Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1nc2ccccc2s1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 38.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (266 mg, 1.40 mmol) and 2-(but-3-ynyl)benzo[d]thiazole (compound 35(A), 260 mg, 1.40 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 80/20 as eluent) to afford 160 mg of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole (Yield: 38%) as a beige powder (Mp=74-76° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:18][C:13]4([CH2:17][CH2:16][NH:15][CH2:14]4)[CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=2)=[N:3][CH:2]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34].[Cl-].[NH4+]>O1CCCC1>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([N:15]1[CH2:16][CH2:17][C:13]2([CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]3[NH:18]2)[CH2:14]1)=[O:34]
Reactant: O=c1cc(-c2ccncn2)nc2n1CCC1(CCNC1)N2
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccc(F)c1)N1CCC2(CCn3c(nc(-c4ccncn4)cc3=O)N2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 0.3 g (1.055 mmol) of 8-pyrimidin-4-yl-3,4-dihydrospiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one dissolved in 5 ml of tetrahydrofuran at room temperature were added 0.18 ml (1.27 mmol) of triethylamine and 0.152 ml (1.27 mmol) of 3-fluoro-benzoyl chloride. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction mixture was added to a saturated aqueous solution of ammonium chloride, extracted with a mixture of dichloromethane/methanol in the proportions of 100/0 to 80/20, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions of 100/0 to 70/30 to give 0.310 g (72%) of pure product as grey solid. Mp: 296-298° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8](OCC)OCC)(=[O:7])[OH:6].[CH2:15]([SH:18])[CH2:16][SH:17].Cl>C(O)(=O)C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8]1[S:18][CH2:15][CH2:16][S:17]1)(=[O:7])[OH:6]
Reactant: CCOC(OCC)P(=O)(O)CCCN
Reactant: SCCS
Agent: Cl
Solvent: CC(=O)O
Product: NCCCP(=O)(O)C1SCCS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.90 g (4.0 mmol) of 3-aminopropyl(diethoxymethyl)phosphinic acid in 10 ml of glacial acetic acid at 0° there are added 0.38 ml (4,4 mmol) of ethane-1,2-dithiol, followed by addition of 2 ml of concentrated hydrochloric acid over a period of 5 min. The mixture is allowed to warm to room temperature and is then stirred for 18 hours. After removal of acetic and hydrochloric acids under high vacuum, the residue is chromatographed (Opti-Up® C12 50%, water) and recrystallized from methanol to yield 3-aminopropyl(1,3-dithiolan-2-yl)phosphinic acid, m.p. 272°-274°.
Reaction SMILES: ClC1C=CC=CC=1N1C(C2C=CC(S(C)(=O)=O)=CN=2)=NN=C1C=CC1[O:29][C:28]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[N:27][N:26]=1.NN.O>CO>[C:34]([C:33]1[CH:32]=[CH:31][C:30]([C:28]([NH:27][NH2:26])=[O:29])=[CH:37][CH:36]=1)#[N:35]
Reactant: CS(=O)(=O)c1ccc(-c2nnc(C=Cc3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-Cyano-benzoic acid methyl ester 1 (1.0 g, 13 mmol) in 30 mL of MeOH was added 3 mL of H2NNH2.H2O. The mixture was stirred at ambient temperature for 16 h. The solid was collected and washed with CH3OH to give 4-Cyano-benzoic acid hydrazide 2 as a solid. Yield: 0.8 g, 80%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4][N:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>[Pd].CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1CNCCN1C(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
A mixture of 85 parts of (1,1-dimethylethyl) 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 55 parts (94.6%) of (1,1-dimethylethyl) 2-methyl-1-piperazinecarboxylate as a residue (int. 42).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH2:18]([Sn](CC=C)(CC=C)CC=C)[CH:19]=[CH2:20].B(F)(F)F.CCOCC.[F-].[K+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]([CH2:20][CH:19]=[CH2:18])([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: C=CC[Sn](CC=C)(CC=C)CC=C
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Agent: FB(F)F
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to 0° C. before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at 0° C. for 1 h and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in 5 mL water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water (100 mL) and brine 100 mL), dried over MgSO4 and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 50% EtOAc in hexanes to obtain 4-allyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.94 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cn2)CC1
