Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].S(Cl)(Cl)(=O)=O.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[S:27])[NH2:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:3][CH:2]([C:1]1[N:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:28])([F:17])[F:29])=[CH:24][CH:23]=2)[S:27][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:4]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
Ethyl isobutyrylacetate (XI-3a) (3.006 g, 19.0 mmol) was dissolved in chloroform (20 mL). Sulfuryl chloride (1.70 mL, 21.2 mmol) was added and the solution was stirred at RT for 18 hours, then was concentrated. The residue was dissolved in ethanol (50 mL). 4-(Trifluoromethyl)benzenethioamide (4.234 g, 20.6 mmol) was added and the solution was heated to reflux for 24 hours. The mixture was cooled to RT and filtered. The solid was washed with cold ethanol and dried to provide the title product (2.68 g, 32%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.99 (qu, J=6.8 Hz, 1H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[O:31]=[C:24]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 18 h
Yield: 7.4 %

Procedure:
To a stirred solution, under N2 atmosphere, of 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) (10.0 g, 38 mmol), and triethylamine (15.35 g, 150 mmol) in methylene chloride (100 mL) was added ethyl 3-chloro-3-oxopropionate (6.32 g, 42 mmol). The reaction was stirred for 18 hours. The reaction mixture was concentrated down in vaco and purified by flash silica gel chromatography eluting with 1:1 ethyl acetate / hexanes to give an orange solid (0.86 g, 7%); 1H NMR (300 MHz, CDCl3) δ 1.32 (t, J=7.2 Hz, 3H), 2.55 (t, J=6 Hz, 4H), 3.46 (s, 2H), 3.56 (t, J=6 Hz, 4H), 4.22 (q, J=7.2 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 9.09 (s, 1H); MS (ES) m/z: 305.3 (MH+, 100%).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:8])[CH2:5][S:6][CH3:7].C(N(CC)CC)C.[CH2:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH2:25][CH3:26])[C:19]=1[C:27](=[O:31])[C:28](Cl)=[O:29])[CH3:17].O>C1(C)C=CC=CC=1>[CH2:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH2:25][CH3:26])[C:19]=1[C:27](=[O:31])[C:28]([N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH2:5][S:6][CH3:7])=[O:29])[CH3:17]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Reactant: CNN=C(C)CSC
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a 200 ml volume four-necked flask, 1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine (5-0-1) (5.0 g), toluene (anhydrous) (9.6 g), and triethylamine (6.97 g) were added under a nitrogen atmosphere at room temperature. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (9.57 g) dissolved in toluene (28.8 g) was added dropwise at 0° C. over 2 hours, and stirred at room temperature for 2 hours. To the reaction mixture was added water (30 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 10.96 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:35]1([N:1]([CH3:42])[C:2]2[CH:3]=[C:4]([C@@H:8]([N:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(N(C)C3CCCCC3)c2)N2CCNCC2)cc1
Reaction time: 6 h

