Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[CH2:10][CH2:11][CH:12]([CH:27]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)C(N1C(C2C=CC=CC=2)COC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:60][O:61][C:62](=O)[O:63]C.Cl>ClCCl>[CH3:60][O:61][C:62](=[O:63])[CH:12]([CH:27]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)[NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:11][CH2:10][CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1
Reactant: COC(=O)OC
Reactant: O=C1OCC(c2ccccc2)N1C(=O)C(CCC(OCc1ccccc1)c1ccc(F)cc1)C(Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CCC(OCc1ccccc1)c1ccc(F)cc1)C(Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
10 gms of 3-[5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one was taken in dichloromethane, to this 3.6 gms of sodium methoxide was added followed by 3.2 ml of dimethylcarbonate, and 500 ml of dichloromethane. Reaction mass was stirred for about 5-7 hours. To the reaction mass 0.1 ml of hydrochloric acid was added. Separated the layers and extract the aqueous layer with 25 ml of methylene dichloride. The organic layer was washed with water and dried over sodium sulphate. Distilled the solvent completely under reduced pressure at 50-55° C. and 85 ml of methanol was added. Stirred the reaction mass for about 1-2 hours, filtered and washed with methanol and dried at 50-55° C. to get 5 gms of 5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoic acid methyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:32][C:33]3[CH:39]=[C:38]([C:40]([O-])=[O:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:32][C:33]3[CH:39]=[C:38]([C:40]([NH:22][C:20]4[CH:19]=[CH:18][C:16]5[NH:17][C:13]([C:10]6[CH:11]=[CH:12][C:7]([N:4]7[CH2:5][CH2:6][O:1][CH2:2][CH2:3]7)=[CH:8][CH:9]=6)=[N:14][C:15]=5[CH:21]=4)=[O:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Reactant: Nc1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Product: N#Cc1ccc(-c2nc3ccc(C(=O)Nc4ccc5[nH]c(-c6ccc(N7CCOCC7)cc6)nc5c4)cc3[nH]2)cc1

Procedure:
Compound 292 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinophenyl)-5-aminobenzimidazole and 2-(4-cyanophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C32H25N7O2: 540.21; found: 539.97.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([NH2:11])=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)[CH3:13].C([O-])(=O)C.[Na+]>CN(C)C=O>[CH2:8]([C:9]1[N:11]=[C:12]([CH3:13])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: N=C(N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cc2ccccc2)nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To 100 ml of N,N-dimethylformamide, 17.1 g (100 mmol) of 2-phenylacetoamidine hydrochloric acid salt, synthesized in accordance with a method described in “Tetrahedron”, page 887 (1984), 18.6 g (100 mmol) of ethyl 2-acetyl-3-ethoxyacrylate and 9.0 g (110 mmol) of sodium acetate were suspended, followed by stirring at 100° C. for 3 hours. The reaction liquid was cooled and then poured into ice water, and extracting with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 22.8 g (yield: 89%) of ethyl 2-benzyl-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][NH2:31]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:20]([NH:31][CH3:30])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C2(O)CCCCC2)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C1(O)CCCCC1
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 274 mg (0.67 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-hydroxycyclohexyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 22) in 10 ml of methanol was saturated with gaseous methylamine by passing the gas through the solution whilst ice-cooling, and then the flask containing the reaction mixture was stoppered tightly, and allowed to stand at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane, to give 286 mg (yield 97%) of the title compound as white crystals, melting at 175°-177° C.
Reaction SMILES: C(O)(=O)C.[Br:5]N1C(=O)CCC1=O.[CH2:13]([CH:15]([C:18]1[N:23]2[N:24]=[C:25]([CH3:38])[C:26]([C:27]3[S:31][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][N:36]=4)=[N:29][CH:28]=3)=[C:22]2[N:21]=[C:20]([CH3:39])[CH:19]=1)[CH2:16][CH3:17])[CH3:14]>C(#N)C>[Br:5][C:28]1[N:29]=[C:30]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][N:36]=2)[S:31][C:27]=1[C:26]1[C:25]([CH3:38])=[N:24][N:23]2[C:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[CH:19][C:20]([CH3:39])=[N:21][C:22]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 22 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Add acetic acid (1 mL) and N-bromosuccinimide (4.1 g, 22 mmol) to a solution of 7-(1-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-pyrazolo[1,5-a]pyrimidine (8 g, 21 mmol) in acetonitrile (80 mL). Stir the mixture 2 h at 22° C. Then evaporate the solvent and add water (50 mL) and methyl-t-butyl ether (100 mL) to the resulting residue. Separate the organic portion, dry over sodium sulfate, filter, and evaporate the solvent. Recrystallize the resulting residue from isopropyl alcohol to afford the title compound (8.7 g, 90%). ES/MS (m/z): (79Br/81Br) 460/462 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]2=[O:38])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12]3=[O:38])(=[O:9])=[O:10])=[CH:6][CH:7]=2)=[CH:43][CH:42]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1C(S(=O)(=O)c2ccc(Br)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
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: Cc1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1

