Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[C:35](C1NC=CN=1)(C1NC=CN=1)=[O:36]>C1COCC1>[CH3:22][CH:21]([CH3:23])[CH:16]([NH:15][C:13]([C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([C:25]([F:33])([F:34])[F:24])=[CH:27][CH:28]=3)=[O:36])=[CH:3][CH:4]=2)[CH:12]=1)=[O:14])[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(C)C
Temperature: 65 °C

Procedure:
To Methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate (example 151, step 3, 500 mg) dissolved in THF (10 ml) were added 4-(trifluoromethyl)aniline (254 mg) and carbonyl diimidazole (283 mg) and heated to reflux at 65° C. overnight. THF was removed completely under reduced pressure to get pale brown residue which was purified by silica gel column chromatography in 3:7 EtOAc: CHCl3 to get off white solid which was crystallized from methylene chloride to yield 375 mg (47%) off white solid. MS (ES+): m/z 505 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.19 (s, 1H), 9.18 (d, 1H), 9.09 (s, 1H), 7.85 (d, 2H), 7.67 (s, 1H), 7.65 (d, 2H), 7.63 (d, 2H), 7.6 (d, 2H), 4.29 (m, 1H), 3.66 (s, 3H), 2.2 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:21]=[O:22]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:21][OH:22])[C:16](=[O:20])[N:15]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: C=O
Solvent: CCO
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1CO

Procedure:
To an ethanol/water solution (2/1 (v/v)) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (94 mg, 0.34 mmol) synthesized in Reference Synthesis Example 3, a formaldehyde aqueous solution (42 mg, 0.51 mmol) was added and the resultant solution was stirred at 50° C. for 5 hours. To the reaction solution, a formaldehyde aqueous solution (83 mg, 1.02 mmol) was added and the resultant mixture was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1-(hydroxymethyl)-1,3,5-triazin-2(1H)-one. Subsequently, to a dichloromethane solution (2 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1-(hydroxymethyl)-1,3,5-triazin-2(1H)-one, triethylamine (57 mg, 0.41 mmol) and p-toluenesulfonic acid anhydride (123 mg, 0.38 mmol) were added and the resultant mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound and the crude product was used in the next reaction as it was.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)(=O)=O.[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1.[H-].[Na+]>CN(C)C=O>[CH3:13][C:9]1([CH3:12])[O:8][C@@H:7]([CH2:6][N:25]2[CH:26]=[C:22]([B:17]3[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]3)[CH:23]=[N:24]2)[CH2:11][O:10]1
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Temperature: 90 °C

