Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC=C(OC)C=1C(=O)COC1C=C(C)C=C(C)C=1C)(C)C.[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[CH2:35][O:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=2[CH3:45])=[C:30]([O:47][CH3:48])[CH:29]=1)([CH3:27])[CH3:26].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:42]3[C:41]([CH3:43])=[CH:40][C:39]([CH3:44])=[C:38]([CH3:45])[C:37]=3[O:36][CH:35]=2)=[C:30]([O:47][CH3:48])[CH:29]=1)([CH3:27])[CH3:26]
Reactant: COc1cc(C(C)C)ccc1C(=O)COc1cc(C)cc(C)c1C
Agent: COc1cccc(C(C)C)c1C(=O)COc1cc(C)cc(C)c1C
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(C)C)ccc1-c1coc2c(C)c(C)cc(C)c12
Temperature: 90 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A mixed solution of the mixture of 1-(2-isopropyl-6-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone and 1-(4-isopropyl-2-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone obtained in Reference Example 171 (6.27 g, 19.2 mmol) and Montmorillonite KSF (9.40 g) in toluene (100 mL) was stirred under argon atmosphere at 90° C. for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=15:85) to obtain 2.34 g (yield 40%) of the title compound. Oily matter.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([Cl:37])[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:33]4[CH:32]=[C:31]([Cl:30])[CH:36]=[C:35]([Cl:37])[CH:34]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)cc(Cl)c4)c3O2)cc1
Yield: 14.7 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3,5-dichlorophenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.22 g (15%) of (±)-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.48 (silica, ethyl acetate:hexanes 1:3); mp 113-115° C.; Anal. calcd. for C22H18Cl2O4S: C, 58.8: H, 4.04. Found: C, 58.73; H, 3.77.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9]/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O/C=C\C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCc1ccc(OCCC(=O)O)cc1
Reaction time: 2 h

Procedure:
(E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) was dissolved in EtOH (10 mL) and Pd/C (5%, degussa type E101, 40 mg) was added. The mixture was hydrogenated at atmospheric pressure for 2 hours and then filtered and the solvent removed to dryness. After purification by column chromatography using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). 1H NMR (CDCl3, 400 mHz, ppm); 2.85 (t, 4H), 3.35 (s, 3H), 3.55 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: Nc1ncc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Product: Nc1ncc(C(=O)Cl)cc1Cl

Procedure:
6.3 g (36 mmol) of 5-chloro-6-amino-nicotinic acid are heated under reflux in 60 ml of thionyl chloride for 4 hours. After the volatile constituents have been distilled off, 50 ml of toluene are added to the residue and the mixture is evaporated. 6.9 g of 5-chloro-6-amino-nicotinoyl chloride are obtained as crystals of melting point: >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[N:13]=[CH:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>C1COCC1>[C:17]([N:15]1[CH:16]=[C:12]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])[N:13]=[CH:14]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Nc1cccc(B(O)O)c1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 60 °C
Yield: 37.5 %

