Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].Cl[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].C(N(CC)CC)C>O1CCCC1>[C:10](=[O:11])([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])[O:12][CH2:13][CH:14]=[CH2:15]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of N-hydroxysuccinimide (4.78 g, 0.042 mol) and allyl chloroformate (5.0 g, 4.40 ml, 0.042 mmol) in dry tetrahydrofuran (60 ml) was cooled to 0° C. under nitrogen. A solution of triethylamine (4.2 g, 5.78 ml, 0.042 mol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. After completion of the addition, the mixture was stirred at room temperature for 4 hours, and then filtered and concentrated. Ethyl acetate (200 ml) was added and the resulting solution was washed sequentially with water (3×), saturated sodium bicarbonate solution and water (3×). Drying (MgSO4) and removal of the solvent in vacuo gave the title compound as a clear, colourless oil. (D23).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].Cl[C:13]([C:15]1[C:16]([Cl:26])=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([O:20][CH3:21])=[O:19])=[O:14]>ClCCl>[Cl:26][C:16]1[C:15]([C:13]([NH:11][O:10][CH3:9])=[O:14])=[C:24]([Cl:25])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CON
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
20 4.60 g (0.045 mol) of triethylamine and 3.75 g (0.045 mol) of methoxyamine hydrochloride were added to a solution of 5.35 g (0.02 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate and in 100 ml of dichloromethane. After the reaction solution had been stirred for 12 hours at room temperature, it was washed with dilute phosphoric acid, dried and concentrated. The resulting residue was extracted by stirring with diethyl ether. This gave 4.80 g of methyl 2,4-dichloro-3-(N-methoxy)aminocarbonylbenzoate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[C:20]2=[N:21][S:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Li+].[OH-].Cl>C1COCC1>[N:23]1[S:22][N:21]=[C:20]2[C:15]([S:12]([NH:11][C:5]3[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=3[C:3]([OH:24])=[O:2])(=[O:14])=[O:13])=[CH:16][CH:17]=[CH:18][C:19]=12
Reactant: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a stirred suspension of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid methyl ester (2.0 g, 5.2 mmol) in THF (12 mL) at rt was added LiOH (2 M in water, 10 mL). The resulting orange mixture was stirred overnight at rt then poured into 0.5 M HCl (150 mL) causing precipitation of the desired benzoic acid. After stirring the mixture several minutes to complete precipitation, the product was collected by suction filtration and air-dried to afford the acid as a tan solid (1.87 g, 97%). MS (ESI−): mass calcd. for C13H8ClN3O4S2, 369.8; m/z found, 368 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.22 (br s, 1H), 8.43 (dd, J=7.2, 1.0, 1H), 8.26 (dd, J=8.8, 1.0, 1H), 7.90 (d, J=8.8, 1H), 7.80 (d, J=2.0, 1H), 7.75 (dd, J=8.8, 7.2, 1H), 6.99 (dd, J=8.8, 2.0, 1H). Anal. calcd. for C13H8ClN3O4S2: C, 42.22; H, 2.18; N, 11.36. Found: C, 41.92; H, 2.50; N, 11.38.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[CH:28][CH:29]=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:8][C:6]1[CH:7]=[C:2]([CH:29](/[CH:28]=[CH:27]/[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:32][CH:31]=2)[OH:30])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: O=CC=Cc1ccc(Cl)cc1
Reactant: COc1ncc(Cl)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ncc(Cl)cc1C(O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4.0 g of 3-bromo-5-chloro-2-methoxypyridine in 75 ml of anhydrous ether was cooled to -70° C. under nitrogen. The resulting slurry was stirred rapidly and there was added 12.0 ml of 1.65M n-butyllithium/hexane dropwise over a period of about 5 minutes while keeping the temperature below -70° C. The reaction mixture became homogeneous and, after 15 minutes, a solution of 3.0 g of 4-chlorocinnamaldehyde in 35 ml of ether was added dropwise while keeping the temperature below -60° C. The cold mixture was then poured into aqueous saturated sodium bicarbonate solution and the resulting mixture was extracted with ether. The ether layer was washed with aqueous saturated sodium chloride solution, dried over potassium carbonate and concentrated under reduced pressure to give a white solid. This solid was recrystallized from a mixture of ethyl acetate/hexane to give (E)-5-chloro-α-[2-(4-chlorophenyl)ethenyl]-2-methoxy-3-pyridinemethanol as white needles melting at about 135°-139.