Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH:7]([C:11](=[O:13])[CH3:12])[C:8](=[O:10])[CH3:9])[CH3:2].[C:15]([O:19][CH2:20][C:21]([CH3:29])([CH2:23][O:24][C:25](=[O:28])[CH:26]=[CH2:27])[CH3:22])(=[O:18])[CH:16]=[CH2:17]>N12CCCN=C1CCCCC2>[C:8]([C:7]([C:11](=[O:13])[CH3:12])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:17][CH2:16][C:15]([O:19][CH2:20][C:21]([CH3:29])([CH3:22])[CH2:23][O:24][C:25](=[O:28])[CH2:26][CH2:27][C:7]([C:8](=[O:10])[CH3:9])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:11](=[O:13])[CH3:12])=[O:18])(=[O:10])[CH3:9]
Reactant: CCOC(=O)CCC(C(C)=O)C(C)=O
Reactant: C=CC(=O)OCC(C)(C)COC(=O)C=C
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(CCC(=O)OCC(C)(C)COC(=O)CCC(CCC(=O)OCC)(C(C)=O)C(C)=O)(C(C)=O)C(C)=O
Reaction time: 3 h

Procedure:
5.0 g of 4-acetyl-5-oxohexanoic acid ethyl ester and five drops 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed and 2.6 g of neopentyl glycol diacrylate was added dropwise. The mixture was stirred for three hours to yield a highly viscous colorless oil. Gel permeation chromatography showed a main peak at 690 g/mol, nuclear magnetic resonance spectra and infrared spectrum are according to the expected structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:32])[C:10]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[C:24]([C:25]([OH:27])=O)=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[N:21]2)[CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:67][O:68][C:69]1[CH:76]=[CH:75][CH:74]=[CH:73][C:70]=1[CH2:71][NH2:72]>C(Cl)Cl>[CH3:67][O:68][C:69]1[CH:76]=[CH:75][CH:74]=[CH:73][C:70]=1[CH2:71][NH:72][C:25]([C:24]1[N:20]([C:18]2[N:19]=[C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:32])[CH:15]=[CH:16][CH:17]=2)[N:21]=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)=[O:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)O)n1
Reactant: COc1ccccc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 21 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a stirred solution of 49 (38 mg, 0.083 mmol) in CH2Cl2 (0.83 mL) were added triethylamine (0.025 mL, 0.183 mmol) and BOP (44.1 mg, 0.100 mmol) followed by 2-methoxybenzylamine (0.013 mL, 0.100 mmol). The resulting solution was allowed to stir at 21° C. overnight and evaporated to dryness. The residue was purified via ISCO flash chromatography (40% to 100% EtOAc/hexanes; 12G column). The title product 50 (28 mg, 59% yield) was isolated as a pale yellow oil. LRMS (ESI): calc. 576.6; found 577.6 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[CH:19]1[CH:24]=[N:23][CH:22]=[C:21]([N:25]=[C:26]=[S:27])[CH:20]=1>O1CCOCC1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:26]([NH:25][C:21]3[CH:22]=[N:23][CH:24]=[CH:19][CH:20]=3)=[S:27])[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: S=C=Nc1cccnc1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=S)Nc3cccnc3)nc12
Temperature: 100 °C

