Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 61.4 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-02) (1 g, 61.34%) was synthesized as a yellow liquid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-02) (2 g, 3.23 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)C.C1COCC1.Cl>CO>[CH3:37][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:38])=[O:5])=[CH:8][CH:9]=3)=[N:15][CH:16]=2)[CH:25]=[C:24]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][N:28]=2)[CH:23]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(Oc3ccc(C(=O)O)cc3)nc2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
Sodium hydroxide (1 M in water, 1.41 mL, 1.41 mmol) was added to a solution of ethyl-4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]oxy}benzoate (349 mg, 0.706 mmol) in methanol (3.53 mL) and stirred at 60° C. for 16 hours. THF (5 mL) was added to the reaction mixture and heated at 60° C. for 6 hours. The reaction was cooled to room temperature and acidified with aqueous 1N HCl. The aqueous layer was extracted with 3:1 CHCl3:isopropanol (3×). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]oxy}benzoic acid (114 mg, 0.244 mmol) as a white solid. MS ESI calc'd for C24H18F3N4O3 [M+H]+ 467. found 467.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([C:10]2[N:11](COC)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.C(OCN1C=CN=C1C(C1C=CC(Cl)=CC=1)(C1C=CC=CC=1)O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: COCn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
Using the procedure described in Example VIC but substituting an equivalent amount of α,α-bis(p-chlorophenyl)-1-(methoxymethyl)imidazole-2-methanol for the 1-[(benzyloxy)methyl]-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol, α,α-bis(p-chlorophenyl)imidazole-2-methanol was obtained. Melting point of the product was 195°-197° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=O)[CH:3]=1.[CH3:14][NH2:15]>CO>[CH3:14][N:15]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: CN
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Solvent: CO
Product: Cc1cc(=O)n(C)c2c1C(=O)CCC2
Temperature: -9 °C

Procedure:
4.46 g (0.025 mol) of 4-methyl-5,6,7,8-tetrahydro- cumarin-5-one are dissolved in a mixture of 41.9 g of liquid methylamine in 100 ml of methanol pre- cooled to -9° C., With cooling, and heated to 180° C. for 3 hours in an autoclave. After cooling the methanol and methylamine are distilled off using a rotary evaporator, the residue is chromatographed on a silica gel column using ethylene chloride/ethanol (95:5) and recrystallised from cyclohexane/ethyl acetate (1:1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:12][C@@H:13]1[CH:17]([O:18][CH3:19])[O:16][C@H:15]([CH2:20][OH:21])[C@H:14]1[OH:22].CO>CN(C)C=O>[F:12][C@H:13]1[C@H:14]([O:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH3:3])=[CH:5][CH:6]=2)[C@@H:15]([CH2:20][O:21][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([CH3:8])=[CH:6][CH:5]=2)[O:16][CH:17]1[O:18][CH3:19]
Reactant: COC1O[C@H](CO)[C@@H](O)[C@@H]1F
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC1O[C@H](COCc2ccc(C)cc2)[C@@H](OCc2ccc(C)cc2)[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
In a nitrogen atmosphere, 0.44 g of sodium hydride and 2.03 g of 4-methylbenzyl bromide were added to a solution of 0.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 7.0 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 2.5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added thereto. The reaction mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 1.33 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolane in the form of a colorless oily product.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C.[F:52][C:53]([F:63])([F:62])C1C=CC=CC=1CBr>>[CH3:22][C:18]([CH3:23])([CH2:17][S:16][C:13]1[S:12][C:11]([NH:10][C:9]([N:8]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[C:53]([F:63])([F:62])[F:52])=[O:24])=[N:15][CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2C(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 3-(2-amino-thiazol -5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester and 2-trifluoromethylbenzyl bromide.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Cl[C:8]1[C:13]([C:14]2[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=2)=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[CH3:19][C:17]1([CH3:20])[CH2:16][O:15][C:14]([C:13]2[C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:18]1
Reactant: CC1(C)COC(c2cccnc2Cl)=N1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1C1=NC(C)(C)CO1
Reaction time: 1.25 h
Yield: 95 %

