Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.C[N+:7](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH:46]([C:51]([OH:53])=O)[CH2:45][C:44]=3[N:43]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)[C:42](=[O:64])[NH:41]2)=[CH:36][CH:35]=1)#[N:33].N>CN(C)C=O.O>[C:32]([C:34]1[CH:35]=[CH:36][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH:46]([C:51]([NH2:7])=[O:53])[CH2:45][C:44]=3[N:43]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)[C:42](=[O:64])[NH:41]2)=[CH:38][CH:39]=1)#[N:33]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(C(=O)O)C3)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(C(N)=O)C3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (60 μL, 0.34 mmol) are added to a solution of 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquina zoline-7-carboxylic acid (example 10, 70 mg, 0.154 mmol) in N,N-dimethylformamide (1.0 mL). After 10 min aqueous ammonia (35%, 0.5 mL) is added and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is extracted with diethyl ether. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of methanol in water, 0.1% TFA). Yield: 15 mg; ESI mass spectrum [M+H]+=455; Retention time HPLC: 1.02 min (V001—006).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18].S1(CCCC1)(=O)=O>O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.03 h

Procedure:
20 g of anthraquinone are introduced into 100 ml of 98 % HNO3 at 0°, the temperature rising to 10° in two minutes as a result of this addition. The reaction mixture is then nitrated at 10° for 20 minutes, with cooling by iced water. 100 ml of sulpholan are added, the temperature rising to 50° as a result. The reaction mixture is suction-filtered at 20° and the precipitate is washed with 50 ml of sulpholan and then with water, and dried. 12.7 g of 1-nitro-anthraquinone, formed by analysis to have the following composition, are obtained:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: C=C
Product: O=C1CCc2ccc(Br)cc2C1

Procedure:
Scheme 3 illustrates a route to 7-substituted tetralin derivatives 10 and 11. 3-Bromophenylacetic acid is converted to the corresponding acid chloride and this is subjected to Friedel-Crafts reaction with ethene, affording the 7-bromo-2-tetralone 9. This intermediate may be elaborated using the procedures described in scheme 1 to provide the acid (10) and aniline (11).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.7 %

Procedure:
4-amino-3-fluorobenzoic acid (2.115 g, 13.6 mmol), 4-Amino-1-Ethyl Piperidine (Fluorochem; 1.923 g, 15 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7.1 mL, 40.8 mmol) were combined in DMA (60 mL) and the resulting yellow solution stirred at room temperature for 20 minutes. The reaction was left over the weekend at room temperature, solvent evaporated and the residue dissolved in methanol (10 mL) and loaded onto an SCX-2 column (50 g) which pre-wet with MeOH (40 mL), flushed with MeOH (4×30 ml) and eluted with 7N ammonia in MeOH (4×30 mL). Product containing, ammoniacal fractions were combined to yield the title compound as a brown solid (0.819 g, 22%)
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[C:67]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[CH:85]=[CH:84][C:83]([CH:86]=O)=[CH:82][CH:81]=2)[CH2:76][CH2:75]1)=[O:73])([CH3:70])([CH3:69])[CH3:68]>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:86]([C:83]3[CH:82]=[CH:81][C:80]([N:77]4[CH2:76][CH2:75][N:74]([C:72]([O:71][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:73])[CH2:79][CH2:78]4)=[CH:85][CH:84]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 32.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.057 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.17 mmol, 0.17 mL) and 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.063 mmol, 20 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (11 mg, 41%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.43 (s, 9H, C(CH3)3), 7.08 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.55 (dd, J=8.5, 4.4 Hz, 1H, pyridine H-5), 7.99 (d, br, J=8.4 Hz, 1H, pyridine H-4), 8.03 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.14 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.69 (d, J=4.4 Hz, 1H, pyridine H-6), 8.75 (s, br, 1H, pyridine H-2), 13.36 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:13]=[CH2:14])=[C:7]([CH:9]([OH:12])C=C)[CH:8]=1>C(Cl)Cl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:8]=[C:7]2[C:6]([CH:13]=[CH:14][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(C(F)(F)F)cc1C(O)C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: OC1C=Cc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of the 1-[5-(trifluoromethyl)-2-vinylphenyl]prop-2-en-1-ol (462 mg, 2.02 mmol) in methylene chloride (20 mL) under nitrogen was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (70 mg, 0.08 mmol). The dark mixture was stirred at 25° C. for 30 min and concentrated. The residue was purified by flash chromatography to give the desired compound (278.1 mg, 68%). LC-MS [M+1]=279.2.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[H-].[Na+].[C:13]([O:21][CH2:22][C:23]1([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:25][CH:24]1[CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:40]([O:39][CH2:38][C:23]1([CH2:22][O:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][CH:24]1[CH2:26][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])(=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: Cc1ccc(S(=O)(=O)OCC2CC2(COC(=O)c2ccccc2)COC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CC1CC1(COC(=O)c1ccccc1)COC(=O)c1ccccc1
Reaction time: 3 h
Yield: 22.5 %