Procedure:
To a stirred solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (80 mg, 0.3 mmol) in dioxane (3 ml) was added pyridine-3-isothiocyanate (64 mg, 0.47 mmol) and the mixture heated to 100° C. for 69 h. After cooling to r.t. the resulting yellow suspension was filtered, washed with ether (5 ml) and dried under vacuum (0.05 mmHg, 50° C., to afford the title compound as a; light yellow solid (98 mg, 80% yield), MS: m/e=393.1 (M+H+).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([NH2:11])[CH2:10][CH:4]([CH2:5]2)[CH2:3][CH:2]1[CH2:9]3.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CN(P(N(C)C)(N(C)C)=O)C>O>[C:8]12([NH:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:10][CH:4]3[CH2:5][CH:6]([CH2:1][CH:2]([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A mixture of 1.51 g. (0.01 mole) of 1-adamantamine, 1.41 g. p-fluoronitrobenzene and 1.38 g. K2CO3 in 10 ml. HMPA was stirred overnight in an oil bath at 135°. The mixture was allowed to cool, diluted with H2O and extracted thoroughly with C6H6. The organic layer was washed in turn with H2O and brine and taken to dryness. The waxy residue was recrystallized twice from Me2CO:cyclohexane to give 1.82 g. (67%) of N,1-adamantyl-p-nitroaniline, m.p. 188°-189°.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:27][C:26](=[O:28])[C:25]([CH3:29])=[C:24]([OH:30])[C:23]=1[CH3:31].OS([O-])(=O)=O.[K+]>C1COCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:27][C:26](=[O:28])[C:25]([CH3:29])=[C:24]([O:30][S:9]([CH3:8])(=[O:11])=[O:10])[C:23]=1[CH3:31]
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Et3N (130 μl) and methanesulfonyl chloride (24 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in THF (5 ml), and the mixture was stirred at room temperature for one hour. The reaction solution was poured into aqueous KHSO4 and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one.
Reaction SMILES: C[NH:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][NH:2][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: C=C1CC(=O)O1
Reactant: CNCC(O)CO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(O)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 22.5 g (0.21 mol) 3-methylamino-1,2-propanediol in 200 ml of tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.21 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 32.00 g (0.17 mol, 79% yield) of a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH3:42])=[C:34]1[C:43](O)=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH3:42])=[C:34]1[C:43]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:44]
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Yield: 71.6 %

Procedure:
The procedure of Example 77 was followed using N-(valinyl)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (213.9 mg, 0.47 mmol), 1,3-dimethylindole-2-carboxylic acid (107 mg, 0.57 mmol), NMM (0.3 ml, 2.8 mmol), HOBt (151 mg, 0.99 mmol), and EDAC (198 mg, 1.04 mmol) in methylene chloride to prepare the titled product (210 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:41][CH:40]=1
Reactant: NCc1ccc(CN2CCCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CN4CCCCC4)cc3)c2CC1)C(F)(F)F
Yield: 72.5 %

Procedure:
Use a method similar to the General Procedure)-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethansulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.69 mmol) and 4-(piperidin-1-ylmethyl)-benzylamine (174 mg, 0.84 mmol). Purify by chromatography on silica gel (150 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain 7-chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (240 mg, 71%). MS (ES+) m/z: 480 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.Cl[C:30]1[NH:31][CH2:32][CH2:33][N:34]=1>CC(O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:30]4[NH:34][CH2:33][CH2:32][N:31]=4)=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=S(=O)(c1ccccc1)N1CCC(Cc2ccc(NC3=NCCN3)cc2)CC1
Yield: 87.7 %