Procedure:
To a room temperature solution of INTERMEDIATE 5a (300 mg; 0.64 mmol) in 1,2-dichloroethane (15 mL) were added cyclohexanone (0.20 mL; 1.93 mmol), sodium triacetoxy borohydride (0.43 g; 2.05 mmol) and acetic acid (37 μL; 0.64 mmol). The reaction mixture was stirred for 6 hours then was washed with two portions of saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 4% methanol in dichloromethane gave the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CCO.O.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])/[CH:9]=[CH:19]/[C:18]2[CH:21]=[CH:22][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:16][CH:17]=2)[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1O
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (20 g, 93.4 mmol) in EtOH (114 mL) and H2O (6 mL) was added 4-(trifluoromethoxy)benzaldehyde (17.75 g, 93.4 mmol) and NaOH (33.6 g, 840.6 mmol). The reaction mixture was stirred overnight. Ethoxyethane was added to the mixture and filtered to give a residue. The residue was dissolved in water and acidified by 1 M HCl to give a solid. The solid was collected by filtration to give (E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (30 g, 80%). 1H-NMR (CDCl3): 6.87 (d, 1H), 7.21 (d, 2H), 7.49 (m, 1H), 7.52 (m, 1H), 7.59 (d, 2H), 7.84 (t, 1H), 7.92 (s, 1H).
Reaction SMILES: [C:1]([CH:9]1[C:13](=O)[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]([CH3:21])[C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CC1=NN(c2ccccc2)C(=O)C1C(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution containing 2.0 g of 4-benzoyl-3-methyl-1 -phenyl-2-pyrazolin-5-one (commercially available e.g. Aldrich 15,660-4) in 4 ml of phosphorus oxychloride was stirred under nitrogen at 100° C. for 30 min. The mixture was poured into 40 ml of saturated sodium hydrogen carbonate solution and extracted three times with 30 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated to give 2.0 g of (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-phenyl-methanone as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[Li][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.CO.[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=1
Reactant: [Li]c1ccccc1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(C[N+](=O)[O-])c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a cold (−78° C.), stirred solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (153 mg, 0.86 mmol) in THF (20 mL) was added PhLi (0.64 mL, 1.6M) under Ar. After 1.5 h, the reaction was treated with MeOH, sat. NH4Cl and brine, and allowed to warm to room temperature. The reaction was extracted with EtOAc (3×), dried (MgSO4), filtered, concentrated then purified on Biotage Horizon to provide the product (150 mg, 68%) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm: 7.32 (2H, t, J=7.20 Hz), 7.19-7.25 (3H, m), 7.14 (2H, d, J=8.84 Hz), 6.84 (2H, d, J=8.84 Hz), 4.90-4.96 (2H, m), 4.81-4.87 (1H, m), 3.77 (3H, s).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.C([O-])(O)=O.[Na+].[F:34][C:35]1[CH:36]=[C:37]([S:44](Cl)(=[O:46])=[O:45])[CH:38]=[CH:39][C:40]=1[N+:41]([O-:43])=[O:42].CC(O)C>ClCCl>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:44]([C:37]2[CH:38]=[CH:39][C:40]([N+:41]([O-:43])=[O:42])=[C:35]([F:34])[CH:36]=2)(=[O:46])=[O:45])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C

Procedure:
(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]-furan-3-yl ester (6) (9.81 g, 25 mmol, 1 equiv) was dissolved in dichloromethane (100 mL), followed by the addition of saturated NaHCO3 solution (100 mL). A solution of 3-fluoro-4-nitro-benzenesulfonyl chloride (6.11 g, 25.50 mmol, 1.02 equiv) in dichloromethane (100 mL) was added drop wise to the previous solution. The solution was vigorously stirred at 20° C. After stirring for 4 h, the organic layer was separated and washed with saturated NaHCO3 solution (100 mL), water (100 mL), 5% HCl solution (100 mL) and brine (100 mL). The organic layer was dried on MgSO4, filtered, and evaporated to dryness. The crude product was recrystallized from 2-propanol (550 mL) (9.58 g, 25 mmol, 64.30%). LRMS (ES+): m/z 596 [M+H]+; 1H-NMR (CDCl3) δ 0.90 (d, 3H, CH3), 0.92 (d, 3H, CH3), 1.40-1.72 (m, 2H, CH2, H4), 1.80-1.92 (m, 1H, CH (isobutyl)), 2.79 (dd, 1H, CH2—N), 2.87-3.19 (m, 5H, CH2—N (isobutyl), CH, H3, CH2—N and CH of CH2C6H5), 3.19-3.29 (m, 1H, CH of CH2C6H5), 3.29-3.39 (brs, 1H, OH), 3.60-3.78 (m, 2H, CH2, H5 and H2), 3.78-3.90 (m, 3H, CH, H5, CH—OH and CH), 3.95 (dd, 1H, CH2, H2), 4.90 (d, 1H, NH), 4.98-5.10 (m, 1H, CH, H3), 5.66 (d, 1H, CH, H6a), 7.19-7.33 (m, 5H, C6H5), 7.68-7.74 (m, 2H, CH of C6H3FNO2), 8.15-8.20 (m, 1H, CH of C6H3FNO2).
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[F:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:34])[C:32]=1F>>[F:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:34])[C:32]=1[O:25][C:22]1[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=1
Reactant: Fc1cncc(F)c1F
Reactant: Nc1ccc(O)cc1
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: Nc1ccc(Oc2c(F)cncc2F)cc1