Procedure:
The mixture of 3-(4-Bromo-benzenesulfonyl)-1-trityloxy-azepan-2-one prepared from step F (10.1 mg, 0.0171 mmol), 4-Methoxybenzeneboronic acid (10.2 mg, 0.0671 mmol) and Pd(PPh3)4 (3.1 mg, 0.00268 mmol) in 2.0 ml of toluene was added 0.4 ml of saturated Na2CO3 aqueous solution and the resulting mixture was stirred and heated to reflux for 4 hours. The reaction mixture was filtered through celite and diluted with EtOAc and water. The organic phase was washed sequentially with water and saturated NaCl solution, and then dried over anhydrous Na2SO4. The EtOAc solution was concentrated under reduced pressure to give a crude material, which was then purified by a column chromatography (0˜30% EtOAc in hexane). MS: 618.2 (M+H)+, 640.2 (M+Na)+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Si:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][C:27]=1[Cl:34])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[Si:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:28][C:27]=1[Cl:34])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OCc1ccc([Mg]Br)cc1Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(Cl)c1
Temperature: 60 °C

Procedure:
Then, 1-iodopentane (910 mg) was added to a suspension of copper bromide-dimethyl sulfide complex (62 mg) in hexamethylphosphoric triamide (0.3 ml) under a nitrogen atmosphere, and the mixture was heated to 60° C. Thereto was dropwise added the above-mentioned solution (5 ml) of 4-((tert-butyldiphenylsilyloxy)methyl)-3-chlorophenyl magnesium bromide in tetrahydrofuran over 10 min after removal of unreacted magnesium. After completion of the dropwise addition, the reaction mixture was refluxed under heating for 2 hr. Aqueous ammonium chloride was added to the reaction mixture and the resulting product was extracted three times with hexane. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane) to give the objective compound (914 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1.[NH:20]1[C:24]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=2)=[N:23][N:22]=[N:21]1.Cl.O>CN(C)C=O>[OH:1][C:2]1[C:3]([C:17](=[N:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][C:25]([C:24]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:26][CH:27]=2)[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc(-c2nnn[nH]2)cc1)c1csc(-c2ccc3c(c2)CCCC3)c1O
Yield: 1.9 %

Procedure:
21.6 mg (0.0793 mmol) of 1-[4-hydroxy-5-(5,6,7,8-tetrahydronaphthalen-2-yl)thiophen-3-yl]ethanone and 17.9 mg (0.0877 mmol) of 4-(1H-tetrazol-5-yl)benzohydrazide in N,N-dimethylformamide (1.0 ml) was stirred with a drop of concentrated hydrochloric acid at 60° C. for 3 hours. After completion of the reaction, water was added, and the precipitated solid was collected by filtration, washed with chloroform (2.0 ml) and dried under reduced pressure to obtain the desired product (0.7 mg, yield 2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[Cl:19])=[O:23])=[N:16][CH:17]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)c(-c3ccc(N)nc3)cc2o1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2cc(Cl)c(-c3ccc(NC(=O)c4ccccc4Cl)nc3)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 5-(5-chlorob-2-methylenzoxazol-6-yl)-2-pyridylamine (36) (19 mg, 0.073 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (19 μl, 0.14 mmol) followed by addition of DIEA (64 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (140 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 20.6 mg 37 as pale yellow solid. (yield: 71%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of ethyl [4-({(2-methoxyethyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (90 mg, 0.18 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M NaOH aq. (1 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue diluted with water (10 mL) acidified with 2M HCl, before extraction into ethyl acetate (2×20 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (28 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[C:11]([O:13]C)=[O:12].[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12]
Reactant: COC(=O)/C=C\c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C\c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl (2Z)-3-(2,4-difluorophenyl)acrylate, from preparation 34 (1.3 g, 6.56 mmol) and 1M lithium hydroxide (314 mg, 13.1 mmol) in tetrahydrofuran (51 mL) was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL) and ethyl acetate (20 mL) was added. The phases were separated and the aqueous phase was acidified to pH 2 using 2M hydrochloric acid solution (3 mL). The aqueous phase was extracted with diethyl ether (2×30 mL). These organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a white solid, 1.03 g (86%).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C)C1C=CN=CC=1.ClCCl>[C:21]12([C:31]([O:13][CH:10]3[CH2:11][O:12][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][CH2:9]3)=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OC1COC(c2ccccc2)OC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1COC(c2ccccc2)OC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 80 %