Yield: 53.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (350 mg) described in Preparation Example 151 and (R)-4-methyloxazolidin-2-one (97 mg) described in Preparation Example 25, the title compound (197 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20]C)=[O:19])=[CH:7][C:6]=2[CH:22]=1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][C:8]([C:18]([OH:20])=[O:19])=[CH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2cccs2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=Cc2cc(Br)ccc2N(Cc2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of methyl 7-bromo-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (810 mg) in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was added 1N sodium hydroxide solution (21 ml), and the mixture was stirred at room temperature overnight. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-bromo-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (574 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>O1CCCC1.O>[OH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Yield: 96.7 %

Procedure:
To a solution of 2-amino-1,3-benzothiazol-6-ol (9.03 g, 54.3 mmol) and triethylamine (8.27 mL, 59.7 mmol) in tetrahydrofuran (100 mL) was added with stirring under ice-cooling a solution of cyclopropanecarbonyl chloride (5.19 mL, 57.0 mmol) in tetrahydrofuran (25 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with hexane-ethyl acetate to give the title compound (12.3 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH2:2][CH2:3][CH3:4].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][CH2:25][O:26][CH2:27][C:28]([NH2:30])=[NH:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:30][C:28](=[NH:29])[CH2:27][O:26][CH2:25][CH2:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[F:16])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: N=C(N)COCCc1cc(F)ccc1F
Reactant: CCCCc1cnc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cc(F)ccc2F)c1

Procedure:
In analogy to the procedure described in example 78.3, 5-butyl-2-chloro-nicotinic acid (example 126.3) was reacted with 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2) in the presence of TBTU and DIPEA to give 5-butyl-2-chloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=410.1 [M+H+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.O[C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Oc1cccc2cccnc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of quinolin-8-ol (300 mg, 2.07 mmol) in THF (5 mL) was added (R)-methyl 2-hydroxypropanoate (215 mg, 2.07 mmol), PPh3 (647 mg, 2.47 mmol) and DEAD (430 mg, 2.47 mmol). The mixture was stirred at 25° C. for 16 hours. Subsequently, 1M HCl was added (10 mL) and the solution was washed with EtOAc (20 mL×3). The pH of the aqueous solution was raised by addition of aqueous NaHCO3 (10 mL), and then this solution was washed with EtOAc (10 mL×3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step. LCMS (m/z): 232.1/233.1 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 91.2 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and m-toluidine (0.073 g, 0.68 mmol), the title compound (0.21 g, 92%) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.N1C=CC=CC=1.[N:18]#[C:19][C:20]#[N:21]>CN(C)C=O>[C:19]([C:20]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:21]=1)#[N:18]
Reactant: N#CC#N
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1nc(-c2ccccc2)c[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
0.85 g (5 mmol) of 2-aminoacetophenone hydrochloride and 1.98 g (25 mmol) of pyridine were dissolved in 30 ml of N,N-dimethylformamide in a four-necked flask equipped with a dry ice condenser. The solution was then cooled to a temperature of -50° C. To the solution was then added about 0.5 g (9.6 mmol) of cyanogen which had been cooled and solidified at a temperature of -50° C. The solution was heated at a temperature of 60° C. for 1 hour, and at a temperature of 80° C. for 1 hour. The reaction solution was then extracted with ethyl acetate and water. The resulting organic phase was then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and then concentrated. The material was then subjected to silica gel column chromatography to obtain 0.29 g (yield: 34 %) of 2-cyano-4-phenylimidazole.
