Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:32]([O-:34])=[O:33])=[C:14]([CH:31]=1)[C:15]([NH:17][C:18]1[CH:23]=[C:22]([C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:30])=[O:16]>>[CH:27]1([NH:26][C:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:30])=[C:18]([NH:17][C:15](=[O:16])[C:14]3[CH:31]=[C:10]([N:6]4[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]4)[CH:11]=[CH:12][C:13]=3[N+:32]([O-:34])=[O:33])[CH:23]=2)=[O:25])[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1, which is concerned with the preparation of starting materials, N-ethylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-ethylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 1.02 (t, 3H), 2.30 (s, 3H), 2.37 (m, 2H), 2.48 (m, 4H), 2.83 (m, 1H), 3.49 (m, 4H), 7.06 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.04 (d, 1H), 8.35 (d, 1H), 9.91 (s, 1H);
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].Cl.Cl[CH2:16][CH2:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:19][N:18]1[CH2:20][CH2:21][N:2]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[OH:13])[CH2:16][CH2:17]1
Reactant: Nc1c(O)ccc2ccccc12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2c(O)ccc3ccccc23)CC1
Reaction time: 48 h

Procedure:
1-Aminonaphthalen-2-ol hydrochloride (5 g, 25.6 mmol) is brought to the reflux point of 1-butanol (100 ml) in the presence of 2-chloro-N-(chloroethyl)-N-methylethanamine hydrochloride (4.9 g, 25.6 mmol) and sodium carbonate (5.4 g, 51 mmol). After 48 h, the reaction mixture is concentrated and impregnated onto silica and then purified by flash chromatography with a mixture (93/7/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C@@H:6]1[C@H:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[CH2:8][C@@H:7]1[CH3:29])#[N:2]>CCO>[NH2:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[C@@H:9]1[CH2:10][C@H:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[C@H:7]([CH3:29])[CH2:8]1
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OCCC#N
Solvent: CCO
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1OCCC#N
Yield: 31 %

Procedure:
Method 6 was followed using (+/−)-tert-butyl (1R,5S,65)-6-(2-cyanoethoxy)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate with SFC (15% EtOH, 100 mL/min, OJ column) to yield tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-(2-cyanoethoxy)-3-methylcyclohexyl)carbamate (31% yield, 99% ee) and tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-(2-cyanoethoxy)-3-methylcyclohexyl) carbamate (26% yield, 99% ee). LC/MS (m/z)=375.3 (MH+), Rt=0.65 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OCC=C)=O)[C@H:3]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=1
Reactant: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of rac-cis-allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carboxylate (1.18 g, 3.32 mmol), Pd(PPh3)4 (0.384 g, 0.003 mmol) and THF (20 mL) was added morpholine (3.0 mL, 33.2 mmol). The mixture was degassed for 5 min and stirred at rt. The reaction was monitored for disappearance of starting material by analytical reverse-phase HPLC. After ˜1 h, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated and the resulting crude residue was purified by silica gel chromatography (0˜100% DCM/EtOAc) to afford the title compound ESI-MS (m/z): 472, [M+1]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:36])([F:35])[C@H:29]([OH:34])[CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][C@@H:29]([OH:34])[C:28]([F:36])([F:35])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (79 mg, 68%), MS (ISP) m/z=467.2 [(M+H)+], mp 166° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (R)-4,4,4-trifluoro-3-hydroxy-butyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[Br:1][C:2]1[C:7]2[C:8](=[O:10])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Br)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Br)c2C(=O)N2CC[C@@H]12

Procedure:
25 g (103 mmol) of 6-bromo-isatoic acid anhydride and 10.44 g (103 mmol) of L-azetidine-2-carboxylic acid in 100 ml of dimethyl sulphoxide are stirred at 95° for 25 minutes, the dimethyl sulphoxide is removed in vacuo and the residue is heated to 150° for 3 hours in a high vacuum. By chromatography of the resulting material on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained (S)-5-bromo-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 182°-183°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1.[OH:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>O1CCCC1>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:34][CH2:35]1.[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:34][CH2:35]1
Reactant: CN1CCC(O)CC1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.4 %