Procedure:
A suspension of 965 mg (7.14 mmoles) of adenine in 25 ml of dry DMF was stirred and 171 mg (7.14 mmoles; 286 mg of 60%) NaH emulsion was added. All of the NaH had reacted after 30 minutes and a solution of 3 g (6.5 mmoles) of 1,1-bis(benzoyloxymethyl)-2-(p-toluenesulfonyloxymethyl)cyclopropane (Example 2, product of Step D) in 10 ml of DMF was added and the mixture was heated at 40°. TLC in CMW (90:10:1), Rf 0.2, 0.95 (starting materials) 0.45, 0.55 (products) showed that the reaction was complete in 3 hours. The mixture was concentrated to dryness and the residue was triturated with three 20 ml portions of ether, filtered and dried. The resultant solid was washed with twenty 3 ml portions of water and dried (1.2 g, largely a mixture of the two isomeric products). One gram of the crude product was chromatographed on five 2000 micron silica gel plates in CMW (95:3:0.3) and the zones (UV absorbing) at Rf 0.29 and 0.18 (the 9 and 7 isomers, respectively) were eluted with CMW (70:30:3). After concentration of the solvents, there was obtained 670 mg (25%) of the title compound and 78 mg (2.5%) of the 7-isomer.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])[C:18]4[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: OCCOCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: OCCOCCn1c(NC2CCNCC2)nc2ccccc21
Yield: 46 %

Procedure:
A mixture of 140 parts of 2-[2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-1H-benzimidazol-1-yl]ethoxy]ethanol and 480 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was crystallized twice from acetonitrile. The product was filtered off and dried, yielding 53.3 parts (46.0%) of 2-[2-[2-(4-piperidinylamino)-1H-benzimidazol-1-yl]ethoxy]ethanol; mp. 163.7° C. (compound 38).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:9][C:8]([NH:10]C(=O)OC(C)(C)C)=[N:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O.Cl>O>[NH2:10][C:8]1[S:9][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][N:7]=1
Reactant: CNC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNC(=O)c1cnc(N)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159 %

