Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH2:13]1)=[O:6])[CH2:2][CH3:3].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:14][C:12]1[CH2:13][C:7]([C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=1
Reactant: CCCNC(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of tert-butyl (1E,4E)-4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate (450 mg, 0.87 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (1.36 mL, 17.4 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude material that was diluted with CH2Cl2 (10 mL) and sat'd aq NaHCO3 (15 mL) again. The resulting mixture was stirred for 30 min at room temperature. The aqueous layer was separated and extracted with CH2Cl2 (1×10 mL). The combined organic layers were washed with sat'd aq NaHCO3 (2×10 mL) and brine (1×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material again that was purified by silica gel flash column chromatography (1 to 5% MeOH in CH2Cl2, gradient) to yield 27 mg (7%) of (1E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide. MS APCI(+) m/z 417 (M+1) detected; 1H-NMR (400 MHz, d6-DMSO) δ 8.27 (t, 1H), 7.75 (d, 2H), 7.62 (d, 2H), 7.50 (d, 2H), 7.41 (d, 2H), 3.43-3.51 (m, 4H), 3.18 (q, 2H), 2.99 (s, 2H), 1.81-1.90 (m, 4H), 1.48-1.58 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][CH2:23][C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O.C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:26]5[S:27][CH:28]=[C:24]([CH2:23][F:22])[N:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1nc(CF)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(CF)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-(fluoromethyl)thiazol-2-yl)methanol (105 mg), triphenylphosphine (280 mg) and THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (250 mg), and the mixture was stirred at room temperature for 2 h, then at 70° C. for 2 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH) to give the title compound (4.0 mg) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]3=[CH:23][CH:22]=[CH:21][N:9]23)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(Cl)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(Cl)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(4-chloro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 376 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[OH:13][C:14]1[N:21]=[C:20](C)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(Br)C=C>C1COCC1>[CH2:1]([C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([OH:13])[N:21]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Cc1ccc(C#N)c(O)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CC(C)NC(C)C
Product: C=CCCc1ccc(C#N)c(O)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
n-Butyllithium (100 mL of a 1.6 M solution in hexanes, 160 mmol, 2.5 equiv) was added via cannula over 10 min to a solution of diisopropylamine (22.4 mL, 160 mmol, 2.5 equiv) in THF (600 mL) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 5 min, then was warmed to 0° C. for an additional 5 min. 2-Hydroxy-6-methylnicotinonitrile (8) (8.58 g, 64.0 mmol, 1 equiv) was added as a solid in small portions over 15 min and the deep orange solution thus obtained was stirred for 1 h at 0° C. Allyl bromide (8.31 mL, 96.0 mmol, 1.5 equiv) was then added and the reaction mixture was warmed to 23° C., maintained at that temperature for 30 min, and was partitioned between 1.0 M HCl (300 mL) and EtOAc (2×250 mL). The combined organic layers were dried over Na2SO4 and were concentrated. The resulting orange solid was triturated with boiling Et2O (100 mL) and subsequently cooled to 23° C., then was filtered through a medium frit, washed with Et2O (2×50 mL) and air-dried to give a1 (6.42 g, 58%) as a tan solid: mp=122-125° C.; IR (KBr pellet, cm−1) 2223, 1654; 1H NMR (DMSO-d6) δ 2.32-2.37 (m, 2H), 2.62 (t, 2H, J=7.6), 4.96-5.06 (m, 2H), 5.69-5.83 (m, 1H), 6.23 (d, 1H, J=7.3), 8.03 (d, 1H, J=7.3), 12.55 (s, br, 1H); Anal. C10H10N2O·0.10H2O: C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[N:12](C)[C:13](=O)C)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:17]>>[ClH:17].[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)N(C)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Agent: Cl
Product: CN[C@@H]1C[C@H]1c1ccc(F)c(F)c1

Procedure:
A solution of the product from step b) (443 mg) in 4M HCl (10 ml) was refluxed for 8 h. The solvent was removed in vacuo to give the sub-title compound (357 mg).
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[OH-:13].[Na+].C>O>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[C:10]([CH:2]=[O:13])[CH:9]=1
Reactant: [OH-]
Reactant: O=C1OC(Br)c2cc(Br)ccc21
Agent: [Na+]
Solvent: O
Product: O=Cc1cc(Br)ccc1C(=O)O
Temperature: 80 °C
Yield: 89 %

