Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=2[F:19])[S:6][C:5]=1[NH:20][C:21]1[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=1)=[O:3].[O:30]1[CH2:33][CH2:32][CH:31]1[CH2:34][NH2:35].O.ON1C2C=CC=CC=2N=N1.N=C=N>CN(C=O)C>[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=2[F:19])[S:6][C:5]=1[NH:20][C:21]1[N:26]=[C:25]([C:27]([NH:35][CH2:34][CH:31]2[CH2:32][CH2:33][O:30]2)=[O:29])[CH:24]=[CH:23][CH:22]=1)=[O:3]
Reactant: NCC1CCO1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(=O)O)n3)s2)c(F)c1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(=O)NCC4CCO4)n3)s2)c(F)c1

Procedure:
A mixture of 6-({3-(aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridine-2-carboxylic acid (Table 3, Example 40) (50 mg, 0.12 mmol), 1-oxetan-2-ylmethanamine (11 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol), and PS-Carbodiimide (240 mg, 0.30 mmol, 1.25 mmol/g) in DMF (4 mL) was irradiated in a microwave at 100° C. for 10 minutes. Upon completion, the crude reaction was filtered, concentrated, and purified by silica gel chromatography (0-7% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methanol (4.44 g, 17 mmol) was dissolved in a mixture of triethylamine (2.9 ml, 19 mmol) and dichloromethane (100 ml). The resulting solution was cooled to 0° C., then a 1 M solution of tert-butyldimethylsilylchloride (19 ml) in dichloromethane was added dropwise over 5 minutes. 4-Dimethylamino pyridine (0.423 g, 3.4 mmol) was added and the reaction mixture left to stir overnight at room temperature. A second portion of tert-butyldimethylsilylchloride (19 ml) in dichloromethane and triethylamine (2.9 ml, 19 mmol) were added and the reaction mixture left to stir overnight at room temperature. The reaction mixture was concentrated in vacuo then redissolved in dichloromethane (200 ml) and washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo onto silica gel (5 ml). This was then subjected to column chromatography (50 g silica gel bond elut: 0% to 50% ethyl acetate/hexanes) to yield 5.405 g (84%) of the desired compound as white crystals.
Reaction SMILES: [OH:1][C@@:2]1([CH2:17][OH:18])[C:11]2[C:6](=[C:7]([O:13][CH:14]([F:16])[F:15])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.O.C(=O)([O-])[OH:21].[Na+]>CC(C)=O.[Pt]>[OH:1][C@@:2]1([C:17]([OH:21])=[O:18])[C:11]2[C:6](=[C:7]([O:13][CH:14]([F:15])[F:16])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: OC[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Agent: [Pt]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of (S)- or (R)-4-hydroxy4-hydroxymethyl-6-chloro-8-difluoromethoxychromane (3.2 g, 11.4 mmol, from step (vii) above) in acetone (25 mL) was added non-ionized water (110 mL), then sodium hydrogencarbonate (2.13 g, 22.2 mmol) and Pt/C 5%, 58% water (2.13 g). A stream of air was bubbled through the solution with stirring at 75° C. (oil-bath) overnight. The solution was filtered through Celite and the filter-cake was washed with water. The acetone-water solution was acidified (HCl, 2M) to pH 2, saturated with NaCl and extracted with EtOAc (3×). The combined ethyl acetate phases were washed with water (2×) and with brine, then dried (Na2SO4) and concentrated. The residue was dissolved in ether. The ether solution was washed with water (3×) and concentrated, yielding 2.4 g (71%) of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1C
Yield: 85.7 %

Procedure:
A solution of methyl 5-bromo-3-(cyclopentylamino)-2-methylbenzoate (1 g, 3.22 mmol), Cs2CO3 (2.10 g, 6.45 mmol) and methyl iodide (2.3 g, 16.12 mmol) in acetonitrile (15 mL) was heated at 80° C. for 14 h. After complete consumption of starting material reaction mixture was filtered. The filtrate was concentrated and the obtained residue was purified by column chromatography to provide the desired compound (0.9 g, 86%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C.C(Cl)Cl>[Cl:16][C:17]1[N:22]=[C:21]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:15][CH2:14]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccnc(Cl)n2)CC1