Procedure:
(3-Aminophenyl)boronic acid (1.0 g, 7.3 mmol), 4-bromo-1-trityl-1H-imidazole (2.8 g, 7.3 mmol), tri-t-butylphosphonium tetrafluoroborate (424 mg, 1.5 mmol) and KF (1.4 g, 24.1 mmol) are added into dry THF (20 mL) and argon is bubbled through the mixture for 10 min. Tris-(dibenzylideneacetone)dipalladium(0) (669 mg, 0.7 mmol) is added and the reaction mixture is sealed and heated at 60° C. for 16 hrs. The solid is filtered and the filtrate is diluted with EtOAc (250 mL). The solution is washed with H2O (3×100 mL), brine (100 mL), dried (Na2SO4) and concentrated. The crude product is purified by flash column chromatography using methanol/CH2Cl2 to afford the title compound (1.1 g, 36%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7](=O)([O:13]C(C)(C)C)[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([O-])(O)=O.[Na+]>ClCCl>[C:9]([O:8][C:7]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A solution of 2-amino-2-methyl-1-propanol (921.2 mg, 10.33 mmol) in dichloromethane (5 ml) was cooled to 0° C. To the mixture was added a solution of di-t-butyl carbonate (Boc2O)(2.1045 g, 9.64 mmol) in dichloromethane (5 ml) dropwise for 30 minutes. After addition, the mixture was warmed to room temperature and stirred for 5 hours. The mixture was added to sat. NaHCO3 aqueous solution and extracted three times with ethyl acetate. The extract was dried over MgSO4 and concentrated to give the crude title compound (1.7204 g: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10](O)=[O:11]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: O=C(O)Cc1cc(Cl)ccc1Br
Solvent: C1CCOC1
Product: OCCc1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-(2-bromo-5-chloro-phenyl)acetic acid (1.00 g, 4.01 mmol) in THF (16 mL) was cooled to 0° C. Borane-tetrahydrofuran complex (6.0 mL, 62.69 mmol) was added and the solution allowed to warm to room temperature and stirred for 3 h. Another portion of borane-tetrahydrofuran complex (6.0 mL, 62.69 mmol) was added and the reaction stirred overnight. The reaction was cooled to 0° C. and quenched by the careful addition of cold water. The aqueous was extracted with EtOAc and the organic layer washed with 2M HCl, dried (Na2SO4), and concentrated. The material was dissolved in DCM and PS-DEAM (1 g) was added and stirred overnight. The resin was filtered washing with DCM and concentrated to afford 2-(2-bromo-5-chlorophenyl)ethanol as an oil (944 mg, quant). 1H NMR (500 MHz, CDCl3) δ 7.40 (1H, d), 7.30 (1H, s), 7.00-7.03 (1H, m), 3.80-3.84 (2H, m), 2.91-2.94 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].C1COCC1.[CH3:26][NH2:27]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:27][CH3:26])=[O:16])=[C:5]2[OH:20]
Reactant: CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.10 g, 3732 μmol, see Example 2) was dissolved in 2M methanamine in THF (9331 μL, 18661 μmol). The resulting mixture was stirred at 60° C. for 16 hours and then diluted with 100 mL of EtOAc. The resulting mixture was added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 20 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4 and concentrated in vacuo to give the title compound (131 mg) as a white solid after purification via preparatory LC. MS m/e=280 (M+H)+. Calculated for C14H14ClNO3 279.07.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][CH:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=2)[CH3:23])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:30][C:26]4[N:25]=[C:24]([CH:22]([O:21][C:20]5[CH:31]=[CH:32][C:17]([Cl:16])=[CH:18][CH:19]=5)[CH3:23])[CH:29]=[CH:28][N:27]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(Oc1ccc(Cl)cc1)c1ccnc(N)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: CC(Oc1ccc(Cl)cc1)c1ccnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 4-(1-(4-chlorophenoxy)ethyl)pyrimidin-2-amine (50 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 437.9, found 438.1 (M+1)+. Retention time 3.16 minutes.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:14]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:14]2
Reactant: CCOC(=O)c1cnc2cccc(OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc2cccc(O)c2c1
Yield: 91.4 %

