Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([CH3:37])=[C:10]([CH2:14][N:15]2[C:19]3[CH:20]=[C:21]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=[C:23]([C:24](O)=O)[C:18]=3[N:17]=[C:16]2[C:33]([F:36])([F:35])[F:34])[CH:11]=[CH:12][CH:13]=1.COC(OC)[N:41]([CH3:43])C.O.[NH2:47][NH2:48]>ClCCl>[Cl:7][C:8]1[C:9]([CH3:37])=[C:10]([CH2:14][N:15]2[C:19]3[CH:20]=[C:21]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=[C:23]([C:24]4[N:41]=[CH:43][NH:48][N:47]=4)[C:18]=3[N:17]=[C:16]2[C:33]([F:35])([F:34])[F:36])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.9 %

Procedure:
Oxalyl chloride (0.347 mL, 3.97 mmol) was added to a suspension of 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 53 (450 mg, 0.992 mmol) in Dichloromethane (DCM) (8 mL). The reaction mixture was stirred at rt for 10 minutes and then the solvent was evaporated. The residue (crude acid chloride), was suspended in Tetrahydrofuran (THF) (8 mL). NH3 gas was bubbled in (the mixture changed color yellow to white) and the mixture was stirred at rt for 15 minutes and then partitioned between brine (15 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and CH2Cl2 (10 mL). The organic phases were combined, dried over Na2SO4 and concentrated. The crude product was suspended in N,N-dimethylformamide dimethyl acetal (10 mL, 74.7 mmol) and stirred at 105° C. for 2 h. The excess solvent was evaporated and the residue was suspended in Acetic Acid (10 mL). After the addition of hydrazine monohydrate (0.194 mL, 3.97 mmol), the mixture was stirred at 100° C. for 1.5 h. The solvent was evaporated and the residue was dissolved in warm DMSO (8 mL) and purified by reverse phase-HPLC (20-90% AcCN in water plus 0.1% TFA) to give the desired product (96 mg, 0.197 mmol, 19.90% yield) as a white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.08 (br. s., 1H), 8.11 (s, 1H), 7.98 (d, J=2.27 Hz, 1H), 7.36 (d, J=8.08 Hz, 1H), 7.01 (t, J=7.96 Hz, 1H), 6.51 (d, J=2.02 Hz, 1H), 6.32 (d, J=7.83 Hz, 1H), 5.51 (s, 2H), 3.73-3.97 (m, 4H), 3.12-3.30 (m, 4H), 2.50 (s, 3H). MS (ES+) m/e 476.9 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][C:19]2=[O:27])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2C(=O)Nc3ccccc32)cc(C(C)(C)C)c1O
Yield: 43.2 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5.28 g; 22.5 mmol), 2-oxindole (3.0 g; 22.5 mmol), and p-toluene sulfonic acid (0.25 g) in toluene (100 ml) is heated under reflux for 18 hours. The reaction mixture is cooled and filtered. The residue is washed with ether and dried @80° C. under vacuum for 18 hours to give 3.4 g (43.2%) of a yellow solid, mp 224°-225° C. (lit. mp 227° C.*).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[F:13].[NH4+].[Cl-]>O1CCCC1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[F:13]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methylmagnesium bromide (22.5 mL, 31.5 mmol; 1.4 M solution in toluene/tetrahydrofuran) was added dropwise to a solution of 4-chloro-3-fluorobenzaldehyde (5.0 g, 31.5 mmol) in 100 mL of dry tetrahydrofuran at −78° C. over 15 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into saturated NH4Cl (100 mL). The aqueous layer was extracted with diethyl ether (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-(4-chloro-3-fluorophenyl)ethanol (5.50 g, 100%) as a yellow oil which was used in the next step without further purification, MS (ES) m/z 175 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([CH3:8])=[N:5][CH:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[CH3:8][C:6]1[S:7][C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[CH:4][N:5]=1
Reactant: Cc1ncc(CBr)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2C(=O)c3ccccc3C2=O)s1
Yield: 40.1 %