Procedure:
Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (6.80 g. 39.0 mmol) in tetrahydrofuran (THF) (25 mL) was added drop-wise at ambient temperature to a stirring solution of triphenylphosphine (10.23 g, 390 mmol) in THF (100 mL). The resulting solution was allowed to stir at ambient temperature for 30 min. 4-Hydroxy-1-methylpiperidine (3.05 g, 26.5 mmol) and 3-hydroxypyridine (3.71 g, 39.0 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 h. The solution was concentrated by rotary evaporation, and the resulting residue was dissolved in CHCl3 (100 mL). The suspension was cooled in an ice-water bath, and a solution of 1 M HCl (75 mL) was added with stirring. The aqueous phase was separated. The organic phase was extracted with water (3×75 mL). The combined aqueous extracts were cooled in an ice-water bath, basified with 1 M NaOH solution (125 mL) to pH˜11 and extracted with CHCl3 (6×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude product was dissolved in CHCl3 (75 mL), and the CHCl3 solution was extracted with 1 M NaOH solution (4×25 mL) to remove residual 3-hydroxypyridine. The CHCl3 phase was separated, and the combined NaOH layers were back extracted with CHCl3 (3×50 mL). All CHCl3 extracts were combined, dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified by vacuum distillation using a test-tube distillation apparatus, collecting the fraction with bp 83-93° C. at 0.10-0.075 mm Hg. Further purification by a second vacuum distillation yielded 120 mg (2.4%) of a colorless oil, bp 72-75° C. at 0.75 mm Hg. The compound exhibits a Ki of 4897 nM.
Reaction SMILES: FC1C=CC(C[O:7][C:8](=[O:35])[C:9]2[C:10](=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[C:11]([O:13]CC2C=CC(F)=CC=2)=[O:12])=CC=1>O1CCCC1.O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:23]2[CH:22]=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[CH:25][CH:24]=2)[C:8]([OH:35])=[O:7])=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)cc1C(=O)OCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid bis-(4-fluoro-benzyl) ester (7.8 g, 15.4 mmol) lithium hydroxide monohydrate (1.8 g, 46.2 mmol) in tetrahydrofuran (60 mL) and water (60 mL) was stirred at room temperature for 72 h. The mixture was then evaporated followed by acidification to pH 2 at 0° C. with concentrated HCl. The organic layer was then diluted with ethyl acetate, separared, washed with water and dried over sodium sulfate. Filtration and half evaporation gave a white suspension which was filtered off and washed with ether to afford the title compound (2.5 g, 56%) as a white solid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][N:5]=1)[NH2:3].C(O)(C(F)(F)F)=O.[F:21][CH:22]([F:34])[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=O>C(O)C(F)(F)F>[CH:27]1([C:25]2[N:2]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][N:5]=3)[N:3]=[C:23]([CH:22]([F:21])[F:34])[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C1CCCCC1)C(F)F
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2CCCCC2)nc1
Yield: 48.7 %