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.O>[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[O:11]([CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cncc(OCCOc2ccccc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc(OCCOc2cncc(N3CCNCC3)n2)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the product from step 1 above (1.29 g, 5.15 mmol), piperazine (1.30 g, 15.1 mmol) and K2CO3 (0.71 g, 5.14 mmol) in acetonitrile (5 mL) was heated in a sealed pyrex flask at 100° C. for 4 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The light-brown semi-solid residue was purified by silica gel chromatography (15×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the residue was redissolved in ether/CHCl3 (1:1). Filtration and concentration in vacuo furnished 1.05 g (68%) of the title compound as a white solid. HRMS m/z calcd for C16H20N4O2 (M)+ 300.1586, found 300.1578. Anal. (C16H20N4O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[H-].[Na+].Cl[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:16][CH2:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH3:11])=[N:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(COCc2ccccc2)c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a 0° C. stirred solution of 5-bromo-3-methyl-indazole (from Preparation 1, 1.00 g, 4.33 mmol) in anhydrous DMF (30 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.21 g, 5.19 mmol). After 30 min, benzyl chloromethyl ether (60%, 1.47 g, 5.63 mmol) was added vial syringe in about 1 min. Stirring was continued for 1 h. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give an oil that was purified by chromatography on silica gel (hexane/ethyl acetate 10:1) to give the title compound (0.72 g, 50%) that was pure by NMR.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].[C:15]([Br:19])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][C:15]1[C:4]([CH3:3])=[C:5]([CH:8]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(Br)cc(C(F)(F)F)cc1C#N
Reaction time: 0.5 h
Yield: 83 %

Procedure:
3-Hydroxymethyl-5-trifluoromethyl-benzonitrile (23.4 g) is dissolved in methylene chloride (230 mL) and thereto is added carbon tetrabromide (42.4 g), followed by an addition of triphenylphosphine (32.0 g) under ice-cooling and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-bromo-methyl-5-trifluoromethyl-benzonitrile (25.5 g). NMR (CDCl3): 4.51 (2H, s), 7.86 (1H, s), 7.88 (2H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12]C)[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: COc1cc(Br)cc2c1C(=O)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2c(O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 64, 0.24 g, 0.83 mmol) in anhydrous dichloromethane (4 mL) was treated with aluminum chloride (0.4 g, 3 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. It was poured into water and extracted with dichloromethane and ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title product as a pale yellow solid (0.13 g, 56%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH:15]([OH:17])[CH3:16].N12CCCN=C1CCCCC2.[Cl:37][C:38]([Cl:42])([Cl:41])[C:39]#[N:40]>C(OCC)C>[Cl:37][C:38]([Cl:42])([Cl:41])[C:39](=[NH:40])[O:17][CH:15]([C:6]1[C:5]2[C:10](=[C:2]([Br:1])[N:3]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:4]=2)[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=1)[CH3:16]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (1.07 g, 2.44 mmol) was dissolved in diethyl ether (10 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (70 μL, 0.49 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (370 μL, 3.65 mmol) dropwise over 10 min. The reaction was allowed to warm to room temperature overnight and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 1.29 g (91%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.25 (s, 1H), 7.86 (s, 1H), 6.66 (q, J=6.6 Hz, 1H), 6.27 (d, J=11.7 Hz, 1H), 5.68 (d, J=11.7 Hz, 1H), 3.52-3.59 (m, 2H), 1.77 (d, J=6.6 Hz, 3H), 0.82-0.87 (m, 2H), 0.05 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][Mg]Cl)=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:13][C:14]1[CH:22]=[CH:21][C:17]([CH3:18])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: Cc1ccc(C[Mg]Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc(C)cc1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (32) prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=9/1) to give 1,1-diethoxy-3-(4-methylphenyl)propan-2-one (33) as a colorless oily substance (1.96 g, 8.27 mmol, 82.4%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[C:13]1([CH2:19]CCN)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([CH2:19][CH2:11][CH2:12][NH:8][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[O:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (33.00 g, 0.203 mol) in THF (100 mL) at room temperature under N2, was added 3-phenylpropylamine (25.00 g, 0.185 mol) in THF (50 mL), dropwise. The reaction mixture became clear during the addition of the 3-phenylpropylamine. After completion of the addition, the clear solution was stirred for 30 min at room temperature and then quenched with water (150 mL) and ethyl acetate (200 mL). The layers were separated and the organic layer washed with water (150 mL), brine (150 mL), and dried with Na2SO4. The solvents were removed in vacuo to yield a white wax-like solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C1CCN2C(=NCCC2)CC1.