Procedure:
12 g of sodium hydride (50% in oil=0.25 mole) are added during 10 minutes to 150 ml of dry tetrahydrofuran and 40 ml of isopropanol to give a suspension, the temperature of which rises to 50° C. A solution of 10.52 g (0.05 mole) of 2-chloro 3-(4,4-dimethyl 2-oxazolinyl)pyridine in 30 ml of dry tetrahydrofuran is then added during 20 minutes and the mixture is left to stand for 1.25 hours at ambient temperature. Excess isopropanol and the tetrahydrofuran are then removed under a partial vacuum and the residue is taken up in 50 ml of water and 100 ml of diisopropyl ether. The ethereal phase is then evaporated under reduced pressure to give 12.5 g of 3-(4,4-dimethyl 2-oxazolinyl)2-isopropoxy pyridine in the form of a clear brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([C:20](O)([CH3:22])[CH3:21])[CH:16]=[C:17]([CH3:19])[CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:22])=[CH2:21])[CH:14]=2)[CH3:11])=[CH:24][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CN(C)Cc2ccc(C(C)(C)C)cc2)cc(C(C)(C)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)c1cc(C)cc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Yield: 31.6 %

Procedure:
Compound 86 (0.40 g; 1.18 mmol) was dissolved in pyridine (20 ml). While the solution was stirred in an ice bath, phosphorus oxychloride (1.81 g; 11.8 mmol) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 30 minutes at room temperature, followed by heating under reflux for 4 hours. The mixture was brought to room temperature, and poured into ice+saturated aqueous sodium bicarbonate solution. The mixture was neutralized with sodium bicarbonate, and extracted with chloroform (70 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1), to thereby yield 0.12 g of the target compound (yield: 31.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: FC(F)(F)c1cccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (80 mg, 0.33 mmol) in 5 mL methanol, was added 3-(trifluoromethyl)benzaldehyde (114 mg, 0.66 mmol). The reaction mixture was stirred overnight, after which, sodium borohydride (24.8 mg, 0.656 mmol) was added and the mixture was for stirred for 10 min. The reaction was diluted the water (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and dried with sodium sulfate. The solvent was removed and the residue was chromatographed on a combiflash machine (6% methanol/methylene chloride) to give 61 mg (46%) of the desired product. MS +m/z: 401.9 (M+H)+
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[NH:11][C:12]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:14]=2)[CH2:6][O:5]C(=O)[NH:3]1.CO.O1CCCC1.[OH-].[Na+]>O>[NH2:3][C@:2]([CH3:1])([CH2:8][CH2:9][C:10]1[NH:11][C:12]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:13][CH:14]=1)[CH2:6][OH:5]
Reactant: C[C@@]1(CCc2ccc(C(=O)CCCCc3ccccc3)[nH]2)COC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@](N)(CO)CCc1ccc(C(=O)CCCCc2ccccc2)[nH]1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of (4R)-4-methyl-4-{2-[5-(5-phenylpentanoyl)pyrrol-2-yl]ethyl}-1,3-oxazolidin-2-one (41.0 mg, 0.12 mmol) obtained in Example (42a) in a mixed solvent of methanol (2 ml), tetrahydrofuran (2 ml) and water (2 ml) was added 10N aqueous sodium hydroxide solution (0.12 ml, 1.17 mmol), and the resulting mixture was refluxed for 4 days. After cooling to room temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (20:1) as the eluent to afford the title compound (30.0 mg, yield: 79%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:19]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(CCC(=O)OC(C)(C)C)cc1

Procedure:
To a fast stirring suspension of anhydrous magnesium sulfate (4.81 g, 40.0 mmol) in dichloromethane (40 ml) was added sulfuric acid (0.55 ml, 10.32 mmol). The reaction was vigorously stirred for 15 minutes at room temperature and then 3-(4-methoxyphenyl)propionic acid (1.8 g, 9.99 mmol) and tert-butanol (4.78 ml, 50.0 mmol) were added. The reaction was sealed and stirred at room temperature overnight. The reaction was quenched with 75 mL of saturated sodium bicarbonate solution and washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (0 to 80% ethyl acetate/hexanes) to afford tert-butyl 3-(4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.11 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 3.78 (s, 3H), 2.85 (t, J=7.7 Hz, 2H), 2.50 (t, J=7.7 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:26][CH2:25]1.[C:38](OCC)(=[O:40])C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([C:38]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:26][CH2:25]3)=[O:40])[C:8](=[O:10])[N:7]([CH:11]([CH3:12])[CH3:13])[C:6]=2[CH:14]=1
Reactant: NCC1CCN(CC2(O)CCOCC2)CC1
Reactant: CCOC(C)=O
Reactant: CC(C)n1c(=O)[nH]c2ccc(F)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(O)CCOCC3)CC2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred mixture of 6-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (Step 2 of Example 9, 0.58 g, 3 mmol) and p-nitrophenylchloroformate (0.66 g, 3.3 mmol) in dichloromethane (15 mL) was added triethylamine (1.25 mL, 9.0 mmol) at room temperature. After being stirred for 2 h, a solution of 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (Step 2 of Example 1, 0.75 g, 3.3 mmol) in dichloromethane (15 mL) was added to the mixture. After being stirred for 4 h, the mixture was diluted with ethyl acetate (100 mL). Then, the organic layer was washed with 0.5 N NaOH aq. (10 mL) for 5 times and brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1) to give 0.97 g (79%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]3[N:34]([CH2:38][CH3:39])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:38]([N:34]1[C:33]2[C:40]([CH3:42])=[CH:41][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:23]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37])[CH3:39]
Reactant: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)oc2cc(C(=O)c3cc(N4CCC(N5CCc6cc(OC)ccc6NC5=O)CC4)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 mg (0.20 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 50 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one and 56 μL (0.30 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21](O)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:29](=[O:32])([O-])[O-].[Na+].[Na+]>C(N(CC)C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:21](=[O:22])[N:8]([CH2:1][CH3:2])[CH:9]=[C:20]([CH:29]=[O:32])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: CCN(C=O)CC
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 60 %

