Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]2[C:12]([CH3:14])([CH3:13])[CH:9]([CH2:10]2)[CH2:8][CH:7]=1.CC1(C)C2CC1CCC2=C.C=CC1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:5][C:6]1[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][CH:7]=1
Reactant: CC1=CCC2CC1C2(C)C
Agent: C=C1CCC2CC1C2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1C
Product: C=C(C)[C@H]1CC=C(C)CC1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a 1.0 Liter flask is charged 140 g of xylene and 5.7 g of anhydrous aluminum chloride and the suspension is stirred under a nitrogen atmosphere at ambient temperature. The suspension is then warmed to 45° C. Using an addition funnel, 175 grams of a blend of alpha pinene, beta pinene and styrene (30:40:30 weight ratio) is introduced into the flask over a period of 60 minutes, while maintaining the polymerization temperature at 45-47° C. (cooling externally, as needed, using a water-ice mixture). After the blend has been fed, the reaction contents are quenched (catalyst is neutralized) with 100 g cold water. The contents are stirred and heated to 75-80° C. After stirring at 75-80° C. for 10 minutes, the aqueous layer is removed and the organic solution is washed with 100 g of water. The contents are heated again to 75-80° C. and the aqueous and organic layers separated. The organic layer constitutes the resin solution. This resin solution is then heated under a nitrogen atmosphere to 240° C. Most solvent and low boiling by-products are distilled between 140-200° C. Once the temperature reaches 240° C., a sample of the molten resin is collected and its softening point measured. The resin is stripped further using a nitrogen sparge (to remove low molecular weight by-products) till the desired s.p. is achieved. The maximum softening achieved was 91.1° C. At this point, the molten resin is poured into a container for storage. Resin had a neat color=2+Gardner, and overall yield was 84%. If required, the resin can be bleached, to lighten its color, at 240° C. during the stripping process, by introducing of a solution of iodine in xylene and stirring for 15 minutes. The iodine is 300 ppm by weight of total molten resin in the flask. Bleaching results in a resin neat color of about 1+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[OH:15][C@@H:16]1[CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCO>[C:26]1([CH2:25][O:24][C:23](=[O:32])[NH:22][CH2:21][C@@H:17]2[C@H:16]([OH:15])[CH2:20][N:19]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][CH:4]=3)[CH2:18]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=Cc1ccnc2ccc(OC)nc12
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Solvent: CCO
Product: COc1ccc2nccc(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2n1
Yield: 79.6 %

Procedure:
To a stirred solution of 8-ethenyl-2-(methyloxy)-1,5-naphthyridine (4.2 mmole) in EtOH (5 mL) was added phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (1.05 g, 4.2 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (1.46 g, 80%) as a light yellow foam: LC-MS (ES) m/e 437 (M+H)+.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[F:5][C:6]1[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:20]([CH3:23])(=[NH:22])=[O:21])[CH:14]=2)=[N:10][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+]>[F:5][C:6]1[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:8][C:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:19][S:20]([CH3:23])(=[O:21])=[N:22][C:2]([NH:1][CH3:4])=[O:3])=[N:10][CH:11]=1
Reactant: CN=C=O
Reactant: COc1cc(F)ccc1-c1nc(Nc2cccc(CS(C)(=N)=O)c2)ncc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N=S(C)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
Isocyanatomethane (7.3 μL; 0.12 mmol) was added to a solution of (rac)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine (50 mg; 0.12 mmol) in DMF (2.0 mL) and triethylamine (17.2 μL; 0.12 mmol) at RT. The batch was stirred for 17 hours at RT. The batch was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/EtOH 95:5) to give the desired product (24 mg; 0.05 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][O:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (255 ml) was dissolved 4-bromophenol (51.0 g). To the mixture was added at room temperature potassium carbonate (81.5 g) and then was added dropwise chloromethylmethyl ether (44.8 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(methoxymethoxy)benzene (61.4 g). In ether (240 ml) was dissolved 1-bromo-4-(methoxymethoxy)benzene (30 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (90.7 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (43.1 g) in THF (43 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added water (150 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was stirred in methanol/water (2/1, 1000 ml) for 3 days. Under reduced pressure, methanol was removed, and the residue was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethoxy)phenyl borate (2.4 g). 1H-NMR (200 MHz, CDCl3) δ 3.51 (3H, s), 5.26 (2H, s), 7.14 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=8.4 Hz).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]>CN(C=O)C>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]
Reactant: Cc1ccccc1-n1c(CBr)cc2cccc(C)c2c1=O
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
9H-Purin-6-amine (1901) (540 mg, 4.0 mmol) was dissolved in anhydrous DMF (20 mL). NaH (60% in mineral oil, 160 mg, 4.0 mmol) was added and the resulting mixture was stirred at RT for 30 min. 3-(Bromomethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1607) (1.37 g, 4.0 mmol) was added. The reaction mixture was stirred at RT for 30 min, poured into ice-water (30 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the desired product, 3-((6-amino-9H-purin-9-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1902) (1.1 g, 70% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To (S)—N—((R)-(4-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 22-a, (16 g, 43.83 mmol), ethyl methylphosphite (9.47 g, 87.67 mmol) and Et3N (13.3 g, 132 mmol) in THF (200 ml) was added PdCl2(dppf) (1.6 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the crude product, 22-b, (9.5 g, 55%).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]([CH2:14][CH2:15]Cl)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH:22]=[C:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CO>[OH:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][N:26]2[CH2:27][CH2:28][C:23](=[CH:22][C:21]3[CH:29]=[CH:30][CH:31]=[C:19]([F:18])[CH:20]=3)[CH2:24][CH2:25]2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Oc1nc(-c2ccc(F)cc2)c(CCCl)s1
Reactant: Fc1cccc(C=C2CCNCC2)c1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Yield: 21.4 %