Procedure:
Add 5-bromomethyl-2-methylthiazole (390 mg, 2.03 mmol) in dimethylformamide (2 mL) dropwise to a suspension of potassium phthalimide (434 mg, 2.34 mmol) in dimethylformamide (8 mL). Stir the reaction under nitrogen at room temperature overnight. Concentrate the mixture in vacuo, dissolve in ethyl acetate (100 mL), and wash with water (100 mL). Dry the organic phase (sodium sulfate), filter, and concentrate. Perform flash chromatography on silica gel, eluting first with 4:1 hexane/ethyl acetate, then 100% ethyl acetate to afford 210 mg of 2-(2-methylthiazol-5-ylmethyl)isoindole-1,3-dione as a tan solid. MS: m/z=259 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[CH3:17][C:18]([CH3:28])([CH3:27])/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22]>C1COCC1>[CH3:17][C:18]([CH3:28])([CH3:27])[CH:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: c1cscn1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(NS(=O)C(C)(C)C)c1nccs1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of thiazole (247 mg, 206 μl, 2.91 mmol) in 10 mL dry THF under argon at −73° C. was slowly added a 1.6M solution of BuLi in hexane (1.82 ml, 2.91 mmol). The resulting reaction mixture was stirred at −75° C. for 30 min and a solution of (E)-N-(2,2-dimethylpropylidene)-2-methylpropane-2-sulfinamide (Example 306a) (500 mg, 2.64 mmol) in 5 mL dry THF was added. The reaction mixture was stirred at −75° C. for 30 min, then cooling bath was removed and reaction stirred at r.t for 1 h. The reaction was quenched by the addition of few drops of water, the reaction mixture poured into ethyl acetate, and the solution was then extracted with aqueous NaHCO3 1M. The organic phase was collected, dried over Na2SO4 and evaporated down to dryness to give the title compound (666 mg, 92%) as crude dark orange oil. The crude was used without any further purification, MS (EI): m/e=275.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]2[CH2:13][O:12]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>CCO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@H:16]2[CH2:15][OH:14])=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: COc1cc(C2CO2)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc1C#N
Temperature: 25 °C

Procedure:
A Pyrex vessel was charged with magnetic stirring bar, (0.350 g, 2.00 mmol) of 2-methoxy-4-(oxiran-2-yl)benzonitrile, (0.457 g, 2.20 mmol) of tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate, and 6 mL of EtOH. Then it was introduced in the microwave reactor and irradiated at 150° C. for 3 hr. Then the mixture was cooled to room temperature and the solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, 1-20% dichloromethane/MeOH) which afforded the title compound as a mixture of two diastereomers (1:1). LC/MS: (IE, m/z) [(M+1)-t-Bu]+=336.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH2:38])=[CH:28][CH:27]=1>C(Cl)Cl.C(N(CC)CC)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH:38][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])=[CH:30][CH:31]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccc(Cl)cc2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A solution of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.68 g) and oxalyl chloride (0.49 g) in methylene chloride (30 ml) is stirred for 2 hours at room temperature in the presence of a catalytic amount of DMF. The resulting acid chloride solution is then added to a solution of 4′-chlorobiphenyl-2-ylamine (0.71 g) and triethylamine (0.36 g) in 15 ml of methylene chloride at 0° C. The reaction mixture is then stirred for 4 hours at room temperature. After distilling off the solvent in a water-jet-vacuum, the residue is taken up in ethylacetate/water. The ethylacetate phase is extracted twice with water. After drying of the organic phase with Na2SO4, the solvent is distilled off in a water-jet-vacuum and the residue purified by column chromatography (silica gel; eluant: ethylacetate/hexane=1:1). 0.8 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4′-chlorobiphenyl-2-yl) amide are obtained in the form of slightly brownish crystals having a melting point of 144–146° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)CC)C>CN(C)C=O>[N:16]1([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([I:15])=[N:6]2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1c(I)nn2CCCn1ccnc1
Temperature: 70 °C
Reaction time: 25.5 h
Yield: 17.8 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with imidazole (0.107 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 25.5 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 14 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as the eluent. The column afforded 0.086 g (18%) of pure 1-[3-(1H-1-imidazolyl)propyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.211 (s, 1H), 7.896 (s, 1H), 7.264 (s, 1H), 6.96 (s, 1H), 4.32-4.227 (m, 2H), 4.011-3.977 (m, 2H), 2.329-2.215 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 0.46 min (100%), MH+ 370.0.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.[Cl-].Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>CC(O)C.C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][C:21]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]3)[CH2:1]2)=[CH:22][CH:23]=1
Reactant: Clc1cc[nH+]cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(c3ccncc3)C2)CC1

Procedure:
tert-Butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and N-ethyl-diisopropylamine (2.7 ml, 15.724 mmol) were refluxed in 2-propanol (8 ml) for 15 h, saturated NaHCO3 solution (20 ml) and ethyl acetate (8 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate/methanol/ammonia (25 aq.) 100:10:0.25). Yield: 0.67 g (51.4%)
Reaction SMILES: [C:1]([CH2:4][CH:5]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:6][NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)([OH:3])=[O:2].CC(N(C)C)=O.C[Si](N[Si](C)(C)C)(C)C>[Cl-].[Cl-].[Zn+2].C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH:10]=[CH:9][C:8](=[O:14])[N:7]1[CH2:6][CH:5]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Reaction time: 6 h
Yield: 74.8 %

