Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C(C)=CC=CC=1.NC1C=CC=CC=1S.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH:26]([OH:30])[C:27]([NH2:29])=[O:28]>CO.C(O)C.O>[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][C@@H:25]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[C@@H:26]([OH:30])[C:27]([NH2:29])=[O:28]
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: Nc1ccccc1S
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)glycidamide (1.93 g) and xylene (15 ml) is refluxed under nitrogen atmosphere. To the reaction solution is added a solution of 2-aminothiophenol (1.38 g) and iron sulfate·heptahydrate (0.28 mg) in methanol (0.2 ml) immediately after the refluxing starts. After reaction at the same temperature for 5 minutes, the reaction solution is cooled to room temperature. The reaction solution is subjected to HPLC analysis to confirm the production of 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (2.69 g) (threo/erythro=91/9). The reaction solution is concentrated under reduced pressure to remove the solvent, and the residue thus obtained is dissolved with heating in ethanol (3 ml) and water (3 ml). The solution is gradually cooled with stirring to 0° C. for crystallization. The precipitated crystals are collected by filtration. The collected crystals are washed with iced 50% ethanol, and dried at 50° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propioamide (0.84 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][NH2:17])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[S:28][C:29]([C:33](=[O:35])[CH3:34])=[C:30]([CH3:32])[N:31]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[C:33]([C:29]1[S:28][C:27]([NH:26][C:25]([NH:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:24])=[N:31][C:30]=1[CH3:32])(=[O:35])[CH3:34]
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Reactant: NCC1CCCN(CCc2ccc(F)cc2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(NC(=O)NCC2CCCN(CCc3ccc(F)cc3)C2)nc1C
Yield: 67.6 %

Procedure:
A solution of C-{1-[2-(4-fluorophenyl)ethyl]-piperidin-3-yl}methylamine (25 mg, 106 μmol), (5-Acetyl-4-methylthiazol-2-yl)-carbamic acid phenyl ester (24 mg, 106 μmol) and triethylamine (29 μL, 210 μmol) in acetonitrile (3 mL) was stirred for 18 hours and concentrated. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane, to provide an off-white solid (30 mg, 68%). 1H NMR (300 MHz, CD3OD) δ7.21 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.16 (m, 2H), 3.02 (m, 2H), 2.82 (m, 2H), 2.61 (m, 2H), 2.56 (s, 3H), 2.47 (s, 3H), 2.09 (m, 1H), 1.85 (m, 4H), 1.65 (m, 1H), 1.05 (m, 1H). Mass spec (ES+) m/z 419.2 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
2-chloro-3-nitrobenzoic acid (543.6 g, 2.7 mol) was suspended in methanol (3425.0 ml), and concentrated sulfuric acid (108.5 ml) was added thereto. The mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature, and then the solvent was concentrated under reduced pressure. The concentration residue was added into a saturated aqueous solution of sodium bicarbonate. A solid that precipitated was filtered, and washed with water. The solid thus obtained was dissolved in ethyl acetate, washed with saturated saline, and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, the filtrate was concentrated and dried to solid under reduced pressure, and the resultant solid was washed with n-hexane. As a result, 542.6 g (yield: 93%) of the indicated compound was obtained
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[CH:1]1([N:7]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[O:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1F)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 1-fluoro-2-isocyanato-benzene ([16744-98-2]) in toluene for 48 h under reflux conditions to give the title compound as colorless oil. MS: m/e=429.5 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[CH:38]1([CH2:41][O:42][NH2:43])[CH2:40][CH2:39]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>C(Cl)Cl>[CH:38]1([CH2:41][O:42][NH:43][C:34]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:37])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17]2)=[O:36])[CH2:40][CH2:39]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Reactant: NOCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NOCC2CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 21.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.15 g, 0.27 mmol) was reacted with O-cyclopropylmethylhydroxyamine (HUHU Tech) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide as a white solid (30 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]2[C:7]([NH:9][C:10](=[O:11])[C:3]=12)=[O:8].[NH3:12]>>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([NH2:12])=[O:8])[C:3]=1[C:10]([NH2:9])=[O:11]
Reactant: N
Reactant: Nc1snc2c1C(=O)NC2=O
Product: NC(=O)c1nsc(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 10.1 parts of 5-aminoisothiazole-3,4-dicarboximide and 70 parts of concentrated aqueous ammonia solution is stirred for 2 hours at room temperature, and the colorless precipitate is then filtered off under suction, washed with water and dried to give 9.3 parts (83% of theory) of 5-aminoisothiazole-3,4-dicarboxamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:20][N:19]=1
