h
Yield: 92 %

Procedure:
4-(2-(4-chloro-3-nitrophenoxy)ethyl)piperidine (2.3 g, 8.1 mmol, 1 eq.) and tin (II) chloride dihydrate (9.1 g, 40.4 mmol, 5 eq.) were placed in EtOH (81 mL). The reaction mixture was heated at 60° C. and stirred for 19 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-5-(2-piperidinoethoxy)aniline (1.9 g, 92%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[Br:7].CCCCCC.[Li]CCCC.[CH3:20][C:21]([CH3:23])=[O:22]>CCOCC>[Br:7][C:6]1[CH:5]=[C:4]([Br:8])[S:3][C:2]=1[C:21]([OH:22])([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: Brc1cc(Br)c(Br)s1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(O)c1sc(Br)cc1Br
Reaction time: 0.17 h

Procedure:
A solution of 2,3,5-tribromothiophene (8.17 g, 25 mmol) in Et2O (N2 atmosphere) was cooled to −78° C. and treated with a 1.6 M hexane solution of nBuLi (15.6 mL, 25 mmol). The mixture was then stirred for 10 minutes, then treated with acetone (1.84 mL, 25 mmol). The mixture was then stirred for 30 minutes and quenched with H2O. The mixture was extracted with Et2O; the organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. The residue was filtered through a plug of silica gel (gradient elution from hexanes to EtOAc) to provide the title compound.