Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+:36](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([NH2:36])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(N)=O)cc2OCC3)n(C(C)C)n1
Reaction time: 0.67 h

Procedure:
A mixture of 58 mg (0.158 mmol) of 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid, 76 mg (0.20 mmol) of N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate, (HATU, 16 mg, 0.30 mmol) of ammonium chloride and 28 uL (0.200 mmol) of Triethylamine in N,N-3.0 ml of Dimethylformamide was stirred for 40 min. The mixture was concentrated in vacuum and triturated with 10 ml of water. The solid was collected and purified by RP HPLC (acetonitrile gradient) to give 300. Yield 8.1 mg. M/z 367.2, calc. 366.18. 1H NMR (500 MHz, DMSO) δ 8.30 (d, J=8.2, 1H), 7.86 (s, 1H), 7.44 (s, 1H), 7.04 (d, J=8.3, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 5.80 (dt, J=13.1, 6.5, 1H), 4.49 (q, J=6.2, 4H), 3.38 (s, 2H), 2.25 (s, 3H), 1.45 (d, J=6.6, 6H)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:18])[C:9](=[O:16])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:5])C.[OH-].[Na+].Cl>CN(C)C=O>[C:4]([C:6]1[CH:7]=[C:8]([C:17]([NH:19][C:20]2[NH:21][N:22]=[N:23][N:24]=2)=[O:18])[C:9](=[O:16])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(C(=O)Nc2nnn[nH]2)c(=O)n2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cc(C(=O)O)c2ccccn2c1=O
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To a solution of 1-ethoxycarbonyl-N-(1H-tetrazol5-yl)-4H-quinolizin-4-one-3-carboxamide (500 mg) in N,N-dimethylformamide (5 ml) was added 1N aqueous sodium hydroxide (6 ml) at room temperature and the mixture was heated at 100° C. for an hour. After cooling to 0° C., the mixture was acidified to pH 2 with 6N hydrochloric acid and the precipitate was filtered and washed with water to give 1-carboxy-N-(1H-tetrazol-5-yl)-4H-quinolizin-4-one-3-carboxamide (280 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[F:6][C:7]([F:17])([F:16])[C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH:10]=O>O1CCCC1>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:10]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[C:9]([F:13])([F:12])[C:8]([F:15])([F:14])[C:7]([F:17])([F:16])[F:6]
Reactant: c1cc[nH]c1
Reactant: O=CC(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(F)C(F)(F)C(c1ccc[nH]1)c1ccc[nH]1

Procedure:
Pyrrole (2; 50 mmol) and heptafluorobutyraldehyde (7; R=CF3CF2, as the hydrate, 25 mmol ) were condensed in tetrahydrofuran in the presence of acid catalyst as described above to give bis-(pyrrol-2-yl) hepta-fluoroprop-1-ylmethane (8; R=CF3CF2) in >50% isolated yield. GCMS m/z; 314 (M+, 22%), 145 (100%); 1H NMR (δ, CDCl3 at 7.24); 4.92 (t, 1H), 6.22 (d, 4H), 6.75 (s, 2H), 8.07 (bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]=[N+]=[N-])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[C:17]([OH:20])(=S)[CH3:18]>>[CH3:1][O:2][C:3](=[O:16])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:17](=[O:20])[CH3:18])[CH2:9][CH2:8]1)([CH3:6])[CH3:5]
Reactant: CC(O)=S
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask is charged with 0.422 g of trans-2-(4-azido-cyclohexyl)-2-methyl-propionic acid methyl ester. 0.71 ml of thioacetic acid are added and the solution is stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture is concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C@@H:36]1[CH2:46][CH2:45][C@@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C@H:37]1O>O1CCCC1>[Cl:8][C@H:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:46][C@H:36]1[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[F:28]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@@H](Cl)c2cccnc21)(C(C)C)C(C)C
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
In an oven-dried 250 mL round-bottom flask was suspended NCS (0.751 g, 5.62 mmol) in tetrahydrofuran (15 mL). Triphenylphosphine (1.475 g, 5.62 mmol) was added. After stirring under nitrogen for 5 min, (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.007 g, 2.250 mmol) was added in one portion to the gray suspension. The resulting reddish suspension was stirred at room temperature. The solids gradually dissolved to give a tan solution. After 5 h, LCMS indicated complete conversion. Tetrahydrofuran was removed in vacuo and the remaining red oil was directly purified by ISCO (240 g silica column) up to 60% ethyl acetate/hexane. Pure ethyl acetate eluted the non polar component and the product was eluted by 10% methanol (with 2.0M NH4OH) in Methylene chloride. The product fractions were combined and re-purified by FCC up to 50% Ethyl acetate/hexane to afford the desired product as a colorless oil (869 mg, 83%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3=[CH:9][S:10][CH:11]=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1>>[CH:1]1([C:4]2[N:8]([CH2:13][C:14]3[CH:33]=[CH:32][C:17]4/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=5[O:21][CH2:22][C:16]=4[CH:15]=3)[C:7]3=[CH:9][S:10][CH:11]=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: c1scc2[nH]c(C3CC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4cscc43)cc2COc2cc(F)ccc21
Yield: 94 %