Procedure:
{4-[(3,5-Difluoropyridin-4-yl) oxy]phenyl} amine (2E) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-aminophenol and 3, 4, 5-trifluoropyridine, MS ES: 223 (M+H)+, calcd 223, RT=0.50 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CCCCCC.C([Li])CCC.[CH3:22][C:23]([CH3:25])=[O:24]>O1CCCC1>[OH:24][C:23]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: Cn1ccc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(C(C)(C)O)cc2ccccc21
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
5.0 g of 1-methylindole was dissolved in 30 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 30 ml of 1.5 M n-butyllithium hexane solution, at -30° C. in 5 minutes with stirring. The mixture was stirred at 0° C. for 30 minutes. Thereto was dropwise added 4.2 ml of acetone in 10 minutes at the same temperature, and the resulting mixture was stirred at room temperature for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of ethyl acetate and 50 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1 to 20/1), followed by recrystallization from n-hexane, to obtain 3.25 g (yield: 45%) of 2-(1-hydroxy-1-methylethyl)-1-methylindole as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:21]=[O:22])[CH:28]=3)[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
Reactant: O=Cc1cccc(B(O)O)c1
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
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(-c3cccc(C=O)c3)c2)c(N)s1
Yield: 39.5 %

Procedure:
The procedure as in Example 1: step c was followed using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (754.2 mg, 2 mmol, Example 20: step e), 3-formyl phenyl boronic acid (599.7 mg, 4 mmol), Pd(PPh3)4 (462.2 mg, 0.4 mmol), aqueous Na2CO3 (2M, 8 mL, 16 mmol), ethanol (8 mL) and toluene (16 mL). Purification by flash column chromatography (Biotage Flash™ System—40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the title compound (317 mg, 40%) as a brown solid. 1H-NMR (CDCl3): δ 10.10 (s, 1H), 8.10–8.17 (m, 2H), 7.92–7.95 (m, 2H), 7.82–7.89 (t, 2H, J=8.1 Hz), 7.58–7.70 (m, 3H), 6.05 (br s, 2H), 3.80 (s, 3H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][Si:13]([CH3:24])([CH3:23])[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[CH:18]=1>C(Cl)Cl>[CH3:24][Si:13]([CH3:12])([CH3:23])[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH:21]=[O:22])[CH:18]=1
Reactant: C[Si](C)(C)c1cc(CCCO)co1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(CCC=O)co1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring mixture of pyridinium chlorochromate (3.89 g, 18.03 mmol) suspended in methylene chloride (100 ml) at 0° was added 3-(2-trimethylsilyl-4-furyl)propan-1-ol (1.19 g. 6.01 mmol), prepared as in Example 2, in dry methylene chloride (15 ml). This mixture was allowed to warm to room temperature, stirred for 90 minutes, filtered and concentrated to give the desired aldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>O>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:15]([C:14]3[CH:18]=[CH:19][C:11]([NH2:10])=[CH:12][CH:13]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(O)c(N)c1
Solvent: O
Product: Cc1ccc2oc(-c3ccc(N)cc3)nc2c1
Temperature: 190 °C
Yield: 90.3 %