Procedure:
A mixture of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (1.08, 5.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) and NaH (262 mg, 10.9 mmol) in N,N-dimethylformamide (25 mL) was heated at 90° C. for 3 hours, then allowed to cool to room temperature., quenched with water and extracted with ethyl acetate (3×). The combined organics were washed with brine, concentrated and the residue was purified by chromatography on an Analogix® Intelliflash™ purification system using a SF25-25 g column at a flow rate of 80 mL/minute, eluting with 0% to 30% ethyl acetate:hexanes over 30 minutes to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13](Br)=[N:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>O1CCOCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([NH:18][NH2:19])=[N:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1Br
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ncc(Br)nc1NN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3,5-Dibromo-pyrazin-2-yl)-carbamic acid tert-butyl ester (600 mg, 1.7 mmol) was dissolved in dioxane (10 mL) and cooled on an ice bath. Hydrazine monohydrate (3 mL, 61.7 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the remaining residue was re-dissolved in a mixture of ethylacetate, water and brine. The phases were separated and the aqeuous phase was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo to give (5-bromo-3-hydrazino-pyrazin-2-yl)-carbamic acid tert-butyl ester as the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]([CH:18]([CH3:22])[C:19](O)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([C:14]([F:15])([F:17])[F:16])=[CH:12][N:11]([CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
515 mg (purity 51%, 0.71 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 251 mg (purity 79%, 51% of theory)
Reaction SMILES: N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.[CH3:17][C:18](=[CH2:22])[CH:19](O)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42][C:43]1[CH:44]=[N:45][NH:46][CH:47]=1>C1COCC1.FC(F)(F)C(O)=O.ClCCl>[Br:42][C:43]1[CH:44]=[N:45][N:46]([CH:19]([C:18]([CH3:17])=[CH2:22])[CH3:20])[CH:47]=1
Reactant: C=C(C)C(C)O
Reactant: Brc1cn[nH]c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(C)C(C)n1cc(Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(E)-Di-tert-butyl diazene-1,2-dicarboxylate (940 mg, 4.08 mmol) was added slowly to a stirred solution of 3-methylbut-3-en-2-ol (293 mg, 3.40 mmol), triphenylphosphine (1.07 g, 4.08 mmol), and 4-bromo-1H-pyrazole (500 mg, 3.40 mmol) in THF (10 mL) at 0° C. The reaction was stirred for 10 min at 0° C. and then allowed to warm to RT for 1 hour. The reaction was quenched into water and the product was extracted with ethyl acetate (2×20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford an oil. The oil was dissolved in 20% trifluoroacetic acid in dichloromethane (5 mL) and stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 10% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue. The crude residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes) to afford 4-bromo-1-(3-methylbut-3-en-2-yl)-1H-pyrazole. MS ESI calcd. for C8H12BrN2 [M+H]+ 215 and 217. found 215 and 217.
Reaction SMILES: C(OC(=O)NC[CH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1)C1C=CC=CC=1.C([O-])=O.[NH4+:27].[CH3:28]O>>[N:18]1([CH:15]2[CH2:14][CH2:13][CH:12]([NH:27][CH3:28])[CH2:17][CH2:16]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [NH4+]
Reactant: O=C(NCC1CCC(N2CCCC2)CC1)OCc1ccccc1
Reactant: CO
Agent: O=C[O-]
Product: CNC1CCC(N2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of (4-pyrrolidin-1-yl-cyclohexylmethyl)-carbamic acid benzyl ester (292 mg, 0.92 mmol) in MeOH (5 mL) was added ammonium formate (0.58 g, 9.20 mmol). The reaction flask was flushed with N2 prior to addition of 10% Pd/C (300 mg). The mixture was heated at 65° C. for 2 h whereupon TLC analysis (silica gel, 95:4.75:0.25 DCM/MeOH/NH4OH) showed complete consumption of 57. After cooling to room temperature the reaction mixture was filtered through a plug of celite in order to remove the Pd catalyst. The filtrate contained (4-pyrrolidin-1-yl-cyclohexyl)-methylamine which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40].[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH:42]3[CH2:43][CH2:44][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:46][CH2:47]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.08 g, 0.14 mmol) was dissolved in CH2Cl2 (5 mL) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.0365 g, 0.175 mmol) and triethylamine (0.0284 g, 0.28 mmol) were added. The mixture was stirred under argon at room temperature overnight with only minor product formation. The reaction mixture was then heated to reflux for 24 h. The reaction still was not complete, so additional 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.146 g, 0.7 mmol) was added and the mixture stirred at reflux for 5 days. The solvents were pumped off in vacuo. The residue was taken up in EtOAc washed with 1M NaOH (2×), brine (1×), dried over anhydrous Na2SO4, filtered and evaporated The residue was flash chromatographed on silica gel (20 g) eluted with 0-50% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. mp (dec) 167-172° C.; LC-MS m/z 684 (M+H)+, 2.13 min (ret. time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH2:19][CH2:18][C@H:13]2[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].CC(O)=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH2:19][CH2:18][C@H:13]2[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
N-(3,5-dichlorobenzenesulfonyl)-(L)-proline, methyl ester from Step A was dissolved in ethanol (50 mL) and treated with 0.2N sodium hydroxide (26.6 mL) for 1.5 h at rt. The mixture was acidified with glacial HOAc, concentrated by rotoevaporation, and the residue dissolved in CH2Cl2, washed with water, saturated brine solution, dried over anhydrous Na2SO4, and evaporated to give the title compound; yield 1.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2N.N([O-])=O.[Na+].C1CCCCC1.C(OCC)(=O)C.[F:31][B-](F)(F)F.[H+]>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[F:31]
Reactant: COc1cc(N)c2ncc(Br)cc2c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-6-methoxy-quinolin-8-ylamine (preparation described in Journal of Pharmaceutical Sciences (1984), 73(12), 1854-6) (5.0 g) in 20 ml fluoroboric acid, (50 wt % solution in water) at ˜5° C. was treated with a solution of sodium nitrite (1.9 g in 3 ml of water) over a period of 40 minutes. The reaction mixture was stirred at room temperature for 2 hours after which time the precipitate was filtered and washed with cold diethyl ether. The resulting brown powder was added portionwise to hot dichlorobenzene over 1.5 hours. Stirring was then continued for an additional 30 min at 190° C. On cooling to room temperature, the mixture was treated with dilute hydrochloric acid and diluted with ethyl acetate. The organic phase was washed with dilute sodium hydroxide, dried over sodium sulphate, filtered and evaporated under reduced pressure to give a black oil that was fractionated by chromatography (silica; cyclohexane/ethyl acetate) to give the required product (M+256)
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][S+:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.CCOCC>C(O)C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:27][CH2:28][CH2:29][CH2:30]4)[S+:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(-c2cc[s+]c(-c3ccccc3)c2)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccc3)[s+]c(-c3ccc4c(c3)CCCN4)c2)cc1

