Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5]P(=O)(OC)OC.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)/[CH:5]=[CH:20]/[C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CCCCCOc1c(C=O)occc1=O
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCOc1c(/C=C/C(=O)CCc2ccccc2)occc1=O
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution, under nitrogen, of 0.187 g (3.9 mmole) of sodium hydride (50% dispersion in mineral oil) in 10 ml of dry THF was added dropwise 1.2 g (4.95 mmole) of dimethyl (2-oxo-4-phenylbutyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.0 g (3.54 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone, prepared by the procedure of Examples 1 and 2, in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.90 g (64%) of pure 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone, m.p. 38.5°-40°. NMR (CDCl3): δ1.26 (3H, t, J=7 Hz); 2.35 (2H, t, J=6.5 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:23])[C:16]=2[C:17]2[NH:21][C:20]([CH3:22])=[N:19][N:18]=2)=[O:10])=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].COCCOC>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.O>[CH3:23][C:15]1[C:16]([C:17]2[NH:21][C:20]([CH3:22])=[N:19][N:18]=2)=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: Cc1nnc(-c2c(C)csc2NC(=O)Cc2ccc(I)cc2)[nH]1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2c(C)csc2NC(=O)Cc2ccc(-c3ccncc3)cc2)[nH]1
Temperature: 90 °C

Procedure:
A 30 mL reaction vial was charged with 2-(4-iodophenyl)-N-(4-methyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide (140 mg, 0.32 mmol), pyridin-4-ylboronic acid (60 mg, 0.48 mmol), sodium bicarbonate (100 mg, 1.2 mmol), DME (2 mL), and water (2 mL). The heterogeneous mixture was stirred vigorously under a stream of nitrogen for 5 minutes before Pd(PPh3)4 was added and the vial was sealed under its Teflon cap. The reaction mixture was heated to 90° C. for 3.25 h before being transferred to a microwave vial and being microwaved to 150° C. for 5 minutes. The reaction mix was concentrated under reduced pressure and the residue was partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride. The organic solution was washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (3.5% MeOH/methylene chloride) Yield: 10.0 mg (8%). Method [1]: rt=1.136 min; MH+ 390.2. 1H-NMR (300 MHz, CD3OD) δ 8.71 (d, J=6.3 Hz, 1H), 8.60 (dd, J=4.6, 1.6 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.77 (dd, J=4.6, 1.6 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 6.58 (s, 1H), 3.94 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:9]1([PH:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([OH:8])=[CH:2][C:3]=1[P:15](=[O:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: O=C1C=CC(=O)C=C1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(O)ccc1O

Procedure:
Into a flame dried 2 L three neck round bottomed flask equipped with a mechanical stirrer, nitrogen gas inlet, pressure equalizing addition funnel, and drying tube were charged p-benzoquinone (30.16 g, 0.2790 mol) and toluene (750 mL). Diphenylphosphine oxide (56.42 g, 0.2790 mol) in toluene (250 mL) was added dropwise over 0.5 hour to the stirred solution at room temperature under nitrogen. The solution color changed from a dark brown to yellow with the formation of a gum. Upon further stirring, a grey solid formed. The solid was isolated, washed with toluene and then diethyl ether, and dried at 110° C. in flowing air to afford 74.0 g (85% crude yield) of an off-white solid. Recrystallization from ethanol afforded 2,5-dihydroxyphenyldiphenylphosphine oxide as a white solid (62.86 g, 73% recovery), m.p. 216-218° C.
Reaction SMILES: [C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[C@@H:11]([NH:16]C(OC(C)(C)C)=O)[C@@H:12]([CH3:15])[CH2:13][CH3:14])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:55]>C1COCC1>[ClH:55].[C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:39][CH2:40][S:41](=[O:44])(=[O:45])[CH2:42][CH2:43]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[C@@H:11]([NH2:16])[C@@H:12]([CH3:15])[CH2:13][CH3:14])=[O:6])(=[O:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: CC[C@H](C)[C@H](N)C(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
2(S)-tert-Butoxycarbonylamino-3(S)-methyl-pentanoic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12f) (0.82 g, 1.23 mmol), anisole (0.2 mL) and THF (25 mL) are cooled to 0° C. Hydrogen chloride (4 M in dioxane, 9 mL, 36.8 mmol) is added in a dropwise manner. After complete addition, the ice-bath is removed and the mixture is stirred at RT overnight. Under reduced pressure, the mixture is concentrated to one-third of its original volume. Ether is then added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether, and dried under vacuum to give the title compound in 52% yield (0.39 g). 1H NMR (400 MHz, CD3OD): δ 7.51 (d, 1H), 7.36 (t, 1H), 7.26 (d, 1H), 6.05 (d, 1H), 6.00 (d, 1H), 4.87 (m, 1H), 4.20 (m, 3H), 4.09 (dd, 1H), 3.84 (dd, 1H), 3.37 (m, 2H), 3.23 (tt, 1H), 3.11 (m, 2H), 2.54 (s, 3H), 2.34 (m, 2H), 2.17 (m, 2H), 2.06 (m, 1H), 1.56 (m, 1H), 1.39 (m, 1H), 1.06 (d, 3H), 1.00 (t, 3H). MS-APCI (m/z+): 341, 385, 572.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][N:5]=1>O1CCOCC1>[Br:1][CH:10]([C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:3])[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1ccnc(Cl)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: CC(=O)C(Br)c1ccnc(Cl)c1