Procedure:
A mixture of 2-amino-p-cresol (1.5 g, 12 mmol), 4-aminobenzoic acid (1.67 g, 12 mmol) and 40 g polyphosphoric acid was heated at 190° C. under nitrogen for 6 h. The reaction mixture was cooled to room temperature and 300 ml water was added to the viscous liquid. The solid that precipitated was collected by filtration and dissolved in 200 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 100 ml saturated aqueous sodium bicarbonate solution, 100 ml water and 100 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to yield the title compound as an off-white solid (2.43 g, 89% yield).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][C:7](OC(C)=O)=[O:8].[CH2:13]([O:15][C:16](=[O:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:14]>C(Cl)Cl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([C:7](=[O:8])[CH3:6])=[CH:24][C:19]=1[O:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)COc1ccccc1OCC(=O)OCC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC

Procedure:
Perchloric acid (70% aq.; 1.0 ml) was added slowly to freshly distilled Ac2O (25 ml) at 0° C. The compound of example 20a (31.8 g; 125 mmol) in CH2Cl2 (13 ml) was added drop wise at 10-15° C. The reaction mixture was heated on steam bath for 1 h, concentrated, poured over crushed ice and NaHCO3 (˜25 g) and extracted with ether. The ether layer was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5% CH3CN in CHCl3) to obtain the title compound. Yield, 24.6 g (61.5%), semisolid; analysis: C16H20O7: requires C, 59.25; H, 6.22. found: C, 59.57; H, 6.28%.
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3](O)[CH:2]=1.S([O:15][CH3:16])(OC)(=O)=O.[C:17](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:17][O:9][C:1]1[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([O:15][CH3:16])[CH:2]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C)cc(OC)c1
Temperature: 0 °C
Yield: 82 %

Procedure:
Commercially available orcinol (5.77 g) was dissolved in acetonitrile (200 ml), dimethyl sulfate (8.47 ml) and potassium carbonate (12.3 g) were added, and the admixture was refluxed for 2.5 hours. The reaction mixture was poured into ice water and partitioned with chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1) to obtain 5.04 g of the title compound (yield: 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Yield: 38.6 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-amine (6-3, 0.23 g, 0.77 mmol) in THF (3.9 mL) was added triethylamine (0.23 g, 2.30 mmol) followed by isonicotinoyl chloride hydrochloride (0.27 g, 1.52 mmol). The reaction mixture was heated at 60° C. overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in MeOH to give N-{4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-yl}isonicotinamide (6, 0.12 g) as yellow solids in 38% yield: 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=6.0 Hz, 2 H), 8.58 (d, J=4.5 Hz, 2 H), 7.65 (d, J=6.0 Hz, 2 H), 7.04 (t, J=4.8 Hz, 1 H), 6.83 (s, 1 H), 6.70 (s, 2 H), 3.47 (s, 3 H), 1.97 (s, 6 H). ESI-MS: m/z 403.8 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[SH:29].N1C2C(=CC=CC=2O)CCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([S:29][C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1S
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2c1NCCC2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Sc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 130 °C
Yield: 68.2 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (2.00 g; 6.02 mmol) and 2,6-dimethylthiophenol (0.88 mL; 6.62 mmol) in DMF (15 mL) was added CuBr (0.43 g; 3.01 mmol), 1,2,3,4-tetrahydro-quinolin-8-ol (0.45 g; 3.01 mmol) and Cs2CO3 (2.45 g; 7.52 mmol; 1.25 eq.). The resulting mixture was heated, in a closed vessel, at 130° C., for 2 days. After cooling to RT, water was added and the mixture extracted with Et2O. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (Et2O/hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dimethyl-phenylsulfanyl)-phenyl]-morpholine (1.60 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O.N(C(CC)C#N)=NC(CC)C#N.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)c(F)c1
Agent: CCC(C#N)N=NC(C#N)CC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(CBr)c(F)c1
Yield: 80.1 %

Procedure:
To a solution (11 ml) of the compound (2.0 g, 11 mmol) obtained in Example 189a in ethyl acetate were added N-bromosuccinimide (2.9 g, 17 mmol) and 2,2′-azobisbutyronitrile (AIBN) (180 mg, 1.1 mmol), and the mixture was heated under reflux for 5 hr under light irradiation. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give a crude title compound (2.3 g, 81%) as a colorless oil.