Reactant: OB(O)c1ccco1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1coc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 2-furanylboronic acid (141 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 127 mg, 0.56 mmol, 89%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.12 (s, 2H), 6.52 (dd, J=3.4, 1.5 Hz, 1H), 6.89 (t, J=1.2 Hz, 1H), 7.05 (dd, J=3.4, 0.6 Hz, 1H). 7.09 (brs, 1H), 7.43 (dd, J=8.2, 2.1 Hz, 1H), 7.52 (dd, J=1.5, 0.6 Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 109.2, 112.1, 118.6, 118.9, 129.7, 130.2, 135.6, 137.2, 143.6, 148.4, 149.5, 152.9; MS (ESI): m/z=225.93 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[CH3:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]([NH:18][CH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:10])=[O:5]
Reactant: COC(=O)C(OC)OC
Reactant: Cc1ccccc1CN
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1ccccc1C
Temperature: 55 °C
Reaction time: 264 h

Procedure:
A mixture of methyl dimethoxyacetate (2.11 g, 15.6 mmol) and o-xylylamine (1.90 g, 15.4 mmol) in a 15 mL sealed tube was stirred at 55° C. for 11 d. The reaction solution was dissolved in EtOAc (≈60 mL) and washed with dil. HCl, water, sat. NaHCO3 solution, and brine, and dried over MgSO4. The EtOAc extract was filtered, concentrated, and dried in vacuo overnight to give the title compound as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.25-7.16 (m, 4H), 6.69 (brs, 1H), 4.75 (s, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.40 (s, 6H), 2.33 (s, 3H). MS(ES+): m/z=246.07 (83) [MNa+], 224.11 (100) [MH+], 192.14 (60) [MH+-MeOH], 160.10 (95) [MH+-2 MeOH]. HPLC: tR=2.82 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(OC([N:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1)=O)(C)(C)C>>[NH:39]1[CH2:42][CH:41]([C:43]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:30])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][C:14]=4[NH:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]5[NH:27][CH:28]=[CH:29][C:22]=45)[CH:6]=3)[C:2]([CH3:31])([CH3:1])[CH2:3]2)=[O:44])[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Product: CC1(C)CN(C(=O)C2CNC2)c2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]nicotinamide (Example 16) and azetidine-1,3-dicarboxylic acid 1-tert-butyl ester by the method described in Example 13. MS (ES+): 496 (M+H). Calc'd. for C28H29N7O2—495.58.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]COC)=O.[NH2:24][OH:25].CO>[Cl-].[NH4+]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:24][OH:25])=[O:20]
Reactant: NO
Reactant: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1c(CCCCCCC(=O)NO)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (0.3 g) was added to 1M hydroxylamine/methanol (2.85 ml) and the mixture was stirred at room temperature for 1.5 hours. This reaction mixture was poured in saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness, and the residue was recrystallized from hexane-ether to provide the title compound (0.116 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:10](=[O:22])[O:11][C:12]([CH2:20][OH:21])=[C:13]([CH3:19])[C:14]=1[O:15][CH2:16][O:17][CH3:18].[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCOC(C)=O>[CH3:8][C:9]1[C:10](=[O:22])[O:11][C:12]([CH2:20][O:21][S:24]([CH3:23])(=[O:26])=[O:25])=[C:13]([CH3:19])[C:14]=1[O:15][CH2:16][O:17][CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1c(C)c(CO)oc(=O)c1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COCOc1c(C)c(COS(C)(=O)=O)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (606 mg) was added to a solution of 3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one (1.26 g) in THF (50 ml), and after stirring the mixture at room temperature for one hour, methanesulfonyl chloride (1.05 g) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 3,5-dimethyl-4-methoxymethoxy-6-(methylsulfonyloxy) methyl-2H-pyran-2-one.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1cc(F)cc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 37.4 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g, 2.68 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml), 3-Fluoro-5-methoxyphenyl boronic acid (0.592 g, 3.48 mmoles) and sodium carbonate (1.42 g, 13.40 mmoles) were added and the system is degassed for 30 min Palladium tetrakis triphenylphosphine (0.588 g, 0.509 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.260 g, 37% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.64(s, 1H), 8.21(s, 1H), 7.03(m, 2H), 6.93(td, J=11.1,2.3Hz, 1H),3.83(s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C2CCCCO2)=[CH:24][CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OC3CCCCO3)cc1)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)cc1)CC2
Yield: 37.2 %

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-[4-((2RS)-2-tetrahydropyranyloxy)phenyl]ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (780 mg) was dissolved in ethanol (20 ml), and 1N hydrochloric acid (34 ml) was added to the solution under ice-cooling with stirring. After reaction for an hour, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate) gave ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (238 mg) as an amorphous.