Procedure:
The mixture of 3,5-dibromo-3H-isobenzofuran-1-one (B3) (38 g, 130 mmol) in a solution of 10N NaOH (28.6 mL, 286 mmol) and water (240 mL) is heated for 2 h at 80° C. Activated charcoal (2 g) is added and the mixture is refluxed for another 1 hour. Mixture is hot filtered and acidified with 2N methanesulfonic acid (100 mL). The resulting mixture is cooled in an ice-water bath for 1 h. The solid is filtered and washed with water (4×25 mL) and vacuum dried under KOH to yield 4-bromo-2-formyl-benzoic acid (C3) (26.5 g, 89%, mp: 202° C.). Recrystallization: Dissolved 4-bromo-2-formyl-benzoic acid (C3) in hot EtOH (220 mL) and cooled the mixture in an ice-water bath for 4 h. The solid is filtered and rinsed with cold EtOH (3×20 mL). The solid is then vacuum dried over KOH to yield 4-bromo-2-formyl-benzoic acid (16.8 g, 63%, mp: 204-205° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][CH2:21][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: OCCCBr
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCSc1ccccc1O
Reaction time: 0.33 h

Procedure:
2-Hydroxythiophenol (1.00 g, 8.70 mmol) was added to a mixture of DMF (10 mL) and Cs2CO3 (2.90 g, 8,90 mmol). To this was added 3-bromopropanol (0.80 mL, 9.16 mmol) and the mixture was stirred for 20 min. The mixture was added to into water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a clear oil (2.36 g, 100%). MS [M−H]− 183.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@H:25]([CH:30]=O)[CH2:24]2)#[N:20]>>[CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:8][CH2:9][C@H:10]([NH:13][CH2:30][C@@H:25]3[CH2:24][C:23]4[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=4)[CH2:26]3)[CH2:11][CH2:12]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](N)CC1
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(2,5-dimethyl-benzoimidazol-1-yl)-cyclohexylamine and (S)-5-cyano-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H30N4 (m/e) calcd 398.2470, obsd 399.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(-n2cnnn2)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C=O
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-hydroxy-5-tetrazol-1-yl-benzaldehyde (2.63 mmol) in dimethylformamide (5 ml) was added potassium carbonate (3.95 mmol) and iodomethane (3.95 mmol) and the mixture was stirred under nitrogen atmosphere for 2 h. The mixture was poured into water (100 ml) and the white solid formed filtered to afford the title compound in a 67% yield.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23]1[C:32]2[NH:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[NH:28][CH2:27][C:26]=2[CH:25]=[N:24]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:28]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[C:32]=3[NH:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]2=3)=[O:18])=[CH:14][C:13]=1[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1OCCCC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)OC(C)(C)C
Yield: 18 %

Procedure:
WSCD (391 mg, 2.06 mmol) and DMAP (133 mg, 1.09 mmol) were added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid from Example E42 (275 mg, 0.94 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (191 mg, 0.95 mmol) in dichloromethane (30 ml) and triethylamine (0.28 ml, 2.01 mmol). The mixture was heated at reflux for 72 h, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (80 mg, 18%).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([OH:10])[N:4]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>C(O)C>[NH2:2][C:3]1[N:8]=[C:7]([NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: Nc1nc(O)cc(Cl)n1
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: Nc1nc(O)cc(NC2CC2)n1

Procedure:
2-Amino-4-chloro-6-hydroxypyrimidine monohydrate (5.0 g) was refluxed in ethanol (150 mL) with cyclopropylamine for 12 h. The mixture was evaporated in vacuo, codistilled with ethanol (3×50 mL), adsorbed from methanol on silica gel and applied on a column of silica gel (200 mL) in chloroform. Elution with chloroform-ethanol gradient afforded crystalline product which was filtered from ether and dried in vacuo to afford 2-amino-4-cyclopropylamino-6-hydroxypyrimidine, m.p.229° C. Yield, 3.0 g. For C7H10N4O (166.18) calculated 50.59% C, 6.07% H, 33.71% N; found 50.49% C, 6.25% H, 33.61% N. 1H NMR (DMSO): 9.73 brs, 1H (OH); 6.55 bs, 2H (NH); 6.08 brs, 2H (NH2); 4.66 s, 1H (H-5); 2.30 m, 1H and 0.62 m, 2H and 0.40, m, 2H (C—CH2, N—CH).
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].[C:27]([O:35][CH2:36]Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:36][O:35][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:2]
Reactant: O=C(OCCl)c1ccccc1
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCP(=O)(OCOC(=O)c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (0.40 g, 0.97 mmol), chloromethyl benzoate (0.23 g, 1.36 mmol) and triethylamine (0.27 g) in 4 ml of DMF is stirred at RT for 4 days. The reaction mixture is poured into water and extracted with methylene chloride. The combined extracts are washed, dried, evaporated to dryness and purified by prep. TLC (eluting with 50% ethyl acetate/hexane) to yield benzoyloxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:11]=[C:10]([C:12](OCC)=[O:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: CCOC(=O)c1cn2c(n1)sc1cc(C)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)sc1nc(C=O)cn12
Temperature: -78 °C

