Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1>CN(C=O)C>[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH:33][C:12](=[O:14])[CH:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH3:15])=[CH:28][CH:27]=1
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Reactant: NNc1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NNc1ccc(Cl)nn1)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2-(quinolin-6-yl)propanoic acid (3260 mg, 16201 μmol) and DIEA (2830 μl, 16201 μmol) in DMF (25 mL) was added o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uronium hexafluorophosphate (6160 mg, 16201 μmol) whole at 23° C. under nitrogen. The solution was stirred for 60 min, cooled to 0° C., then added 1-(6-chloropyridazin-3-yl)hydrazine (2342 mg, 16201 μmol). After 20 h stirring at 23° C., the reaction was then partitioned between 9:1 CHCl3/IPA (100 mL) and 5% NaHCO3 (50 mL). The organic phase was then dried over MgSO4, concentrated to an oil, then purified on silica (120 g) eluting with 0>10% of 2 M NH3 in MeOH/DCM. The product was isolated as an off white solid. MS (ESI pos. ion) m/z: 328 (MH+). Calc'd exact mass for C16H14ClN5O: 327.
Reaction SMILES: [OH:1][C@H:2]([CH2:38][OH:39])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[C:15](=[O:16])[N:14]([C@@H:17]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[O:19])[C:13](=[O:37])[NH:12]2)=[CH:7][CH:6]=1>CO>[OH:1][C@H:2]([CH2:38][OH:39])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[C:15](=[O:16])[N:14]([C@@H:17]([C@H:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH3:30])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[O:19])[C:13](=[O:37])[NH:12]2)=[CH:9][CH:10]=1
Reactant: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OC[C@H](O)CO)cc2)C1=O
Solvent: CO
Product: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@@H](c2ccc(OC[C@H](O)CO)cc2)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.6 %

Procedure:
(2S,3S)-2-{(R)-4-[4-((R)-2,3-Dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (prepared as described in example 56) (160 mg, 0.25 mmol) was dissolved in methanol (10 ml) and allowed to stir for 48 hours at ambient temperature followed by warming to 50° C. for an additional 6 hours. The solvent was removed in vacuo and the residue was then purified by super-critical fluid chromatography using a Chiracel OD column eluted with carbon dioxide at 100 bar and 30° C. containing 35% methanol in acetonitrile eluted at 2 mL/minute. The second eluted compound was collected and concentrated in vacuo to obtain (2S,3S)-2-{(S)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide as a colorless solid (35 mg, 44%). The compound eluted first was identical with (2S,3S)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([NH2:22])=[N:6][CH:5]=1.O>C(O)CO.Cl.C(Cl)Cl.CO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[NH:10][C:8]3[C:7]([N:22]=2)=[N:6][CH:5]=[C:4]([C:3]([OH:2])=[O:23])[CH:9]=3)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1cnc(N)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: OCCO
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cnc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1