Procedure:
Bromine (1.36 ml, 26 mmol) is added dropwise to a stirred solution of 1-(2-chloro-pyridin-4-yl)-propan-2-one (Example 2a, 5.0 g, 29.5 mmol) in dioxane (150 ml) over 45 minutes at 5-10° C. After 20 minutes at room temperature the solvent is removed in vacuo to afford the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:35])=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(C)cccc2Cl)cc1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(C)cccc2Cl)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
N-[(2,6-Dichlorophenyl)carbonyl]-4-[[(2-chloro-6-methylphenyl)carbonyl]amino]-L-phenylalanine methyl ester was prepared from 4-[[(2-chloro-6-methylphenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2,6-dichlorobenzoic acid using the general procedure described in example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])[N:22]=2)=[CH:14][CH:13]=1.CO.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])[N:22]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](NC(=O)c1csc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)n1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@H](NC(=O)c1csc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)n1)C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of (S)-methyl 2-(2-(4-(3-(2,4-difluorophenyl)ureido)phenyl)thiazole-4-carboxamido)-3-methylbutanoate (100 mg, 0.204 mmol) in THF (4 mL)+MeOH (1 ml), 1 ml of 1N LiOH (42.99 mg, 1.024 mmol) was added at RT and stirred for 2-3 hr. After completion of reaction, THF was removed under reduced pressure. Obtained material was dissolved in water, acidified with 1N HCl and white solid precipitated out. It was filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:7]([C:5]5[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)[nH]n1
Yield: 71 %

Procedure:
In the same manner as in Example 261 and using 3-methyl-1H-pyrazole-5-carboxylic acid (160 mg, 1.2 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2 mmol), triethylamine (190 mg, 1.9 mmol) and N,N-dimethylformamide (3 mL) as starting materials, the title compound (190 mg, 70%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18][CH2:19][CH2:20]Br.O>CS(C)=O>[CH2:18]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(OCc2ccccc2)cc1
Yield: 97.1 %