Procedure:
(Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid (450 mg, 1.60 mmol) in mixture of 10 ml of dry DMA and 50 ml of dry toluene was heated. After the temperature reached at 80° C., HMDS (hexamethyldisilazane, 1.80 ml, 8.63 mmol,) and ZnCl2 (3.2 ml, 1.0 M in diethyl ether) were added. The mixture was continued heated to 115˜125° C. and toluene was collected through Dean-Stark trap. The reaction mixture was fluxed at 120° C. for 6 h. During this period, 2×20 ml of dry toluene was added to keep the mixture volume around 8˜10 ml. Then the mixture was cooled, 1 ml of 1:10 HCl (conc)/CH3OH was added, evaporated, purified on SiO2 chromatography eluted with 1:5:0.01 CH3OH/CH2Cl2/HAc to afford 315 mg (75%) of the title product. 1H NMR (DMF-d7) 6.96 (s, 2H), 4.04 (dd, 1H, J=4.3, 13.8 Hz), 3.47 (m, 1H), 3.23 (dd, 1H, J=7.4, 14.7 Hz), 2.99 (dd, 1H, J=3.3, 16.8 Hz), 2.35 (dd, 1H, J=8.1, 16.9 Hz); 13C NMR 173.58, 172.18, 135.54, 54.61, 40.24, 32.43, ESI MS m/z−261.70 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:17])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[O:5][C:4](=[O:18])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21].CCN(C(C)C)C(C)C.[CH3:32]/[C:33](/[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34]\[CH:35]=O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21]/[C:20](=[CH:35]\[CH:34]=[C:33]([CH3:32])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])/[C:19]([C:3]1[C:4](=[O:18])[O:5][C:6]([CH:8]([CH3:17])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:2]=1[OH:1])=[O:22]
Reactant: CCC(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Reactant: CCCCC/C(C)=C/C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC(C)=C/C=C(\C)C(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Reaction time: 0.33 h

Procedure:
To (E)-methyl 6-(4-hydroxy-2-oxo-3-propionyl-2-H-pyran-6-yl)hept-2-enoate (VII; 0.63 g, 2.05 mmol) in 30 ml anhydrous CH2Cl2 at −72° C., was added titanium tetrachloride (0.88 ml; 8 mmol; Aldrich) under argon, and the reaction mixture was stirred for 20 min. DIPEA (1.64 ml; 9.43 mmol; Aldrich) was added, and the reaction mixture was stirred for 90 min. (E)-3-methyl-octenal (XXI; 1 g; 7.25 mmol) in 5 ml anhydrous CH2Cl2 was added in two portions over 10 min, and the reaction mixture was stirred at −72° C. for 48 h and at 0° C. for 1 hour. The reaction was quenched with 40 ml ice water and extracted with 2×40 ml CH2Cl2. The CH2Cl2 extracts were pooled, washed with saturated NH4Cl, washed twice with saturated NaHCO3, and dried with anhydrous Na2SO4. The product was purified by silica flash chromatography (EtOAc gradient in hexanes).
Reaction SMILES: C1(C)C=CC=CC=1.I[C:9]1([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]2>C(=O)([O-])[O-].[Ag+2].C(OCC)(=O)C.CCCCCC>[CH3:30][N:26]1[C:27]2[C:22](=[CH:21][C:20]([O:19][C:9]3([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][CH2:10]3)=[CH:29][CH:28]=2)[CH2:23][CH2:24][C:25]1=[O:31]
Reactant: CN1C(=O)CCc2cc(O)ccc21
Reactant: IC1(Sc2ccccc2)CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2cc(OC3(Sc4ccccc4)CC3)ccc21
Temperature: 55 °C
Yield: 17.4 %

Procedure:
To a dry toluene solution of [1-Iodo-cyclopropylsulfanyl]-benzene (375 mg, 1.36 mmol) was added 6-Hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 1.13 mmol) and silver carbonate (312 mg, 1.13 mmol) under nitrogen and the reaction mixture was heated to 55° C. It took 3 more additions of the reagents to take the reaction to completion. The reaction was cooled to room temperature, filtered to remove the silver iodide and concentrated under vacuum to yield crude material. This was flash chromatograhed using 30% ethyl acetate/hexane to yield the title compound as a viscous oil (64 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ 1.31–1.33 (2H, m), 1.41–1.43 (2H, m), 2.59–2.62 (2H, m), 2.83–2.87 (2H, m), 3.31 (3H, s), 6.86–6.98 (4H, m), 7.20–7.31 (2H, m), 7.44–7.47 (2H, m). m/z (APCI+) 326 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 6.59 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C(=O)([O-])O.[Na+].C(O)C>CCCCCC.C(Cl)Cl>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCCCCC
Product: c1ccc(-c2cn3ccccc3n2)cc1
Yield: 90 %