Procedure:
To a suspension of 6-Amino-5-(4-nitro-benzoylamino)-nicotinic acid methyl ester (5) (4.05 g, 13 mmol) in ethylene glycol (300 ml) was added conc. HCl (20 drops) and the mixture heated at 160 C for 5 h. TLC in DCM/MeOH (19:1) indicates the absence of starting material. The solution was cooled and poured into H2O and the solid collected by filtration and air-dried. 1H NMR (500 MHz, DMSO-d6) δ14.08 (br s, 1H), 8.97 (s, 1H), 8.51 (br s, 1H), 8.49 (d, J=8.7 Hz, 2H), 8.43 (d, J=8.7 Hz, 2H), 3.92 (s, 3H). EIMS m/z M−1 297.3
Reaction SMILES: C(OC([N:8]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]([CH2:51][CH2:52][C:53]#[N:54])[CH2:45][C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)(=[O:43])=[O:42])(=[O:34])=[O:33])[CH:25]=1)[C:9]([NH:11]C(OC(C)(C)C)=O)=[NH:10])=O)(C)(C)C.Cl.CO.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:30][C:28]1[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]([CH2:51][CH2:52][C:53]#[N:54])[CH2:45][C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)(=[O:42])=[O:43])(=[O:33])=[O:34])[CH:25]=[C:24]([CH:29]=1)[O:23][CH2:22][CH2:21][CH2:20][O:19][NH:8][C:9]([NH2:11])=[NH:10]
Reactant: Cc1cc(OCCCON(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC#N)Cc2ccco2)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Solvent: CO
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC#N)Cc2ccco2)c1
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield from N,N′-bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine, as prepared in the previous step, in a manner analogous to step i of Example 20 (without HCl-methanol acidification). 1H NMR (300 MHz, CDCl3) δ8.23 (dd, 1H, J=7.9, 1.3 Hz), 8.14 (dd, 1H, J=7.9, 1.4 Hz), 7.76 (td, 1H, J=7.7, 1.4 Hz), 7.67 (td, 1H, J=7.7, 1.3 Hz), 7.29 (t, 1H, J=1.3 Hz), 6.56 (m, 2H), 6.51 (m, 1H), 6.28 (m, 2H), 4.61 (s, 2H), 3.91 (m, 4H), 3.62 (t, 2H J=7.1 Hz), 2.53 (t, 2H, J=7.1 Hz), 2.20 (s, 3H), 2.00 (pentet, 2H, J=6.1 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H29N5O8S2: 592.2 (M+H), 614.1 (M+Na). Found: 592.2, 614.4.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=S)[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O1CCOCC1.C(O)(=O)C.[Ni]>[CH3:1][N:2]([CH2:3][CH:4]([C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:21]
Reactant: COc1ccc(C(C(=S)N(C)C)C2(O)CCCCC2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1

Procedure:
A solution of N,N-dimethyl-α-(1-hydroxycyclohexyl)-p-methoxyphenylthioacetamide in 5 ml per gram of thioamide in dioxan/acetic acid (9:1) is added to Raney nickel (20 grams per gram of thioamide) in 50 ml per gram of the thioamide of the same solvent at room temperature to 50° C. After 15 minutes to 10 hours the Raney nickel is filtered through kieselguhr and the solvent is evaporated under reduced pressure. The residue is partitioned between 2N sodium hydroxide solution and methylene chloride. The organic phase is dried and the solvent is evaporated. The residue is converted into the hydrochloride salt of the title compound using 4N isopropanolic hydrogen chloride.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.[CH3:18][NH:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:29])[CH2:24][CH2:23]1>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[N:19]([CH3:18])[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:29])[CH2:24][CH2:23]1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(N(C)CCC2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (20.58 mg, 0.145 mmol) and triethylamine (81 μl, 0.579 mmol) in MeOH (483 μl) was warmed to 45° C. for 30 mins. 3,5-Dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (50 mg, 0.145 mmol) was added drop wise and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated under reduced pressure and the crude oily product was dissolved in water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure. The crude product was suspended in MeOH and sonicated. The resulting white solid was filtered and dried to afford the title compound;
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@@H:9]1[C:13](=[O:14])[CH2:12][O:11][C@@H:10]1[CH3:15])(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C@H:9]1[C@@H:10]([CH3:15])[O:11][CH2:12][C:13]1=[O:14]
Reactant: C[C@H]1OCC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1OCC(=O)[C@H]1N
Reaction time: 0.33 h
Yield: 100 %

Procedure:
HCl in dioxane (4.0M, 9 ml) was added drop-wise with stirring over 1 minute to (2R, 3S) (2-methyl-4-oxo-tetrahydrofuran-3-yl)carbamic acid tert-butyl ester (0.372 g, 1.73 mmol). The mixture was stirred for 20 minutes then the solvents evaporated in vacuo to leave a residue which was azeotroped with toluene (2×20 ml) to leave (4S, 5R) 4amino-5-methyl-dihydro-furan-3-one hydrochloride as a white solid (266 mg, 100%). HPLC-MS, Rt=0.419 mins, 116.1 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:15])=[CH:10][CH:9]=1.[OH:21]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:17][C:18]([OH:20])=[O:19])=[O:21])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(SCC(=O)O)c1ccc(-c2ccccc2Cl)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CC(c1ccc(-c2ccccc2Cl)cc1)S(=O)CC(=O)O
Reaction time: 8 h