Reaction SMILES: [CH:1]1([CH:6]([NH:8][C:9](=[O:38])[C@@H:10]([CH3:37])[NH:11][C:12](=[O:36])[C@H:13]([CH:25](CC2C=CC=CC=2)[C:26](=[O:28])[OH:27])[NH:14]C(OCC2C=CC=CC=2)=O)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH:6]([NH:8][C:9](=[O:38])[C@@H:10]([CH3:37])[NH:11][C:12](=[O:36])[C@H:13]([CH2:25][C:26](=[O:27])[OH:28])[NH2:14])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(NC(=O)[C@@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C1CCCC1
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O)C1CCCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
500 mg 10% Pd/C was added to a solution of 4.5 g (8.60 mmoles) N-carbobenzyloxy-β-benzyl-L-aspartyl-D-alanine-1-cyclopentylethyl amide (from Part b) in 250 ml methanol. The mixture was hydrogenated at 40 psi for 4 hours, then the catalyst removed by filtration through a Celite® filter material. The Celite® filter material was then washed twice with 50 ml H2O and the combined methanol water filtrate concentrated to 100 ml in vacuo. This solution was diluted with 100 ml H2O, warmed to 50° C., and then filtered. The aqueous filtrate was freeze-dried to afford 2.55 g (8.5 mmoles) of L-aspartyl-D-alanine-1-cyclopentylethyl amide. HPLC analysis using a C-18 column and 20% CH3CN in 80% 0.2% KH2PO4 buffer pH 4.0 as eluant showed two peaks with a ratio of 6:1, representing the S and R isomers of the cyclopentylethyl amides. Three recrystallizations of the product from 95% ethanol gave 610 mg of the pure L-aspartyl-D-alanine-(S)-1-cyclopentylethyl amide, mp 204°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)[N:15]=[C:14]([C:24]([OH:26])=O)[CH:13]=2)[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:23][C:19]1[CH:18]=[C:17]([N:16]2[C:12]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=3)=[CH:13][C:14]([C:24]([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=[O:26])=[N:15]2)[CH:22]=[CH:21][N:20]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2ccnc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OC(F)F)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
40 mg (0.10 mmol) of the compound of Example 53A is reacted analogously to the synthesis of the compound of Example 4 with 11 mg (0.11 mmol) of 2-oxopiperazine. 39 mg (80% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.200 g (0.405 mmol) of the product from Example 26 in CH2Cl2 (4 mL) at 0° C. was treated with trimethylacetyl chloride (50 μL; 0.405 mmol) followed by triethylamine (113 μL; 0.810 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 578.0 (M+1), 580.0 (M+3); Rt=4.69 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1.C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
N-[1-(4-Amino-benzenesulfonyl)-piperidin-4-yl]-acrylamide (0.09 g, 0.3 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.1 ml, 0.6 mmol) in one portion followed by the drop wise addition of benzyl chloroformate (0.05 ml, 0.33 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% EtOAc) to give the title compound (0.04 g, 34% yield) as a white powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH2:12]([O:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])[CH3:13].[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:12]([O:14][C:15](=[O:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[C:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1)[CH3:13]
Reactant: CCOC(=O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC=C(c1ccccn1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
NaHMDS (10.01 mL, 10.01 mmol) as a solution in THF was added to (6-ethoxycarbonyl-hexyl)-triphenyl-phosphonium bromide 1 (10.54 mmol) in THF (40 mL) at −78° C. under Ar(g). After 30 min, di-pyridin-2-yl-methanone (1.437 g, 7.81 mmol) in THF (5 mL) was added; the reaction was stirred for 2 h, and was then allowed to warm to rt. After 17 h, saturated aqueous NH4Cl (250 mL) and EtOAc (150 mL) were added; the phases were separated, and the aqueous phase was extracted with EtOAc (2×100 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:0.5 to 100:2) to furnish II as a pale brown oil (990 mg, 40%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](OCC)=[O:7])C.[C:19]1([C:25]([O:27][Si](C)(C)C)=[CH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N#N>CCCCCC.C(OCC)(=O)C>[OH:7][C:6]1[CH:26]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:27][C:4](=[O:3])[C:5]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1oc(-c2ccccc2)cc(O)c1Oc1ccccc1
Temperature: 100 °C
Yield: 18.3 %

Procedure:
To a is pressure reactor was added 2-phenoxypropanedioicacid diethylester 8.11 g (0.032 moles) and 1-phenyl-1-(trimethylsilyloxy)ethylene 12.35 g (0.064 moles). The vessel was pressurized to 600 psi with N2. The mixture was heated at 100° C. for 8 hours then an additional 63.5 hours at 147-154° C. The vessel was cooled to room temperature and rinsed with ethyl acetate. Crude flash chromatography (hexane/ethyl acetate 1/1) afforded partially purified material which was then flashed on silica gel using hexane/ethyl acetate 95/5-40/60 as eluents. The resulting solid was recrystallized from diethyl ether and ethyl acetate to afford 1.64g (18%) of the title compound (mp=215-219° C.). 1H NMR (400 MHz, DMSO-d6) δ6.90 (s, 1 H), 6.95 (dd, 2 H), 7.02 (t, 1 H), 7.28-7.33 (m, 2 H), 7.52-7.56 (m, 3 H), 7.80-7.856 (m, 2 H), 12.0 (bs, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1>CO.[C].[Rh]>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@H:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1
Reactant: C[C@@H](COc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: C[C@@H](CO[C@H]1CC[C@@H](O)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A suspension of tert-butyl [(1S)-2-(4-hydroxyphenoxy)-1-methylethyl]carbamate (40 g) and 5% rhodium-carbon (containing water (50%), 8.0 g) in methanol (600 mL) was stirred at 60° C. for 3 hr under a hydrogen atmosphere (5 atm). The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (8.3 g).