Procedure:
Placing 2-aminopyridine in an amount of 3.5 g (36 mmol), α-bromoacetophenone in an amount of 7.2 g (36 mmol) and sodium hydrogen carbonate in an amount of 3.6 g (43 mmol) into a flask, the resultant mixture reacted among 120 milliliter of ethanol for 4 hours at the room temperature and subsequently for 2 hours under refluxing. Separating insoluble by filtration, the resultant filtrate was concentrated. Extracting with the use of methylene chloride in an amount of 150 milliliter, the resultant extract was washed three times using 200 milliliter of water. After drying an organic layer with the use of magnesium sulfide and removing the solvent, brown crystals were obtained. Refining the crystals by means of silicagel column (hexane/methylene chloride), 6.3 g of 2-phenylimidazo[1,2-a]pyridine Intermediate 1-1b as white crystals was obtained (yield: 90%). The white crystals were confirmed as the aimed compound from 1H-NMR spectrum. The measurement result is shown as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8](=[N:10][OH:11])[NH2:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH:18](OCC)(OCC)OCC>B(F)(F)F.CCOCC>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]2[N:9]=[CH:18][O:11][N:10]=2)=[CH:4][C:3]=1[C:14]([F:15])([F:16])[F:17]
Reactant: CCOC(OCC)OCC
Reactant: NC(/C=C/c1ccc(Cl)c(C(F)(F)F)c1)=NO
Agent: FB(F)F
Solvent: CCOCC
Product: FC(F)(F)c1cc(/C=C/c2ncon2)ccc1Cl
Yield: 71 %

Procedure:
5.2 g (0.02 mol) of (E)-4-chloro-3-trifluoromethylcinnamamide oxime are initially introduced into 50 ml of triethyl orthoformate and 2 drops of boron trifluoride etherate are added at room temperature. The mixture is then stirred at reflux temperature for 2 hours and the whole batch is then concentrated in vacuo. The residue is then taken up in 100 ml of methylene chloride and washed consecutively with 100 ml of 2N hydrochloric acid, saturated sodium carbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is subsequently distilled off. 3.9 g (71.0% of theory) of (E)-3-(4-chloro-3-trifluoromethyl-styryl)-1,2,4-oxadiazole are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:36]2[S:37][CH:38]=[CH:39][C:40]=2[C:41]#[N:42])O1.BrC1SC=CC=1C#N>>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:36]4[S:37][CH:38]=[CH:39][C:40]=4[C:41]#[N:42])[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: CC1(C)OB(c2sccc2C#N)OC1(C)C
Agent: N#Cc1ccsc1Br
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4sccc4C#N)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was reacted with 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)thiophene-3-carbonitrile (synthesised from 2-bromothiophene-3-carbonitrile following the procedure in Example 21) by the method of Example 35 to afford 2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrile as a white solid: δH (400 MHz, CDCl3) 0.67 (6H, q, J 8.1), 0.99 (9H, t, J 8.0), 1.71 (6H, s), 7.66 (2H, m), 7.97 (1H, d, J 5.5), 8.51 (1H, s), 8.79 (1H, d, J 5.5), 9.71 (1H, m), 10.34 (1H, d, J 7.0); m/z (ES+) 477 (M++H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH3:19])=[C:12]([C:20]2[CH:21]=[C:22]([C:42]([F:45])([F:44])[F:43])[C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[N:24][CH:25]=2)[N:11]=1)#[N:9].C(#N)C.C(Cl)[Cl:50]>>[ClH:50].[CH3:19][N:16]1[CH:15]=[N:14][C:13]2[C:17]1=[N:18][C:10]([C:8]#[N:9])=[N:11][C:12]=2[C:20]1[CH:25]=[N:24][C:23]([O:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:22]([C:42]([F:45])([F:43])[F:44])[CH:21]=1
Reactant: Cn1cnc2c(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Reactant: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Cn1cnc2c(-c3cnc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (40 mL) was added to a solution of tert-butyl 4-(2-{[5-(2-cyano-9-methyl-9H-purin-6-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (5.8 g) in CH2Cl2 (80 mL)-acetonitrile (20 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and CH2Cl2 (10 mL) was added to the residue. A 4 M solution of hydrogen chloride in EtOAc (10 mL) was added to the mixture at room temperature, and the resultant mixture was stirred at the same temperature for 10 minutes. EtOAc (5 mL) and disiopropyl ether (150 mL) were added to the reaction mixture at room temperature, and the resultant mixture was stirred for 30 minutes. The precipitate was collected by filtration, whereby 9-methyl-6-{6-[2-(piperidin-4-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-9H-purine-2-carbonitrile monohydrochloride (5.1 g) was obtained as a solid.