Procedure:
50 gm (0.163 mol) of [1-(2'-chloro-4-biphenylyl)-ethylthio]-acetic acid were suspended in 163 ml of glacial acetic acid and 16.0 gm (0.171 mol) of 36.3% hydrogen peroxide were added dropwise to the suspension at 10° C. while vigorously stirring. Afterwards, the mixture was allowed to stand overnight at room temperature, during which time the starting compound dissolved. Subsequently, 500 ml of water were added, the reaction product was extracted with ethyl acetate, and the organic solvent was removed from the extract in vacuo, leaving 45.1 gm (85% of theory) of the title compound, m.p. 144°-147° C. (from ethyl acetate).
Reaction SMILES: [Cl:1][Si:2](Cl)([CH3:7])[Si:3]([Cl:6])([CH3:5])[CH3:4].[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:1][Si:2]([CH3:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[Si:3]([Cl:6])([CH3:5])[CH3:4]
Reactant: [Li]c1ccccc1
Reactant: C[Si](C)(Cl)[Si](C)(Cl)Cl
Product: C[Si](C)(Cl)[Si](C)(Cl)c1ccccc1
Reaction time: 3 h

Procedure:
1,1,2-trichloro-1,2,2-trimethyl disilane 103.8 g (0.5 mole) and petroleum ether 200 g were placed in the same type of reaction apparatus as used in the above Comparative Example, and an petroleum ether solution of phenyl lithium 42.5 g (0.5 mole) was dropwise added thereto for 3 hours while stirring at the reaction temperature of 25° to 30° C. After the dropwise addition, the stirring was continued for 2 hours at 25° to 30° C. to complete the reaction. In order to identify the reaction product, the product obtained by separating the by-produced lithium salt by filtration was subjected to 1H-NMR spectrum (C6D6) analysis in the same manner as in the above Comparative Example. As this result, it was proved that 1,1-dichloro-1,2,2-trimethyl-2-phenyl disilane was not substantially produced and that 1,2-dichloro-1,2,2-trimethyl-1-phenyl disilane could be produced at a favourable selectivity. The reaction product was then purified by a normal purification method to obtain 1,2-dichloro-1,2,2-trimethyl-1-phenyldisilane 113.4 g at the yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[N:24]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36]CN)=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:36][C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:35][CH:34]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: NCCc1ccc(CN2CCCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1CCc1ccc(CN2CCCC2)cc1
Yield: 60.9 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.2 g), 2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethanamine dihydrochloride (0.17 g), N,N-diisopropylethylamine (0.20 g) and ethanol (4 ml) was heated under reflux overnight. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (168 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[O:19]1[CH:20]=[CH:21][C:17]([S:14]([N:13]2[CH:12]=[C:11]([CH2:22][NH:23][CH3:24])[CH:10]=[C:9]2[C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:16])=[O:15])=[CH:18]1
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccoc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (175 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 126 mg, 84%).
Reaction SMILES: C[C:2]([CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4]C.CCCCCC([OH:24])/C(/C)=C/CC>>[CH2:4]([OH:24])[CH:3]=[CH:2][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: CC/C=C(\C)C(O)CCCCC
Product: CCC=CCCC=CCO

Procedure:
4-methyl-3-decen-5-ol (UNDECAVERTOL, Givaudan-Roure)*
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].C(OC(=O)C1C=C(Br)C(OC)=NC=1)C.C([BH-](CC)CC)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(C=O)cc1Br
Agent: CCOC(=O)c1cnc(OC)c(Br)c1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(CO)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5-bromo-6-methoxy-pyridine-3-carbaldehyde and 5-bromo-6-methoxy-nicotinic acid ethyl ester (3 g, 13.9 mmol) was dissolved in THF (30 mL) and cooled to 0° C., and lithium triethylborohydride (1M in THF; 42 mL, 42 mmol) was added. The reaction was stirred for 5 minutes, and then quenched with EtOH, acidified with 1N aqueous HCl, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give (5-bromo-6-methoxy-pyridin-3-yl)-methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([CH:15]1[CH2:17][CH2:16]1)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]>CC(O)=O.[Fe]>[NH2:24][C:3]1[C:2]([Cl:1])=[C:11]([F:12])[C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][N:8]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(Cl)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(Cl)c(N)c2c1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
A mixture of ethyl 6-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (240 mg, 0.624 mmol) and iron powder (209 mg, 3.74 mmol) in AcOH (10 mL) was stirred at 90° C. for 6 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. After water was added, the crude product was extracted with EtOAc, washed successively with saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) Hexane:EtOAc 5:1→1:1) to yield ethyl 5-amino-6-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (141 mg, 64%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[F:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CCO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:35][CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][CH2:39]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[F:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)c(F)c2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccccc2)c(F)c1
Yield: 90.9 %