[N+:34]([C:37]1[CH:38]=[C:39](/[CH:43]=[CH:44]\[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]>C(#N)C>[N+:34]([C:37]1[CH:38]=[C:39]([CH:43]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:44][C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: N#C/C=C\c1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc([N+](=O)[O-])c4)c3)ncnc21
Temperature: 67 °C

Procedure:
To 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by addition of (2Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67° C. for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)+:490
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([N:23]3[CH2:24][CH2:25][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]3)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
172 mg (0.69 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylideneacetic acid, 144 mg (0.78 mmol) of t-butyl 1-piperazinecarboxylate, 148 mg (0.77 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5 N aqueous sodium hydroxide solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: [CH:1]([S:4]Cl)([CH3:3])[CH3:2].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[O:10][C:9](=[O:14])[CH:8]=1>C(Cl)Cl>[CH:1]([S:4][C:8]1[C:9](=[O:14])[O:10][C:11]([CH3:13])=[CH:12][C:7]=1[OH:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CC(C)SCl
Solvent: ClCCl
Product: Cc1cc(O)c(SC(C)C)c(=O)o1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
A solution of 62.7 g. (0.57 mole) of isopropanesulfenyl chloride in 300 ml. of methylene chloride was added dropwise to a suspension of 84.5 g. (0.57 mole) of 4-hydroxy-6-methyl-2-pyrone in 200 ml. of methylene chloride while the reaction mixture was maintained at 20°C. The mixture was then warmed to 40°C. for 1.5 hours and finally stirred at room temperature for 17 hours. The by-product sodium chloride was removed by filtration and the filtrate evaporated to dryness, leaving a red liquid (85.5 g.) which solidified upon cooling in an ice bath. The crude product was recrystallized from cyclohexane to give 33.1 g. (28 percent) of the product as off-white crystals, m. 89°-91°C. A second recrystallization from cyclohexane gave white crystals, m. 91°-92°C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1cc(CBr)no1
Product: Cc1cc(COc2ccn(-c3nc(C)c(C(=O)NCc4ccccc4)s3)c(=O)c2)no1
Yield: 47 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 3-(bromomethyl)-5-methylisoxazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 47% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J=5.9 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.35-7.18 (m, 5H), 6.38-6.35 (m, 2H), 6.26 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 437.2 (M+1).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13]>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([Cl:4])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CCCCl)C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(CCCCl)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (888 mg, 7 mmols) was added to a chloroform (10 ml) solution of the resulting carboxylic acid (0.9 g, 5 mmols) and DMF (catalytic amount, 1 drop), and stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 5-chloro-2,2-dimethylpentanoic acid chloride,
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[CH:9]([NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=3)=[O:30])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([C:31]4[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=4)=[O:30])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)=CN2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 18.1 %

Procedure:
A mixture of N-{5-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]amino}-1,6-dihydropyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (5.85 g, 10.6 mmol), trifluoroacetic anhydride (40 mL) and dichloromethane (40 mL) was stirred at room temperature for 6 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL) were added to the residue and the mixture was stirred for 10 min. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (15 mL) and ethanol (60 mL) were added to the residue. The mixture was stirred at room temperature for 2 hr and at 60° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate/tetrahydrofuran (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (730 mg, 18%) as a white solid.