Procedure:
[step 2] Using 2-cyclopropyl-1H-thieno[3,4-d]imidazole (65 mg, 0.40 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (145 mg, 0.40 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (166 mg, 95%) was obtained.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:5])C.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[NH2:19].C(N(CC)CC)C.O>ClCCl.CO>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:7]2[N:18]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[N:19]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C)=NC(=O)c1cccc(OC)c1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cc2)c1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
N-(1-ethoxy-ethylidene)-3-methoxy-benzamide 462 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3-methoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (503 mg, yield: 70%) was obtained as a solid phase.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[C:16]([C:15]1[CH:14]=[C:13]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1cccc(F)c1
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2cccc(C#N)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-fluorobenzonitrile instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I-].[K+].[CH2:22]([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl)[CH3:23]>CN(C)C=O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:28][CH2:27][CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:30])[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCC(OCc2ccccc2)CC1
Yield: 82 %

Procedure:
To 12 mL of N,N-dimethylformamide was added 4-(benzyloxy)piperidine (0.8 g), sodium bicarbonate (1.05 g), potassium iodide (used as a catalyst), ethyl-4-chlorobutyrate (0.88 mL). The resulting mixture was refluxed for 4 hrs. The resulting mixture was cooled, and concentrated under reduced pressure. The resultant mixture was then extracted by using water and chloroform. An organic solution layer was dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (1.05 g, 82% yield) of the title.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:22][N:21]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:22][N:21]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)cnc1C

Procedure:
Reaction of 2-[3-(dimethylaminomethyl)benzylthio]ethylamine with an equimolar amount of 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone by heating under reflux in ethanol for 48 hours gives 2-[2-(3-(dimethylaminomethyl)benzylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8](O)=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15].CCOC(C)=O.CCCCCC>CN(C1CCCCC1)C.CCOC(C)=O.CCCCCC>[CH3:12][N:13]([CH3:18])[S:14]([C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:16])=[O:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1S(=O)(=O)N(C)C
Reaction time: 4 h