Procedure:
1.00 g (5.55 mmol) of 2-phenyl[1.3]dioxan-5-ol, 1.16 ml (8.32 mmol) of triethylamine and 68 mg (0.56 mmol) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and then further for 15 hours at room temperature. Dichloromethane was distilled off under reduced pressure, and to the residue was added aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 1.52 g of the title compound as a pale yellow powder (yield: 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:3]=1.C([Li])CCC.[CH3:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH:33]=[O:34]>O1CCCC1>[CH3:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH:33]([OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:3]=1
Reactant: CCCCCCCCC(O)/C=C/C=C/c1cccc(Br)n1
Reactant: COC(=O)CCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/C=C/c1cccc(C(O)CCCC(=O)OC)n1
Yield: 5.4 %

Procedure:
Under the conditions of example 1B, 470 mg of 2-bromo-6-[(1E, 3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-pyridine in 7 ml of tetrahydrofuran is mixed with 1.84 ml of n-butyllithium (1.6 molar in hexane) and 200 mg of 5-oxo-pentanoic acid methyl ester in 1.5 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5. 29 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][Br:18])=[CH:4][CH:3]=1
Reactant: OCc1cccc(Oc2ccc(Br)cc2)c1
Reactant: BrP(Br)Br
Product: BrCc1cccc(Oc2ccc(Br)cc2)c1

Procedure:
This compound was prepared from 3-(4-bromophenoxy)benzyl alcohol by a standard reaction with phosphorus tribromide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:29][CH:30]([CH3:33])[C:31]#[CH:32]>C1COCC1.[Pd].[Cu]I>[Cl:27][C:23]1[N:24]=[CH:25][NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([C:32]#[C:31][CH:30]([CH3:33])[CH3:29])[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:28])=[O:21]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Reactant: C#CC(C)C
Agent: [Cu]I
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 53.1 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (95 mg, 0.196 mmol), Palladium dichloropistriphenylphosphine (103 mg, 0.196 mmol), 3-methyl-1-butyne (26.7 mg, 0.392 mmol) and copper(I) iodide (1.869 mg, 9.81 μmol) in THF (4 ml) was added TEA (0.141 ml, 1.012 mmol) and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(3-methyl-1-butyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (49 mg, 0.104 mmol, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (d, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.41-7.50 (m, 2H), 7.32 (t, 1H), 7.11 (s, 1H), 4.49 (d, 2H), 2.76 (dt, 1H), 1.15 (d, 6H). LC-MS (ES+) m/z 471.13, [M+H].
Reaction SMILES: [C@H:1]([NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)([CH2:3][CH3:4])[CH3:2].[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[C@H:1]([N:5]([CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=2)[CH2:26][CH2:27]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC[C@@H](C)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (11 mg) from (R)-2-((sec-butylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H33FN4O4 484.6. found 485.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.87-8.07 (m, 2H) 7.16 (t, J=8.59 Hz, 2H) 4.41-4.58 (m, 2H) 4.19-4.41 (m, 3H) 4.13 (d, J=7.07 Hz, 1H) 3.82-3.99 (m, 2H) 3.34 (br. s., 2H) 3.25 (br. s., 1H) 3.13 (br. s., 1H) 2.87-3.07 (m, 1H) 2.55-2.69 (m, 2H) 2.25 (br. s., 2H) 1.98 (br. s., 1H) 1.88 (br. s., 2H) 1.72 (br. s., 1H) 1.16-1.28 (m, 3H) 1.09 (d, J=6.57 Hz, 1H) 0.69-0.89 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[O:12]([CH2:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>[OH-].[Na+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:20](=[O:21])[CH2:19][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
3-Methylanthranilic acid 5 g (33 mmol) was dissolved in 10% aqueous sodium hydroxide solution 27 ml and to this solution, phenoxyacetyl chloride 6.2 g (36 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 1 hour and acidified with 10% hydrochloric acid solution. Deposited crystals were collected by filtration, washed with water and recrystallized from ethanol to obtain 3-methyl-N-(phenoxyacetyl)anthranilic acid (melting point: 174° to 176° C.) 4.4 g (yield: 47%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH2:11][CH:12]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)(=O)=O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:12]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9][C:1]#[N:2])=[CH:26][CH:27]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
91.9 mg (1.41 mmol) of potassium cyanide were added to 309 mg (0.71 mmol) of the compound from Example 65A in 5 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). DMF was removed by taking the crude product up in dichloromethane, washing twice with water and saturated aqueous sodium chloride solution, drying over magnesium sulfate, filtering and concentrating. 134 mg (52% of theory) of the target compound were obtained.