Procedure:
In 2 ml of methanol were stirred 773 mg of 2-hydroxy-5-(2-chloroethyl)-4-(4-fluorophenyl)thiazole, 683 mg of 4-(3-fluorobenzylidene)piperidine hydrochloride and 1.04 ml of N,N-diisopropylethylamine at 80° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was separated with ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by a flash column chromatography (silica gel; ChromatorexNH NHDM1020 (manufactured by Fuji-Davison Chemical Co.), eluent; hexane-ethyl acetate =1:1), and recrystallized from hexane-ethyl acetate to give 265 mg of 2-hydroxy-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH:22]([CH3:28])[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH:22]([CH3:28])[C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])[CH:7]=1
Reactant: CC(Br)C(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Nc2cnc(Br)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2cnc(Br)cn2C(C)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of N-(5-bromopyrazin-2-yl)-4-methylbenzenesulfonamide (1.73 g) in DMF (20 ml) was added NaH (60% in oil, 0.316 g) at 0° C., and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromo-1-cyclopropylpropan-1-one (1.87 g) at room temperature, and the mixture was stirred overnight. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.02 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:12][C:13]1[O:17][N:16]=[C:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([O:10][CH2:24][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH3:12])[CH:9]=1)=[O:4]
Reactant: Cc1onc(C2CCOCC2)c1CO
Reactant: COC(=O)c1cc(O)nn1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(C3CCOCC3)noc2C)nn1C
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (4.68 g, 30 mmol) and [5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-yl]-methanol (5.92 g, 30 mmol) in THF (400 mL) at 5° C. under argon was added triphenylphosphine (10.6 g, 39 mmol), then diisopropyl azodicarboxylate (8.23 mL, 39 mmol) was added dropwise. The reaction mixture was warmed to room temperature overnight. The reaction mixture was then extracted with ethyl acetate and the organic extract washed with water, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1) afforded the title compound (7.26 g, 85%) as a white solid. MS: m/e=336.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(CO)COc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(CO)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 96.9 %

Procedure:
5-Chloro-2-(3-hydroxy-2,2-dimethyl-propoxy)-benzaldehyde (2.4 g, 10 mmol) and 6-chloro-1,3-dihydro-indol-2-one (1.7 g, 10 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (0.8 g, 11.2 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. Then the precipitate was collected by filtration to give title compound as yellow solid (Yield: 3.8 g).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[S:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=1>C1COCC1>[N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:17]3[S:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)[CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cc(N2CCOCC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)ncn2)s1
Temperature: 45 °C