Procedure:
Dissolved in 4.0 ml of diethylformamide was 0.4 g of the 2-(4-benzylpiperazino)-4-methylpyrimidine-5-carboxylic acid obtained in Referential Example 3. At room temperature, 0.5 ml of phosphorus oxychloride was added dropwise. Thereafter, the contents were heated and reacted at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured in an aqueous solution of sodium carbonate to neutralize same, followed by extraction with chloroform. After washing the chloroform layer with water, it was dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure to obtain 0.29 g of the intended product (yield: 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[N:14](S(C4C=CC=CC=4)(=O)=O)[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of Example 3D (2.6 g, 4.60 mmol) in dioxane was added 6M sodium hydroxide (7.67 mL, 46 mmol). The mixture was stirred at 100° C. for 2 hours, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound, which was used without further purification. MS (ESI+) m/z 425.43 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccn1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(OCc2ccccn2)cc1
Yield: 102.6 %

Procedure:
To a mixture of phenol (5.25 g, 55.8 mmol) and 2-chloromethylpyridine hydrochloride (10 g, 61.0 mmol) in 80 mL of toluene was added sodium hydroxide (5.35 g, 134 mmol. The mixture was refluxed for 16 hours. The mixture was washed twice with 60 mL of water. The organic layer was then extracted three times with 25 mL of 6 N HCl. The aqueous layer was made basic with 250 mL of 10% NaOH and extracted three times with 150 mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (10.6 g, 94%). ES (+) MS m/e=186 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([NH2:7])=[O:6])[CH2:3][OH:4].[C:8]1([CH2:14][CH2:15][CH:16]=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H]>CO.[Pd]>[OH:4][CH2:3][C@@H:2]([NH:1][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)[C@H](N)CO
Reactant: [H][H]
Reactant: O=CCCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@@H](CO)NCCCc1ccccc1

Procedure:
D-Serinamide (0.038 moles, 4 g) and 3-phenylpropanal (0.038 moles, 5.1 g) are dissolved in methanol (400 ml) in a Parr bottle and hydrogenated in the presence of 10% Pd/C (3 g) at 40 psi, until hydrogen absorption ceases. The catalyst is filtered off and the solution is evaporated to dryness under vacuum, taken up in ethyl acetate (300 ml) and washed with water (2×200 ml). The organic phase is dried and dissolved in warm ethyl ether (300 ml) to precipitate the product as a white solid by slow evaporation of the solvent at r.t. Yield: 3.8 g (45%)--m.p.=76-78° C. [α]589 (c=1, methanol)=+13.2°
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26][CH2:27][O:28][CH3:29])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH:7]=[CH:6][C:5]=1[N+:33]([O-])=O)[CH3:2].C(ONC1C=CC(OC2C=CC(C(OCOC)(C(F)(F)F)C(F)(F)F)=CC=2CCC)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26][CH2:27][O:28][CH3:29])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH:7]=[CH:6][C:5]=1[NH2:33])[CH3:2]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(OCC)c1
Agent: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(NOCC)cc1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(N)c(OCC)c1

Procedure:
2-ethoxy-4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propyl-phenoxy)-1-nitrobenzene was used for a similar reaction and treatment as Example 119-a), and -ethoxy-4-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoro methyl-ethyl)-phenoxy]-phenylamine was obtained as a yellow oil.