Procedure:
tert-Butyl 5-(methylcarbamoyl)thiazol-2-ylcarbamate (0.77 g, 3.0 mmol) was added to TFA (1.5 mL) that was cooled in a water bath. The solution obtained was stirred at room temperature for 1.5 h. A second batch of TFA (1.5 mL) was added and the reaction mixture was stirred at 40° C. for 30 min and then concentrated in vacuo. To the residue was added 1 M aqueous solution of HCl (3.0 mL, 3.0 mmol) and deionized water (2.0 mL) and the solution concentrated under reduced pressure. Lyophilization gave 2-amino-N-methylthiazole-5-carboxamide (HCl salt, 750 mg) as a white powder. MS found: (M+H)+=158. The crude product was used as such in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:28]([O:30]CC)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH:9]1[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In tetrahydrofuran (40 ml), 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine (23.0 g) was dissolved, followed by the addition of ethanol (40 ml) and a 3N aqueous sodium hydroxide solution (30 ml). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture, 1N hydrochloric acid was added to make it acidic and then ethyl acetate was added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. The solid precipitated by distilling off the solvent under reduced pressure was collected by filtration, whereby the title compound (23.8 g, quant.) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19](=[O:20])[NH:18][C:13]2=[N:14][CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O([CH2:42][C:43]([F:46])([F:45])[F:44])S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19](=[O:20])[N:18]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:13]2=[N:14][CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)n(CC(F)(F)F)c2nccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (is this correct or did the reaction start with the unprotected species?) (Example 1.3) (0.10 g), potassium carbonate (0.053 g) and 2,2,2-trifluoroethyl triflate (0.130 g) were heated in a microwave at 150° C. for 30 minutes, and then at 170° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between dichloromethane and aqueous hydrochloric acid (2M). The phases were separated. The organic layer was dried over magnesium sulfate and concentrated. The residue was dissolved in dichloromethane and treated with trimethylacetyl chloride (0.063 ml) and pyridine (0.061 ml) and stirred at ambient temperature. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: acetone/iso-hexane 0:10 to 1:9) to give Compound No. C8 of Table C as a beige solid (0.049 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[S:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[CH3:12][O:13][C:14]1([O:22][CH3:23])[C:19](=O)[NH:18][C:17]([CH3:21])=[CH:16][S:15]1>ClCCl>[CH3:23][O:22][C:14]1([O:13][CH3:12])[CH:19]=[N:18][C:17]([CH3:21])=[C:16]([CH:8]2[N:9]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:10]=[CH:11][S:7]2)[S:15]1
Reactant: c1cscn1
Reactant: CCOC(=O)Cl
Reactant: COC1(OC)SC=C(C)NC1=O
Solvent: ClCCl
Product: CCOC(=O)N1C=CSC1C1=C(C)N=CC(OC)(OC)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Ethyl chloroformate (1.0 g) was added dropwise to a stirred solution of thiazole (0.79 g) in dichloromethane (10 ml) under ice-cooling and the mixture was stirred at room temperature for 0.5 hour. Then, 2,2-dimethoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (1.47 g) was added, and the mixture was stirred at room temperature for 3 hours. The solution was washed with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (Merck Lobar column size B: Art.10401, solvent: ethyl acetate-n-hexane=2:3) to give 2,2-dimethoxy-5-methyl-6-(3-ethoxycarbonyl-2,3-dihydro-2-thiazolyl)-2H-1,4-thiazin-(4H-one (510 mg, yield 19%) as colorless prisms.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N1CCCCC1>CN(C)C=O>[NH2:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C)C(N)=O
Yield: 100 %

Procedure:
Condensation of FmocDLys(Boc)OH (1.00 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 0.63 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave FmocDLys(Boc)-Leu-MetNH2 in 87% yield. De-9-fluorenylmethoxycarbonylation of FmocDLys(Boc)-Leu-MetNH2 (1.00 g.) using piperidine in dimethylformamide gave HDLys(Boc)-Leu-MetNH2 in 100% yield.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:42][CH:41]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]2[NH:3][C:4](=[O:7])[O:5][N:53]=2)=[CH:42][CH:41]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogen carbonate (0.67 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.22 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.077 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.065 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCNS(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC(=O)OC(C)(C)C)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
The compound (817.3 mg) obtained in Example 102-2 was dissolved in anhydrous methanol (24.5 ml) and added with 1-methyl-2-imidazolealdehyde (309.4 mg) and sodium cyanoborohydride (235.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 24 hours. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (910.0 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of (2S,4R)-methyl 1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (2.2 g, 5.1 mmole) in THF/water (20 mL, 1:1) was added LiOH (650 mg, 15 mmole) followed by 5 mL of methanol at room temperature. The reaction mass was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified with aqueous 1.5 N HCl solution. The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get desired product (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.8 g, 85%) as white solid. MS: MS m/z 411.2 (M+−1).