Procedure:
A mixture of 4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.28 g, 0.83 mmol) and 2-chloro-2-imidazoline sulfate (0.25 g, 1.25 mmol) in 2-propanol (20 mL) was heated under reflux for 30 minutes under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was basified with 10% sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was chromatographed on neutral aluminum oxide, eluting with 1% methanol/dichloromethane, to give 2-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline (0.29 g, 89%) as a foam. Analysis for C21H26N4O2S.5H2O: Calc.: C, 61.89; H, 6.68; N, 13.75; Found: C, 62.00; H, 6.52; N, 13.85.
Reaction SMILES: [Li]CCCC.[CH2:6]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=2)[C:10]1=[O:22])[CH2:7][CH3:8].[CH3:23][C:24]([O:27][C:28](/[N:30]=[N:31]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])[CH3:25].O>O1CCCC1>[CH3:26][C:24]([O:27][C:28]([NH:30][N:31]([C:9]1([CH2:6][CH2:7][CH3:8])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:15]=2)[C:10]1=[O:22])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: CCCC1Cc2cc(C(F)(F)F)ccc2C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2cc(C(F)(F)F)ccc2C1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of diisopropropylamine (1.3 mL, 9.1 mmol) in 30 mL tetrahydrofuran cooled to −78° C. was added 6.0 mL n-BuLi (1.6M, 9.5 mmol). The mixture was allowed to warm to −20° C. over 20 min, then re-cooled to −78° C. A solution of the product from Step C (2.0 g, 8.3 mmol) in 15 mL tetrahydrofuran was added dropwise. After 30 min, a solution of di-tert-butylazodicarboxylate (2.1 g, 9.1 mmol) in 20 mL tetrahydrofuran was added dropwise. The reaction was allowed to slowly warm to RT and stirred overnight. Water was added and the mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 2.92 g of a white solid, m.p. 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N:29][S:30][N:31]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:32]([NH2:35])([CH3:34])[CH3:33]>C1COCC1>[CH:32]([NH:35][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[C:3]2[C:4]([CH:5]=1)=[N:29][S:30][N:31]=2)=[O:28])([CH3:34])[CH3:33]
Reactant: CC(C)N
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cc2nsnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 25 mg (52 mmol) of 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-7-oxa-2-thia-1,3,5-triaza-cyclopenta[b]naphthalen-8-one in 0.5 ml of THF, is added dropwise 7 ml (77 mmol) of isopropylamine. The reaction is stirred for 18 hours at ambient temperature. Then, the solvent is evaporated and the residue is suspended in a mixture of hexanes and a minimum of EtOAc. After decantation the solid is washed with a minimum of hexanes and after drying 24.5 mg (45 mmol, 87%) of a slightly brown solid were obtained. LC/MS: 544/546 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][SH:35])[CH2:28][CH2:27]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:35][CH2:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:27][CH2:28]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: SCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCCc3ccc(Cl)cc3)CC2)cc1

Procedure:
The procedure described in Example 2 was followed, using 2.5 g of 4-n-butylphenyl isocyanate, 5.0 g of 3-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}propanethiol dihydrochloride, 1.4 g of triethylamine and 50 ml of methylene chloride, to give 2.7 g (34% of theory) of N-(4-n-butylphenyl-S-{3-[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, m.p. 270°-272° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:40]=[C:41]([NH2:45])[CH2:42][CH2:43][OH:44].N1C=CC=CC=1>O1CCCC1>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][C:18]2[O:19][N:45]=[C:41]([CH2:42][CH2:43][OH:44])[N:40]=2)[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: NC(CCO)=NO
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON=C1C[C@@H](Cc2nc(CCO)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 32.3 %