Procedure:
To a stirred solution of Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate (4.0 g, 15.38 mmol) in dry THF at −78° C., DIBAL (1M. solution in toluene) (16.0 ml, 16 mmol) was added. The reaction mixture was stirred at −78° C. and slowly elevated to room temperature. The reaction mixture was stirred at room temperature for 30 minutes and quenched with saturated NH4Cl. The reaction mixture was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO4; filtered and concentrated. The residue was purified bt SiO2 column chromatography by eluting it with chloroform: metrhanol (20:1). Brown solid; (M+H) 217; Yield: 800 mg (24%)
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[C:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([N:19]([CH2:18][C:17]2[CH:33]=[CH:34][C:14]([C:13]#[C:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[C:20]2[CH:32]=[CH:31][C:23]3[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=3[CH:21]=2)=[O:44])=[CH:46][CH:47]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(C(C)(C)C)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 4-tert-butylbenzoyl chloride as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=2.3 Hz, 1H), 7.46 (m, 4H), 7.30-7.16 (m, 8H), 7.01 (dd, J=8.7, 2.3 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.14 (s, 2H), 2.64 (t, J=7.7 Hz, 2H), 1.68 (s, 6H), 1.62 (m, 2H), 1.38 (m, 2H), 1.25 (s, 9H), 0.95 (t, J=7.2 Hz, 3H). HPLC, Rt: 6.12 min (Purity: 97%).
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[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40](O)=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:40]([C@H:36]3[CH2:37][CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH2:35]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Product: CON=C1C[C@@H](c2noc([C@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (3S)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid, the title compound, tert-butyl (3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate, was obtained in 85% yield (97.20% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Oc1cccc(Cl)n1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Cl)cc1)C(Oc1cccc(Cl)n1)n1cncn1
Yield: 706.2 %

Procedure:
8.7 g (0.025 mol) of 1-(6-chloro-pyridin-2-yl-oxy)-2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-one (Example 1) were dissolved in 100 ml of methanol, and 1 g (0.025 mol) of sodium borohydride was added. The mixture was heated under reflux for 30 minutes and concentrated by distilling off the solvent in vacuo, and the residue was partitioned between chloroform and water. The organic phase was separated off, extracted again by shaking with water, dried over magnesium sulphate and concentrated. 62 g (70% of theory) of 1-(6-chloro-pyridin-2-yl-oxy)-2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol were obtained as a viscous oil.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2sccc12
Reactant: CCC(=O)N(C)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Approximately 3 ml of a solution of 4-bromobenzo[b]thiophene (1.85 g; prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 111, 3667-3674) in tetrahydrofuran (20 ml) was added under nitrogen to a mixture of magnesium turnings (0.22 g) and tetrahydrofuran (2 ml). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes, the mixture was heated under reflux for 10 minutes, then it was cooled to ambient temperature. A solution of N-methoxy-N-methylpropionamide (1.01 g) in tetrahydrofuran (10 ml) was added, the mixture was heated under reflux for 30 minutes, then it was cooled to ambient temperature and quenched by the addition of 2M hydrochloric acid (25 ml). The mixture was allowed to stand at ambient temperature for 18 hours, then the tetrahydrofuran was removed in vacuo, the residue was diluted with water (50 ml) and the product was extracted into ethyl acetate (50 ml). The extract was washed with saturated aqueous sodium chloride solution (2×50 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 97:3 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)propan-1-one (0.615 g) as a colourless oil which was used without further purification.
Reaction SMILES: C(OC([S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=S)C.[OH-].[K+]>CCO.O>[SH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:12]=1
Reactant: CCOC(=S)Sc1ccc(CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(S)cc1
Yield: 97.6 %

Procedure:
To a solution of 2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid (50.0 g, crude, 0.195 mol) in EtOH (180 mL) was added a solution of KOH (40.5 g, 0.724 mol) in water (180 mL). The mixture was stirred at reflux overnight. The mixture was concentrated under reduced pressure to remove EtOH. The aqueous phase was adjusted to pH=1˜2 with conc. HCl. The aqueous phase was then extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-(4-mercaptophenyl)acetic acid (32.0 g, 98%) as a gray solid, which was used for next step directly without further purification. 1H NMR (purified by pre-TLC, CD3OD, 400 MHz): δ 7.23 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 3.54 (s, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31]([CH2:30][O:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide in THF (58.7 mL, 58.75 mmol) was added dropwise to a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.41 mmol) in DMF (100 mL) over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes. Ethyl bromoacetate (8.92 g, 53.41 mmol) was added dropwise over 10 minutes (exotherm. Temperature kept below 30° C. using a cold water bath) and the reaction was stirred at ambient temperature for 20 hours.