Procedure:
A solution of 4-N-Boc-aminomethylpiperidine (4.95 g, 23.1 mmol), 2,4-dichloropyrimidine (3.28 g, 22.0 mmol) and triethyl amine (7.84 g, 77.5 mmol) in ethanol (90 ml) was stirred at 85° C. for 45 minutes. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in CH2Cl2 and filtered. The solvent was removed under reduced pressure to give a crude residue that was purified using normal phase chromatography, eluting with iso-hexane and increasing amounts of ethyl acetate to give tert-butyl (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate as an off white solid (6.0 g).
Reaction SMILES: Cl.[CH:2]([C:5]1[N:10]=[C:9]([C:11]#N)[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-:13].[Na+].C[OH:16]>>[CH:2]([C:5]1[N:10]=[C:9]([C:11]([OH:16])=[O:13])[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc(C#N)n1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: CC(C)c1cccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated hydrochloric acid (15 mL) was added to a solution of 6-isopropylpicolinonitrile (example 85, step c) (1.23 g) in methanol (30 mL). The resulting mixture was heated at reflux for 17 h and allowed to cool to RT. The mixture was cautiously poured into sodium hydroxide solution (10M, 50 mL) and stirred at RT overnight. The reaction was concentrated and the pH adjusted to 5 using 2M HCl solution. The aqeuous mixture was extracted with chloroform (3×100 mL). The organic solutions were combined, washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a yellow oil. Yield 0.94 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:16](=[O:17])[NH:15][C:14]3[N:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[CH:6]=[N:7][C:8]=1[O:9][CH3:10].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27]O.CN(C(/N=N/C(N(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC1C=C(N2C(=O)N(CC3C(C)=CC(F)=CN=3)C3C=CC=CC=3S2(=O)=O)C=C(OC)N=1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27][N:15]1[C:14]2[N:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12](=[O:22])(=[O:23])[N:11]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]1=[O:17]
Reactant: OCc1c(F)cc(F)cc1Cl
Reactant: COc1cc(N2C(=O)Nc3ncccc3S2(=O)=O)cnc1OC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: COc1cc(N2C(=O)N(Cc3ncc(F)cc3C)c3ccccc3S2(=O)=O)cc(OC)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3Cl)c3ncccc3S2(=O)=O)cnc1OC
Yield: 80 %

Procedure:
The title compound (118 mg, 0.24 mmol) was prepared from 2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (IntF4) (101 mg, 0.30 mmol), 2-chloro-4,6-difluorobenzyl alcohol (IntA22) (59 mg, 0.33 mmol), TMAD (103 mg, 0.6 mmol) and triphenyl phosphine (157 mg, 0.6 mmol) in DCM (3 mL) using the methods of (162).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].B(O)O>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cnc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 13.7 %