Reaction SMILES: CC([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)=[CH:7][CH:6]=1)C>Br.C(O)(=O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)=[CH:7][CH:6]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Agent: Br
Solvent: CC(=O)O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ncnn12
Yield: 73.2 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (6.00 g), 4-isopropoxyphenylboric acid (5.85 g), copper(II) acetate (5.90 g), pyridine (18 mL), triethylamine (9 mL), molecular sieves 4A (18.0 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 1 day. Ethyl acetate (100 mL) was added to the reaction mixture, the mixture was stirred at room temperature for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile as a colorless solid (6.53 g, 80%). A mixture of 4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (6.53 g) and 25% hydrobromic acid-acetic acid solution (10 mL) was stirred under refluxing for 2 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate 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 solid (4.38 g, 73%).
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:25][CH2:26][C:27](O)=[O:28])([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:14][C:13]2=[O:30])[CH3:11])=[CH:6][CH:5]=1.C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.C1COCC1>[F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:25][CH2:26][C:27]([NH2:33])=[O:28])([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:14][C:13]2=[O:30])[CH3:11])=[CH:6][CH:5]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 49 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (0.0485 g, 0.11 mmol) in DMF (2 mL) was added HATU (0.2603 g, 0.68 mmol), DIPEA (0.5 mL), and 0.8 M NH3 in THF (3 mL). The mixture was stirred at rt for 22 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0235 g (49%) of 3-((R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide. LC-MS Method 1 tR=1.48 min, m/z 459 (MNa+), 393; 1H NMR (400 MHz, CDCl3) δ 7.23-7.20 (m, 2H), 7.04-6.99 (m, 2H), 6.95 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 6.43 (t, J=73.8 Hz, 1H), 5.83-5.78 (m, 2H), 5.62 (q, J=7.0 Hz, 1H), 2.95-2.91 (m, 1H), 2.45 (m, 1H), 2.27-2.15 (m, 5H), 1.98 (m, 1H), 1.49 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −81.51 (d, J=73.7 Hz), −114.66 (m).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1>C1COCC1>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=2)[CH2:15][CH2:16]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
557 mg of NaH (14 mmol) suspended in 10 ml of THF are placed under nitrogen. The mixture is cooled to 0° C. and a solution of 1.5 g (9.3 mmol) of 2-chloro-5-nitropyridine and 1.28 g (11.1 mmol) of 4-hydroxy-1-methylpiperidine in 15 ml of THF is added dropwise. The reaction mixture is refluxed for 4 hours. After hydrolysing the excess NaH, the solvent is evaporated off under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with saturated NaCl solution. It is then dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to 100/4 v/v) to give 1.1 g of 2-(1-methylpiperidin-4-yloxy)-5-nitropyridine.
Reaction SMILES: C(I)I.[C:4](=O)([O-])[O-].[K+].[K+].[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([OH:35])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([SH:29])=[N:26]3)=[CH:21][C:20]=2[Cl:36])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>CN(C)C=O>[C:10]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]4[S:29][CH2:4][N:26]43)=[CH:21][C:20]=2[Cl:36])[CH2:17][CH2:18]1)(=[O:12])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(S)nc2cc(N3CCN(C(C)=O)CC3)c(Cl)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Product: CCOC(=O)c1c2n(c3cc(N4CCN(C(C)=O)CC4)c(Cl)cc3c1=O)CS2
Yield: 80.6 %

Procedure:
Into 50 ml of N,N-dimethylformamide were placed 2.35 g of methylene iodide and 2.5 g of potassium carbonate and a solution of 3.0 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-chloro-4-hydroxy-2-mercaptoquinoline-3-carboxylate in 30 ml of N,N-dimethylformamide was gradually dropped in with stirring. After that, the mixture was stirred at room temperature for 1 hour, concentrated in vacuo, water was added to the residue, and insoluble crystals were collected by filtration. They were washed with water, dried, and recrystallized from a mixed solvent of ethanol and chloroform to give 2.49 g of colorless powdery crystals, m.p. 266°-268° C. (decompn).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Under ice-cooling, trifluoroacetic acid (1.3 mL) was added to a methylene chloride (6.5 mL) solution of methyl 2-(2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzamido)-4-bromobenzoate (0.65 g), followed by stirring at room temperature for 30 minutes. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate under ice-cooling. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 0.54 g of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-bromobenzoate as a white solid.