Procedure:
6-Morpholin-4-yl-pyrimidin-4-ylamine (185 mg, 1.03 mmol) was stirred in 5 mL anhydrous THF under N2. Sodium hydride (82 mg, 60% dispersion, 2.05 mmol) was added and the reaction was warmed to 45° C. for 5 minutes. 2-chloro-thiazole-5-carbonitrile (208 mg, 1.44 mmol) was added and the reaction was heated to reflux. After 30 minutes added additional 2-chloro-thiazole-5-carbonitrile (85 mg, 0.59 mmol). After an additional 1 hour the reaction was cooled to room temperature, quenched with water and the THF was removed in vacuo. The mixture was neutralized with 1 M HCL and the resulting precipitate was filtered and washed with water. The solid was suspended in DMSO, filtered and washed with EtOAc to provide the title compound. 1H-NMR (400 MHz, CD3OD) 8.44 (1H, s), 7.95 (1H, s), 6.13 (1H, s), 3.81 (t, 4H, J=5.0 Hz), 3.63 (t, 4H, J=4.9 Hz). M+1=289.1.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.Br[C:16]1[S:17][CH:18]=[C:19]([Br:21])[CH:20]=1>>[Br:21][C:19]1[CH:20]=[C:16]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)[S:17][CH:18]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: Brc1csc(Br)c1
Product: FC(F)(F)c1ccn2c(-c3cc(Br)cs3)cnc2n1
Yield: 15 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (547 mg, 2.06 mmol) was reacted with 2,4-dibromothiophene over 1 h as described in Example 17. The resulting crude residue was purified by column chromatography on silica, using 40% EtOAc in isohexanes as the eluent, to yield 3-(4-bromothien-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (104 mg, 15%) after recystallisation from dichloromethane/isohexanes: δH (400 MHz, d6-DMSO) 7.57 (1H, d, J 8.3), 7.72 (1H, d, J 1.6), 8.10 (1H, d, J 1.6), 8.34 (1H, s), 9.34 (1H, d, J 7.0); m/z (ES+) 347, 349 (1:1) (M+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise isobutyryl chloride (0.10 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.417 g oil. Crystallization as the oxalate salt from 2-propanol provided 0.194 g colorless crystals. Mp 193° C. Mass spectrum, m+ =399. Anal (C24H35N506) theory C, 58.88; H, 7.21; N, 14.30; found C, 58.60; H, 6.95; N, 14.11.
Reaction SMILES: Br[C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>COCCOC.O.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>[C:10]([C:8]1[CH:7]=[C:4]([CH:5]=[O:6])[C:3]([OH:14])=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=2)[CH:9]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Yield: 85.6 %

Procedure:
A solution of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) (4 g, 15.56 mmol) in DME (30 mL) and water (10 mL) was purged with nitrogen for 15 minutes. Potassium carbonate (3.2 g, 23.15 mmol), 4-trifluoromethoxybenzeneboronic acid (3.2 g, 15.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.78 g, 0.675 mmol) were added and the reaction mixture heated to reflux under nitrogen overnight. The cooled reaction mixture was then filtered through celite washing through with diethyl ether. The filtrate was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 5-(tert-butyl)-2-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carbaldehyde (4.5 g, 85%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:4]=[CH:3]1.[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:11]([NH:19][C:20](=[O:21])[O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCc1c[nH]cn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=C(NC(=O)c1ccccc1)OCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propanol hydrochloride in 10 ml of acetonitrile are maintained at reflux for 2 h with 5 mmol of benzoyl isocyanate. After evaporation under vacuum, the title compound is stirred in water and filtered.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(OC)nc(CCl)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)nc(CC#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
16.7 g of dried sodium cyanide was dissolved in 850 ml of dimethyl sulfoxide at 90° C. under N2 protective gas. At this temperature, 52.8 g of 2-chloromethyl-4,6-dimethoxypyrimidine, dissolved in 280 ml of dimethyl sulfoxide, are added dropwise over the course of 2 hours. Stirring is continued for 1 hour at 90° C., and the mixture is cooled to room temperature and poured into 300 ml of water. The aqueous phase is extracted seven times using ether, and the combined organic phases are washed using saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in a rotary evaporator. This gives 29.1 g of crude product, from which 2-cyanomethyl-4,6-dimethoxypyrimidines of melting point 65°-67° C. are obtained after column chromatography (SiO2 ; CH2Cl2 /CH3OH; 98.5/1.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CCN(CC)CC.C1COCC1>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCNc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the pyrimidine 18-2 (3.76 g, 21.8 mmol), pivaloyl chloride (10.7 mL, 87 mmol), Et3N (15.2 mL, 109 mmol) and THF (80 mL) were stirred at room temperature for 24 hours. A further 3 mL of pivaloyl chloride and 4 mL of Et3N was added and the mixture stirred for another 24 hours. The solution was poured into saturated Na2CO3, extracted with EtOAc (2×), washed with brine, dried (MgSO4) and filtered through a pad of silica gel. Removal of the solvent afforded an orange solid. Trituration with ether/hexane ˜20:1 and filtration provided the title compound 18-4 as a white solid.