Procedure:
A mixture of 5.0 g 2,4-dichloro-5-fluoropyrimidine, 4.683 g p-chlorophenylboronic acid, 1.730 g tetrakistriphenylphosphinpalladium and 8.278 g potassium carbonate in 125 mL tetrahydrofuran and 125 mL water was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The phases were separated and the organic phase was washed with brine dried over sodium sulfate and evaporated. The solid residue was triturated in ca 60 mL methanol for 30 min. The solids were collected by filtration to yield 5.2 g of an off white solid (contains some boronic acid which gives a start spot). The mother liquor was evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=8:2 to 1:1 to yield 1.0 g of the product as white solid. Both crops were combined and dissolved in ca 50 mL dichloromethane and filtered over ca 50 g silica gel with dichloromethane to remove a polar start spot. The filtrate was concentrated under aspirator vacuum whereby precipitation occurred. The solid was collected by filtration to yield 5.76 g of the title compound as white crystals, MS 230.1 and 228.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][C:21](=O)[N:22]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:23][C:24]4[CH:28]=[CH:27][O:26][C:25]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[CH2:23][C:24]4[CH:28]=[CH:27][O:26][C:25]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1ccoc1-3
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1ccoc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 13-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-4,5,6,7-tetra hydrofuro[3′,2′:6,7][1,4]diazocino[1,8-a]indole-10-carboxylate in THF (0.08 M), 10 eq of BH3.Me2S (2 M sol. in THF) were added and the mixture was stirred at RT for 2 h. The solution was carefully quenched by adding 1.25 M HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The crude residue was used directly in the next step; MS (ES+) m/z 450 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:25])([F:24])[C:9]([NH:11][C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14](=O)[CH2:13]1)=[O:10].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:7][C:8]([F:25])([F:24])[C:9]([NH:11][C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14](=[CH2:1])[CH2:13]1)=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Step AF (2): To a solution of methyltriphenylphosphonium bromide (1.6 g) in THF (5 mL) was added potassium t-butoxide (700 mg), and the mixture was stirred at rt for 30 min to form a deep yellow solution. A solution of (S)-2,2,2-trifluoro-N-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide (500 mg) in THF (2 mL) was added, and the reaction was continued for 40 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by Biotage chromatography eluting with 1-10% EtOAc/hexanes to give (S)-2,2,2-trifluoro-N-(6-methoxy-3-methylene-2,3-dihydro-1H-inden-1-yl)-acetamide as a white solid (460 mg). 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d), 6.91 (1H, dd), 6.83 (1H, d), 6.45 (1H, br. S), 5.38 (1H, dt), 5.38 (1H, t), 4.99 (1H, t), 3.81 (3H, s), 3.45 (1H, m), and 2.62 (1H, m).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH2:12]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH3:13].Cl.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1>>[CH2:12]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:26]2[CH2:27][CH2:28][CH2:29][C:24]2=[O:9])=[CH:17][CH:16]=1)[CH3:13]
Reactant: c1ccccc1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: CCOc1ccc(C=O)cc1
Agent: Cl
Product: CCOc1ccc(C=C2CCCC2=O)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 4-ethoxybenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 62.4%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1.Cl[S:13]([N:16]=C=O)(=[O:15])=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][S:13](=[O:15])(=[O:14])[NH2:16])=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 78.7 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 9.6 g (0.059 mole) of α,α,α-trifluoro-p-cresol, 5.7 ml (9.2 g, 0.065 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.2 g (70%) of white solid, mp 111°-112° C. (benzene).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Br:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:25].[Br:24][C:16]1[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[N:15]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)N(C)c1nc2c(nc1Br)CN(Cc1ccccc1)CCO2
Solvent: Cc1ccccc1
Product: CC(C)N(C)c1nc2c(nc1Br)CNCCO2
Product: Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 8-benzyl-2-bromo-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (122 mg) in toluene (2 mL) was added 1-chloroethyl chloroformate (0.040 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (2 mL), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, and concentrated. The obtained residue was purified by recrystallization (methanol-diisopropyl ether) to give the title compound (59 mg, 56%) as pale-yellow crystals.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:20]([CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:20]([OH:21])[CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[CH:27][N:28]([Si:30]([CH3:31])([CH3:32])[CH3:33])[CH:29]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)n1cnc(CCCC=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)c1ccc(C(O)CCCc2cn([Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.95 g of p-(tert-butylaminocarbonyl)-bromobenzene is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of a solution of n-butyllithium (2.7M) in hexane is added dropwise. After reacting 30 min, a solution of 5.69 g of 4-(3-formyl-n-propyl)-1-trimethylsilylimidazole in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of ammonium chloride is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound (b).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[N:3]=1.C(O)(=O)C.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(Oc2ccc(OCc3ccccc3)cc2)nc2nc(-c3ccco3)nn12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(Oc2ccc(O)cc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-5-(4-benzyloxyphenoxy)-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.0 g) in methanol (400 ml) containing palladium-on-carbon catalyst (10% w/w, 200 mg) and acetic acid (20 ml) was treated with hydrogen gas at atmospheric pressure. The reaction was monitored by tlc analysis (system as Example 1) and once no further starting material was detected, the catalyst was removed by filtration. Solvent was evaporated from the filtrate. The solid residue obtained was crystallised from ethanol to give 7-amino-2-(2-furyl)-5-(4-hydroxyphenoxy)-[1,2,4]triazolo[1,5-a][1,3,5]triazine as colourless hygroscopic crystals, m.p. 292°-294° C.; microanalysis, found: C, 53.5; H, 3.6; N, 26.4; H2O, 2.1%; C14H10N6O3 0.33H2O requires: C, 53.2; H, 3.4; N, 26.6; H, 3.6; N, 26.4; H2O, 2.1 %; NMR: 6.7(dd, 1H, furyl-4H), 6.8(d, 2H, phenyl), 7.0(d, 2H, phenyl), 7.1(d, 1H, furyl-3H), 7.9(d, 1H, furyl-5H), 8.7-9.1(d, 2H, NH2), 9.4(br s, 1H, OH;m/e 310 (M+).
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(I)CC>>[CH2:15]([C:12]1[N:13]([CH3:14])[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([CH3:21])[CH:11]=1)[CH3:16].[CH2:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH3:10]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccccc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-benzoyl-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1Br.[I:17]I>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[I:17]
Reactant: II
Reactant: COC(=O)c1cc(Br)c(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(I)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
At −78° C., nBuLi (2.05 mL, 5.13 mmol) was added to a solution of methyl 4,5-dibromo-2-thiophenecarboxylate (1.4 g, 4.67 mmol) in THF (10 mL). After the mixture was stirred for 30 min, I2 (1.185 g, 4.67 mmol) was added in 3 mL THF. After the resulting solution was stirred at −78° C. for 1 h, it was quenched with Na2S2O3 at −78° C., and warmed to RT. The reaction mixture was extracted with DCM, dried over Na2SO4, and concentrated. The crude product was purified on silica (EtOAc/Hex, 0-10%) to give the title compound (1.3 g, 56%) as a yellow solid: LC-MS (ES) m/z 348(M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.Br[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][O:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:11][CH:10]=1
Reactant: COCCBr
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)nc1C
Product: COCCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)cc1
Yield: 37.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-hydroxymethyl-3-{4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-oxazolidin-2-one (424 mg) described in Example 294 and 1-bromo-2-methoxyethane (167 mg), the title compound (179 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[NH:20][C:21](=[O:25])[N:22]=[CH:23][CH:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.ClC[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:39][C:36]4[CH:35]=[N:34][CH:33]=[CH:38][CH:37]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: ClCc1ccccn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2ccn(Cc3cccnc3)c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Yield: 8.2 %

Procedure:
A mixture of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-2,3-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile (100 mg, 0.237 mmol), 2-(chloromethyl)pyridine hydrochloride (58.3 mg, 0.356 mmol) and Cs2CO3 (464 mg, 1.42 mmol) in anhydrous N,N-dimethylformamide (10 mL) was sealed in a microwave vial, then irradiated with a microwave at 110° C. for 2 h and filtered. Purification via mass-directed autopreparation afforded the title product (10 mg). LC-MS (ESI): m/z 513 [M+H]+; 4.12 min (ret time).