Procedure:
210 mg (0.68 mmol) of compound prepared in stage B dissolved in 25 mL of ethanol was stirred in presence of Pd/C5% (75 mg, 0.034 mmol) under an atmosphere of hydrogen for 3 hours. The palladium was then removed by filtration and ethanol was evaporated under reduced pressure. The 1H NMR of the crude product showed a part of a reduced by-product at the pyridine ring (dihydroquinoline derivatives). The mixture was dissolved in ethanol and treated with air gas until complete re-oxidation of the product. Evaporation of the solvent gave 135 mg (yield: 91%) of compound of molecular formula C12H11NO3. Aspect: yellow powder.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18])[CH2:2][CH:3]=C.O.I([O-])(=O)(=O)=[O:21].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[O:18]=[C:6]1[N:5]([CH2:1][CH2:2][CH:3]=[O:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1
Reactant: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCC=O)C(=O)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-but-3-enyl-3-oxopiperazine-1-carboxylate (0.246 mg, 0.97 mmol) in 10 mL of 1:1 acetone:water was added sodium metaperiodate (621 mg, 2.90 mmol), followed by a solution of 0.25 M aqueous osmium tetraoxide (0.192 mL, 0.048 mmol). After stirring overnight, the reaction was partitioned between EtOAc and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 257.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:22][C:23]([C:25]1[S:26][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:28][CH:29]=1)=[NH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]4[O:20][N:24]=[C:23]([C:25]5[S:26][C:27]([S:30]([NH2:31])(=[O:33])=[O:32])=[CH:28][CH:29]=5)[N:22]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) (144 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH)) and crystallization (MeOH/dichloromethane) as a light yellow solid (79 mg, 33%). MS (ISP) 473.3 [(M+H)+]; mp 253° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:17]=[C:18]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2[S:24][C:23]([CH:25]=O)=[CH:22][C:20]=2[N:21]=1.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:15][C:16]1[N:17]=[C:18]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:19]2[S:24][C:23]([CH2:25][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:14])[CH2:13][CH2:12]3)=[CH:22][C:20]=2[N:21]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(Cl)Cl
Product: OC1(c2ccc(Cl)cc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(4-chlorophenyl)-4-hydroxypiperidine (368 mg, 1.74 mmol) in dichloroethane was added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (400 mg, 1.41 mmol) and trimethylorthoformate. After stirring for 1 hour at room temperature, sodium triacetoxyborohydride was added and the reaction mixture stirred overnight. The mixture was quenched with saturated aqueous Na2CO3. Chloroform/brine extraction gave crude material which was then triturated with hot ethyl acetate to give 1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-(4-chloro-phenyl)-piperidin-4-ol. (272 mg, 0.56 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[CH:6][N:7](C)C)[CH3:2].C(OC(=O)C(C(=O)C1C=CC=CC=1)=CN(C)C)C>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:18][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cccc(Cl)c1
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Product: CCOC(=O)c1cnoc1-c1cccc(Cl)c1
Yield: 51 %

Procedure:
The procedure of Example 15 was employed utilizing ethyl-2-(3'-chlorobenzoyl)-3-dimethylaminopropenoate in lieu of ethyl-2-benzoyl-3-dimethylaminopropenoate to yield ethyl-5-(3'-chlorophenyl)-4-isoxazolecarboxylate (3.2 g.; 51% yield) having a melting point of 75°-77° C. and the following analysis:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([OH:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[Cu](C#N)C#N.[Cl-].[Na+].CN(C)[CH:41]=[O:42]>>[CH:41]([O:14][CH:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH2:10][N:11]([C:15]2[N:20]=[CH:19][N:18]([CH2:21][C:22]3[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[C:17](=[O:31])[N:16]=2)[CH2:12]1)=[O:42]
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(C(F)(F)F)s1
Reactant: CN(C)C=O
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Na+]
Product: O=COC1CN(c2ncn(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CC=C1c1ccc(F)cc1
Yield: 2 %

Procedure:
To a crude product synthesized using 4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (50.0 mg, 0.111 mmol) synthesized in Synthesis Example 190 in a similar manner to Reference Synthesis Example 68, N,N-dimethylformamide (1.0 mL) and copper cyanide (49.3 mg, 0.550 mmol) were added and the resultant mixture was stirred at 100° C. for 1 day. After the completion of the reaction, to the reaction solution, saturated sodium chloride aqueous solution was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1) to obtain the title compound (0.8 mg, yield: 2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:28])[CH2:12][CH2:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:16]=[N:15][N:14]([CH2:13][CH2:12][CH:11]([CH3:28])[CH3:10])[CH:18]=2)=[CH:3][CH:4]=1
Reactant: CC(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnn(CCC(C)C)c2)cc1
Reaction time: 0.25 h
Yield: 127.4 %