Procedure:
To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in tetrahydrofuran (2 ml) was added CDI (37 mg, 0.23 mmol). The reaction mixture was stirred 1 h30. A solution of N′,3-dihydroxypropanimidamide (16 mg, 0.16 mmol), pyridine (34 ml, 0.14 mmol) in tetrahydrofuran was then added and the reaction mixture was stirred at reflux overnight The solvent was removed and ethyl acetate was added. The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-{[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]methyl}pyrrolidin-3-one O-methyloxime (19 mg). Yield: 27%. HPLC purity: 94%
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[C:21]([C:23]1[C:24]([SH:31])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1)#[N:22]>CN(C=O)C.C(OCC)(=O)C>[C:29]([C:27]1[CH:28]=[C:23]2[C:21]([NH2:22])=[C:13]([C:12](=[O:15])[C:11]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=3[O:9][CH2:7][CH3:8])[S:31][C:24]2=[N:25][CH:26]=1)#[N:30]
Reactant: N#Cc1cnc(S)c(C#N)c1
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2ncc(C#N)cc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (1.18 g, 8.55 mmol), 2-ethoxy-5-fluorophenacyl bromide (1.34 g, 5.12 mmol) and 3,5-dicyano-2-mercaptopyridine (0.55 g, 3.42 mmol) in dry DMF (8 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 196° C.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][O:56][CH2:57][CH2:58][C:59]1N=C(N)[S:61][N:60]=1>ClCCl>[CH3:55][O:56][CH2:57][CH2:58][C:59]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:61][N:60]=1
Reactant: COCCc1nsc(N)n1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCCc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 84 mg, 0.26 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol) and 1-hydroxybenzotriazole (45 mg, 0.33 mmol). The resulting solution was stirred for 5 min before 3-(2-methoxy-ethyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.31 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(2-methoxy-ethyl)-[1,2,4]thiadiazol-5-yl]-amide (34 mg, 28%) as a light orange solid: HR-ES-MS m/z calculated for C21H25ClN4O4S [M+H]+ 465.1359, observed 465.1358; 1H NMR (300 MHz, DMSO-d6) ppm 0.91 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.47 (br. s., 1H), 1.58-1.74 (m, 1H), 1.80-1.95 (m, 1H), 3.01 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 3.74 (t, J=6.4 Hz, 2H), 4.19-4.36 (m, 1H), 4.41-4.61 (m, 1H), 4.83 (s, 1H), 4.94-5.07 (m, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 13.32 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Br)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:49])[C@H:20]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][CH:31]=1)[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:18][C:19](=[O:49])[C@H:20]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:10]2[C:9](=[O:16])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]=[C:12]([Cl:14])[CH:11]=2)=[CH:34][CH:35]=1)[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: O=c1c(Br)cc(Cl)cn1Cc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
A solution of 1-benzyl-3-bromo-5-chloro-2-pyridone (296 mg, 0.98 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (560 mg, 0.99 mmol) in DMF (15 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). Bis(triphenylphosphine)palladium dichloride (80 mg, 0.11 mmol) was added and the mixture was heated to 90° C. for 4 hr as the mixture turned dark. An additional 60 mg of the catalyst was added and heating continued for 2 hr. The mixture was allowed to cool, was diluted with dichloromethane, and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was chromatographed over 150 g of silica gel eluting with 1:2 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (255 mg, 52%). LMS-Electrospray: m/z 1015 (2M+Na) (4 Cl) 519 (M+Na) 514 (M+NH4) 497 (M+H).
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])C.Cl.[C-:20]#[N:21].[K+]>O>[C:20]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])#[N:21]
Reactant: COc1ccc2c(c1)CCC(CN(C)C)C2=O
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CCC(CC#N)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.5 g of 2-dimethylaminomethyl-6-methoxy-1-tetralone hydrochloride (C. A. 41, 6253 g) are dissolved in 200 ml of water and 4 ml of concentrated hydrochloric acid are added, followed by the concentrated aqueous solution of 6.5 g of potassium cyanide, introduced below the surface of the liquid. The mixture is refluxed for one hour, stirred at room temperature overnight and filtered, to yield the 2-cyanomethyl-6-methoxy-1-tetralone melting at 90°-93°. Similarly prepared are the following nitriles: 2-cyanomethyl-1-tetralone, b.p. 125°-30°/0.005 mm Hg; 2-cyanomethyl-6,7-dimethoxy-1-tetralone, m.p. 116°-118°; 2-cyanomethyl-7-methoxy-1-tetralone, m.p. 80°-84°: 2-cyanomethyl-5-methoxy-1-tetralone, m.p. 91°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Br[C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:18]1[CH:19]=[N:20][CH:21]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccncc1Br
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccncc1NCc1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 3,4-dichlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.95 (d, 1H, J=5.1 Hz), 7.87 (br s, 1H), 7.65 (d, 1H, J=5.1 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.39 (s, 1H), 7.18 (dd, 1H, J=8.2 Hz), 4.48 (d, 2H, J=6.0 Hz), 3.91 (s, 3H). [M+H] calc'd for C14H12Cl2N2O2, 311, 313; found 311, 313.