Procedure:
In 75 ml of dimethylsulfoxide (DMSO) was dissolved 7.5 g (37.5 mmol) of 4-(benzyloxy)phenol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 1.65 g/15 ml) was added thereto. The mixture was stirred until dissolving homogeneously. Next, 5.0 g (40.7 mmol) of n-propyl bromide was added to the mixture, and the resultant mixture was subjected to a reaction at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water, and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from methanol to give 8.82 g (36.4 mmol) of 1-(n-propyloxy)-4-benzyloxybenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)C>[C:27]1([NH:33][C:34]([C:2]2[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CSc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.8 g (0.0022 mol) of 2-bromo-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the obtained solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.6M-hexane solution of BuLl (0.0022×1.1 mol) was added to the solution, followed by stirring the resultant mixture for about 10 minutes. After 0.52 g (0.0022×2.0 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18]Br)[CH2:14]Br.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:18][CH2:17][O:16][CH2:13][CH2:14]2)([CH3:9])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1cc(Br)ccc1C(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(C)(C)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Bromo-2-methyl-phenyl)-1-methyl-ethylamine (preparation 48, 544 mg, 2 mmol), 2,2′-dibromodiethylether (579.8 mg, 2.5 mmol) and N,N-diisopropylethylamine (1.027 ml, 6 mmol) in DMF (7 ml) is heated to 100° C. for 16 h and then allowed to cool to RT. The reaction mixture is partitioned between water and CH2Cl2. The aqueous phase is re-extracted twice, the combined organic phases are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (silicagel, CH2Cl2: EtOAc=1:0=>0:1) to afford the title compound as a pale yellow oil, Rt=0.786 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 298 (M+1, 79Br)+.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH:6]=[C:5]2[NH2:4])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C=CCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(Cl)cc12
Product: COc1cc(F)ccc1CNc1cc(N)c2cc(NCc3ccccc3)ccc2n1

Procedure:
N4-Allyl-6-chloro —N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine (prepared from (4-bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2-methoxy-benzyl)-amine and allylamine as described in example 40, step A) was coupled with benzylamine as described in example 30, step D. The title compound was obtained as a light brown foam (16%), MS: m/e=403.4 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[NH:10][N:11]=[C:12]([C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:25])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:25][C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[C:12]1[CH:13]=[C:9]([CH2:8][NH2:7])[NH:10][N:11]=1
Reactant: Cc1nc(-c2ccccc2)oc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccccc2)oc1-c1cc(CN)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of the above-prepared [5-(4-Methyl-2-phenyl-oxazol-5-yl)-2H-pyrazol-3-ylmethyl]-carbamic acid tert-butyl ester (258 mg, 0.728 mmole, 1.0 eq) in dry CH2Cl2 (4 ml) was treated with trifluoroacetic acid (1 ml, excess) and the brown homogeneous mixture stirred under nitrogen at room temperature for one hour. The mixture was partitioned between CH2Cl2 and 1.0N NaOH, the organic phase washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 177 mg (96%) of the title compound as an off-white solid. The crude solid was used without further purification.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1>CO.[C].[Pd]>[OH:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1O
Yield: 95.5 %

Procedure:
20.0 g of Ferulic acid was dissolved in 250 ml of methanol and subjected to catalytic reduction under normal pressure for 3 hours in the presence of 10% palladium carbon catalyst (50% wet type). After removing the catalyst by filtration, the resulting filtrate was concentrated to collect precipitated crystals by filtration, thereby obtaining 19.3 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH3:16]
Reactant: CCOC(=O)CCCCBr
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)CCCCOc1ccccc1I
Yield: 38.1 %

Procedure:
Under the conditions of example 2A, 3 g of 2-iodophenol in the presence of 8.9 g of cesium carbonate is reacted with 2.84 g of 5-bromovaleric acid ethyl ester, worked up, and 1.8 g of 5-(2-iodophenoxy)valeric acid ethyl ester with a boiling point of 210° C./0.4 mbar is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[C:20]([Br:28])[CH:19]=1>C(O)(=O)C>[Br:28][C:20]1[C:21]([OH:27])=[C:22]([C:23]([OH:25])=[O:24])[CH:26]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1cc(Br)c(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)cc(Br)c1O

Procedure:
A mixture of 8.1 g. (0.038 mole) of 2-phenacylcyclohexanone, 8.7 g. (0.038 mole) of 5-amino-3-bromosalicylic acid, and 50 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled and filtered. Recrystallization of the collected solid from acetonitrile gave 7.0 g. (46%) of yellow crystals, m.p. 209°-210°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(O)Cc1ccc(OCCN2CCOc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCN2CCOc3ccccc32)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
A solution of ethyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5 mL) was added to a stirred ice cooled suspension of sodium hydride (60% dispension in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69 mmol). The mixture was allowed to warm to 25° C. and stirring was continued for further 18 h. Water (25 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) as eluent to afford the title compound (0.3 g) along with benzyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4yl)ethoxy]phenyl]-2-benzyloxypropanoate. This mixture (1:1) is used in example 47 without any separation.