Procedure:
A mixture of (S)-ethyl 2-(5-(4-(benzyloxy)-3-fluorophenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.019 g, 0.033 mmol) and LiOH (7.89 mg, 0.329 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(5-(4-(benzyloxy)-3-fluorophenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid (0.0162 g, 0.030 mmol, 90% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.47-7.51 (m, 2H), 7.42 (dt, J=3.0, 7.3 Hz, 2H), 7.34-7.39 (m, 1H), 7.08 (t, J=8.4 Hz, 1H), 7.03 (dd, J=1.9, 11.5 Hz, 0.5H), 6.89-6.94 (m, 1H), 6.80 (d, J=8.2 Hz, 0.5H), 5.83 (br. s., 0.6H), 5.78 (br. s., 0.4H), 5.18-5.26 (m, 2H), 2.74 (s, 1.3H), 2.72 (s, 1.7H), 2.27 (s, 1.7H), 2.26 (s, 1.3H), 1.26-1.39 (m, 4H), 1.23 (s, 9H), 0.82 (br. s., 6H). 4H of piperidine were not resolved. LCMS (M+H)=549.47.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[N:25]1[N:26]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[N:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N:25]1[N:26]([C:30]2[CH:31]=[C:32]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]4[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=3[C:23]#[N:24])[CH:34]=[CH:35][CH:36]=2)[N:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-n2nccn2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-n3nccn3)c2)n1
Reaction time: 20 h
Yield: 157.5 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.574 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (123 mg, 0.574 mmol) and DIEA (0.150 mL, 0.862 mmol) in NMP (3 mL) was stirred at room temperature for 20 h. HOAc (0.3 mL) was added. Then, water was added to induce precipitation. The precipitate was collected, dried on vacuum to give tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (165 mg). A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (80 mg, 0.227 mmol), 3-(2H-1,2,3-triazol-2-yl)aniline (50 mg, 0.312 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated. The aqueous phase was extracted with EtOAc again. The combined organic phases were dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg). The crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg) was dissolved in TFA (4 mL). After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1ccc2oc3ccccc3c2c1
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, 150 g of dibenzofuran and 1 l of acetic acid were loaded into a 300-ml three-necked flask, and then the contents were dissolved under heat. 188 Grams of bromine were added dropwise to the solution. After that, the mixture was stirred for 20 hours under air cooling. The precipitated crystal was separated by filtration, and was then sequentially washed with acetic acid and water. The washed crystal was dried under reduced pressure. The resultant crystal was purified by distillation under reduced pressure, and was then repeatedly recrystallized with methanol several times. Thus, 66.8 g of 2-bromodibenzofuran were obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:11]([OH:26])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38](O)=[O:39].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@H:11]([OH:26])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:39]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.9 %

Procedure:
A mixture of 60 mg (0.13 mol) of 2(S)-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide, 25 mg (0.13 mmol) of 3,5-dichlorobenzoic acid, 18 mg (0.13 mmol) of hydroxybenzotriazole hydrate and 27 mg (0.13 mmol) of dicyclohexylcarbodiimide in 2 ml of dimethylformamide was stirred at room temperature under nitrogen for 20 hours. The mixture was then filtered and the solid was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness and the residue was partitioned between 50 ml of ethyl acetate and 10 ml of saturated aqueous sodium hydrogen carbonate solution. The separated organic phase was dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on silica gel using 5% methanol in dichloromethane for the elution. The product was purified further by recrystallization from a mixture of 2 ml of dichloromethane and 10 ml of n-hexane to give 37 mg of 2(S)-[3(S)-[[N-(3,5-dichlorobenzoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 220°-226° C.