Procedure:
2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (448 mg, 2 mmol) and TFA (1.38 mL, 18 mmol) were mixed in trifluoroethanol (10 mL) and stirred for 5 minutes 4,4-Difluoro-1-cyclohexyl-1,3-butanedione (408 mg, 2 mmol) was added. The resulting reaction mixture was heated at reflux temperature for 60 hours. The solvent was then removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with brine and concentrated in vacuo. The product was purified by recrystallization from 3:1 of isooctane:methylene chloride to give the title compound (346 mg, 49%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10]1.C([O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37])C>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:34][C:32]3[CH:31]=[CH:30][C:29]([O:36][CH3:37])=[C:28]([CH:33]=3)[C:27]([OH:38])=[O:26])[CH2:20][CH2:19]2)=[CH:10]1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1COCCO1
Product: COc1ccc(CN2CCC(c3cn(CCC4COCCO4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.06 g (0.19 mmol) of 1-(2-[1,4]dioxan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole and 0.071 g (0.26 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification, 0.019 g (65% of yield) were obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared by following General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0 g) and methylamine (2 M in THF, 6.95 mL) in DMF (5 mL). The crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:27][C:4]1[N:3]=[C:2]([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: COC(=O)[C@H](COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H](COc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (80 mg, 0.20 mmol), (S)-methyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(tritylamino)propanoate (113 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (2 mg, 0.03 mmol), and Na2CO3 (42 mg, 0.40 mmol) were added to a mixture of ethanol (5 mL) and water (5 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was purified by chromatography to get (2S)-methyl 3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)-2-(tritylamino)propanoate, which was deprotected by TFA and LiOH respectively to afford 50 mg of (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)propanoic acid as the HCl salt. 1H NMR (300 MHz, CD3OD): δ 7.95 (m, 2H), 7.71 (s, 3H), 7.61 (m, 2H), 7.48 (m, 2H), 7.26 (m, 1H), 7.11 (m, 1H), 7.01 (s, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.40-4.55 (m, 3H); M+1=543.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[Cl:16].C(Cl)(=O)C([Cl:23])=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:23])=[O:12])=[CH:9][C:8]=1[Cl:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then was warmed up to room temperature over 18 h. The solvents were removed under reduced pressure. The resultant residue, crude compound 27e, was dried under reduced pressure for 2 h and used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[C:9]=2[F:18])=[CH:4][N:3]=1.Cl[CH:20]([C:30]1([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][CH:37]=[CH:36]3)[CH2:32][CH2:31]1)[CH:21](N1C(=O)CCC1=O)O>C(O)C>[F:17][C:10]1[C:9]([F:18])=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:20]([C:30]4([C:33]5[CH:34]=[C:35]6[C:40](=[CH:41][CH:42]=5)[N:39]=[CH:38][CH:37]=[CH:36]6)[CH2:32][CH2:31]4)=[CH:21][N:1]=3)[CH:4]=2)[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(C(=O)O)c(F)c2F)cn1
Solvent: CCO
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A mixture of 4-(2-aminopyrimidin-5-yl)-2,3-difluorobenzoic acid (15 mg, 0.060 mmol) and 1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione (20 mg, 0.058 mmol) in ethanol (1.0 mL) was stirred at 100° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (9 mg, 40%). LCMS: (M+H)=443.0.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9](O)=[O:10])([CH3:3])[CH3:2].C(Br)C1C=CC=CC=1.O.[NH2:30][NH2:31]>O1CCCC1>[CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9]([NH:30][NH2:31])=[O:10])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Agent: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NN
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid (IM3-a: 2.84 g, 10 mmol), N,N′-carbonyldiimidazole (1.62 g, 10 mmol) and tetrahydrofuran 100 mL were placed in a 300 mL eggplant shaped flask and stirred at room temperature for 4 hours. The reaction mixture was mixed with benzylbromide (1.19 mL, 10 mL), stirred at room temperature for further 4 hours and then mixed with hydrazine mono hydrate (0.63 mL, 13 mmol) and stirred at room temperature overnight. After completing the reaction, most of the reaction mixture was removed under reduced pressure, and the residue was mixed with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and saturated sodium chloride solutions, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column chromatography to obtain the title compound (IM4-a: 2.44 g, 82%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:21])[CH:16]=[C:17]([F:20])[C:18]=1[F:19]>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:21][C:15]2[CH:14]=[C:13]([F:12])[C:18]([F:19])=[C:17]([F:20])[CH:16]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)c(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile (200 mg, 1.341 mmol) and 3,4,5-trifluorophenol.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([B:13]([OH:15])[OH:14])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:17]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:21]([CH3:31])[N:20]=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C:22]2[C:17]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([B:13]([OH:15])[OH:14])[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)=[N:18][CH:19]=[N:20][C:21]=2[CH3:31])=[CH:29][CH:28]=1
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Reactant: OB(O)c1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (1.20 g, 5.2 mmol), 4-chloro-5-(4-fluorobenzyl)-6-methylpyrimidine (reagent preparation 5) (1.24 g, 5.2 mmol), diisopropylethylamine (0.40 mL, 2.10 mmol) 50% aqueous 1,4-dioxane (50 mL) was deoxygenated for five minutes by bubbling nitrogen gas then stirred at 95° C. for 18 hours. The reaction mixture was concentrated, diluted with water (50 mL), adjusted to pH 14, and then washed with isopropyl acetate (3×30 mL). The aqueous mixture was adjusted to pH 8 and the white solid precipitated was collected by filtration, washed with water and dried to give (4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (0.72 g, 35% yield). MS (EI) for C2H21BFN3O3: 394 (MH+).
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[CH2:1]([S:8]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:19])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: Nc1ccccc1NS(=O)(=O)Cc1ccccc1

Procedure:
The sulfonamide was synthesized from benzyl sulfonyl chloride (0.01 mol) and o-phenylene diamine (0.01 mol) by general Method C. It was purified by recrystallization from EtOH (0.87 g, 33%) EI-MS m/z 263 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CS(O[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:26][CH:27]=[CH2:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH:27]=[CH2:28]
Reactant: C=CCC1CCCCC1OS(C)(=O)=O
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1CCCCC1Nc1ccc(CCC(=O)OCC)cc1

Procedure:
A mixture of 5.0 g. of ethyl 4-aminohydrocinnamate, 10.0 g. of 1-methanesulfonyloxy-2-allylcyclohexane (prepared by the method of Example 189), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 80 for 17 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.