Procedure:
To p-bromoanisole (0.25 g, 1.33 mmol) was added a solution of 1-(3-methylbutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.41 g, 1.55 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.29 g, 2.1 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.023 mmol) and the mixture refluxed under nitrogen for 17 h. Water (50 ml) was added to the reaction mixture and stirring continued at RT for 15 min followed by extraction with ether (2×50 ml), drying (MgSO4) and evaporation of the ether extract to give a brown oil (0.414 g). Purification by column chromatography (silica gel, 100% chloroform) afforded 4-(4-methoxyphenyl)-1-(3-methylbutyl)-1H-pyrazole (12) as a waxy pale yellow solid (37 mg, 11%). 1H nmr (CDCl3, 300 MHz) 0.97, d (6.6 Hz), 2×Me; 1.64, sept (6.6 Hz), H3″; 1.80, dt (7.2 Hz), H2″; 3.82, s, OMe; 4.15, t (7.5 Hz), H1″; 6.90, d (8.7 Hz), H3′,5′; 7.39, d (8.7 Hz), H2′,6′; 7.54, s, H3 or H5; 7.69, s, H5 or H3. ESI (+ve) MS m/z 245 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]([OH:27])([CH3:26])[CH3:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I.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>[F:16][C:15]([F:18])([F:17])[C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[CH:5]=[C:4]([C:19]3[S:23][C:22]([C:24]([OH:27])([CH3:26])[CH3:25])=[N:21][CH:20]=3)[CH:3]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:7]=2)[N:14]=1
Reactant: CC(C)(O)c1ncc(-c2cc(Br)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)c1ncc(-c2cc(C#C[Si](C)(C)C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of the product of Step 1 (50 mg, 0.109 mmol), trimethylsilylacetylene (30.6 μL, 0.218 mmol), DIPEA (57 μL, 0.33 mmol), CuI (4.2 mg, 0.022 mmol) and Pd(PPh3)4 (12.6 mg, 0.011 mmol) in DMF (2.0 mL) was heated to 85° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate (30 mL) and washed with 1:1 water:brine (2×30 mL). The aqueous layers were further extracted with ethyl acetate (30 mL), then the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 35 mg (0.073 mmol, 68%) of 2-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-[(trimethylsilyl)ethynyl]phenyl)-1,3-thiazol-2-yl]propan-2-ol as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:24][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C2=CC(=O)CCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CC(NCCc3ccccc3)CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 3-(4-methoxy-phenyl)-cyclohex-2-enone (prepared following the procedure described in CA:54-10947d) (2.0 g, 9.89 mmol), phenethylamine (1.20 g, 9.89 mmol), toluene (50 ml) and a catalytical amount of p-toluenesulfonic acid was refluxed in a Dean-Stark apparatus overnight. After removal of the solvent, the residue was dissolved in MeOH (30 ml) and sodium borohydride (excess) was added. After stirring for 1 h at RT, the solvent was evaporated, H2O was added to the residue. Extraction with CH2Cl2, drying of the organic layer over Na2SO4, evaporation of the solvent and flash-chromatography of the residue over SiO2 (Biotage-40, 90 g) eluting with CH2Cl2—MeOH 95:5 gave (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-phenethyl-amine (1.7 g, 56%, light yellow solid, MS: m/e=308.2 (M+H+)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:29]=1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:28])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:29]=1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2

Procedure:
Following the procedure for 109, 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-amino-2-methylpropan-1-ol gave 161. MS: (ESI+)=478.1. 1H NMR (400 MHz, DMSO) δ 8.12 (d, J=2.1 Hz, 1H), 7.63 (dd, J=6.0, 3.4 Hz, 1H), 7.53 (dd, J=6.1, 3.2 Hz, 2H), 7.50-7.44 (m, 3H), 7.36 (s, 1H), 7.28 (d, J=1.1 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.00 (s, 1H), 4.41 (s, 4H), 3.55 (d, J=5.1 Hz, 2H), 1.36 (s, 6H)