Procedure:
To a solution of vanillin (4.56 g, 30 mmol) in N,N-dimethylcyclohexylamine (30 mL) at 80-90° C., was added N,N-dimethylsulfamoyl chloride (3.79 mL, 35.27 mmol). The mixture was stirred at this temperature for 4 h, transferred to a separating funnel and diluted with EtOAc (100 mL). The organic layer was washed with water (2×200 mL), 6M HCl (aq.) (200 mL), brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave a golden-yellow oil which solidified on standing. The product was stirred in n-hexane, filtered and air-dried to give OBS02011 as yellow plates (6.92 g, 89%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.65; 1H-NMR (270 MHz, CDCl3)=2.98 (6H, s), 3.93 (3H, s), 7.44 (1H, d, J=1.6), 7.48 (1H, dd, J=1.6, 8.1), 7.53 (1H, d, J=8.1), 9.92 (1H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)[CH:22]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@H](CCCOCc3ccccc3)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(COCCC[C@H]2CCN(c3cncc(OC[C@@H]4CCCN4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a 25 mL round-bottom flask containing a solution of 3-[3(S)-[3-(benzyloxy)propyl]-1-pyrrolidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (500 mg, 1.01 mmol) in CH2Cl2/H2O (7.5/0.15 mL) was added CF3COOH (1.5 mL) at 0° C. under N2. The reaction mixture was stirred for 3 h at room temperature. After evaporation under reduced pressure, the crude product (310 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 270 nm; flow 20 mL/min; mobile phase: A, water with 0.05% CF3COOH; B, methanol; 40-50% B in A in 6 min, 50-100% in 1 min, back to 40% in 1 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was washed with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentrated in vacuo, the free amine (280 mg, 70%) was obtained as light-yellow solid. 1H NMR (CDCl3, 300 MHz) δ 7.66 (s, 1H), 7.61 (s, 1H), 7.37-7.30 (m, 5H), 6.34 (s, 1H), 4.54 (s, 2H), 4.01-3.94 (m, 2H), 3.54-3.49 (m, 3H), 3.48-3.22 (m, 3H), 3.12-3.00 (m, 2H), 2.91 (t, 1H , J=9.6 Hz), 2.36-2.23 (m, 1H), 2.21-2.10 (m, 1H), 2.06-1.79 (m, 3H), 1.76-1.50 (m, 6H). LC-MS (ESI) m/z 396 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:23].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[OH:20][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:21]
Reactant: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(N2CCN(CC(O)c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 3-methyl-5-(2-oxo-3-(2-oxo-2-phenylethyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide (0.09 g, 0.20 mmol) in methanol (3 mL) and chloroform (1.5 mL) at 0° C. was added sodium borohydride (0.01 g, 0.29 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford the title compound as a brownish solid in 92% yield (0.08 g): mp 75° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.43 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.39-7.17 (m, 6H), 6.37 (t, J=5.5 Hz, 1H), 5.98 (s, 1H), 4.94 (dd, J=7.7, 3.3 Hz, 1H), 4.52 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 3.75-3.35 (m, 6H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 156.6, 149.0, 148.5, 142.4, 141.7, 141.6, 135.6, 134.3, 128.5, 127.9, 125.8, 123.6, 119.0, 112.4, 72.8, 52.3, 43.8, 43.1, 41.1, 16.1; MS (ES+) m/z 437.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.F[C:15](F)(F)C(O)=O.C(C1C=CC(NC(C2C=C(OC)C(OC)=CC=2F)C2NC(=O)N(C3C=CC=CC=3C(O)=O)N=2)=CC=1)(=N)N.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrCCl.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]2[O:10][CH2:15][O:13][CH2:12][CH2:11][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(Br)cc(CCO)c1O
Agent: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: ClCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc2c1OCOCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 898 mg of 4-bromo-2-(2-hydroxyethyl)-6-methoxyphenol in 10 ml of DMF there was added 1g of sodium bistrimethylsilylamide while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After adding 1 ml of bromochloromethane to the reaction mixture, it was stirred at 80° C. for 20 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (420 mg) as an oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH:46]([CH:57]([CH3:59])[CH3:58])[C@@H:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH3:48]>C1COCC1>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[C@H:46]([CH:57]([CH3:59])[CH3:58])[C@@H:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH3:48]
Reactant: CC(C)C(O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@H]([C@H](C)NC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
Phthalimide (4.3 g), triphenylphosphine (9.6 g), and DIAD (19.2 ml) were added to a THF (40 ml) solution containing tert-butyl ((2S)-3-hydroxy-4-methylpentan-2-yl)carbamate (5.3 g) obtained in the 4th step, followed by stirring at room temperature for 16 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 5:1). Yellow oily matter of tert-butyl ((2S,3R)-3-(1,3-dioxoisoindolin-2-yl)-4-methylpentan-2-yl)carbamate (3 g) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@H:4]2[O:3]1.[CH:13]1([Mg]Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[OH:11])[CH2:9][C@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2O[C@H](C=O)C[C@H]2O1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2O[C@H](C(O)C3CCCC3)C[C@H]2O1
Temperature: -20 °C
Reaction time: 20 h
Yield: 21.3 %

Procedure:
To a solution of (3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (4.0 g, 23.2 mmol) in THF (20 mL) was added cyclopentylmagnesium bromide (1M in THF, 30 mL, 30 mmol) at −20° C. under argon. After being stirred at −20° C. for 20 hours, the reaction was quenched by saturated NH4Cl solution. The reaction mixture was extracted with EtOAc (30 mL) three times. The organic layers were combined and concentrated in vacuo to afford 1.2 g crude product of [(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methanol (compound 11a) as a colorless oil, which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 243.
Reaction SMILES: [N:1]1([C:51](OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (Example 1, 0.93 g.) and HGly-DLeu-MetNH2 (0.63 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-DLeu-MetNH2 in 59% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-DLeu-MetNH2 (0.88 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-DLeu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt in 59% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:3]=1.Cl.[NH2:21][C:22]1[C:27]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][CH:25]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[N:23]=1>>[ClH:1].[NH2:21][C:22]1[N:23]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][CH3:19])[N:3]=3)[CH2:36]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: COC(=O)c1ccc(-c2ccccc2OC)nc1Cl
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Product: COC(=O)c1ccc(-c2ccccc2OC)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1

Procedure:
Analogously to the preparation of Example 8, 255 mg (0.84 mmol) of methyl 2-chloro-6-(2-methoxyphenyl)pyridine-3-carboxylate (Example 17A) and 299 mg (0.92 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) were used to obtain, after purification of the crude product by means of preparative HPLC (method 10), 275 mg (58% of theory) of the product in solid form.