Procedure:
2,4-diphenylthiopyrylium trifluoromethane sulfonate (2.0 g) and 1,2,3,4-tetrahydroquinoline (1.4 g) in ethanol (20 ml) were heated at 90° for 30 minutes. After cooling the solution was poured into ether (50 ml) and the precipitated dye was filtered, washed with ether and recrystallized from ethanol as black needles having a melting point of 233° C., λmax (CHCl3) 656 nm.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]([CH2:21][C:22](=[O:24])[CH3:23])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-bromophenoxy)-1H-benzo[d]imidazole (5.72 g) in DMF (60 mL) was added NaH (60% in oil, 950 mg) at 0° C. After stirring for 5 min, chloroacetone (2.36 mL) was added to the mixture at 0° C. The mixture was stirred at room temperature for 5 h. The mixture was diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt in hexane) and recrystallized from THF/Et2O to give the title compound (3.47 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:25])[C:10]([C@H:12]1[CH2:16][CH:15]([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:17][CH:15]1[CH2:14][NH:13][C@@H:12]([C:10]([N:9]([CH3:25])[CH3:8])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@H]1CC(F)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@H]1CC(F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added under ice cooling to a 30 mL chloroform solution of 2.09 g of the compound obtained in step 6-2, after which the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, which gave 3.42 g of residue (pale yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.Cl[P:16]([O:22][CH3:23])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([P:16]([O:22][CH3:23])[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:5][C:6]=1[Cl:7]
Reactant: COP(Cl)N1CCCC1
Reactant: Clc1nc[nH]c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COP(c1nc(Cl)c(Cl)[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 146.5 %

Procedure:
To a stirred solution of 4,5-dichloroimidazole (4.62 g, 33.7 mmol) and triethylamine (18.8 mL, 13.65 g, 134.9 mmol) in THF (40 mL) was added dropwise Chloro(methoxy)pyrrolidinophosphine (3.31 g, 19.76 mmol) CH2Cl2 (13.4 mL) at room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (7.76 g, 86%). 31P NMR (CDCl3) δ 125.9.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O.C1COCC1>[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(N)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Oc2ccccc2)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Reaction time: 5 h

Procedure:
0.24 g of NaOH pellets in 2 ml of water was added at 5° C., with stirring, to a solution of 1.05 g of the compound obtained in Example 7 in 25 ml of THF. 1 ml of phenyl chloroformate was then added with continued stirring. The reaction mixture was then stirred for 5 hours, the temperature being allowed to rise to 20° C. The mixture was then concentrated under vacuum, the residue was taken up with water, extracted with ether and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. 1.35 g of the expected product were obtained by crystallization from iso ether. M.p.=236° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH:10]N1C(=O)C2=CC=CC=C2C1=O.[C:22]([OH:25])(=[O:24])[CH3:23]>>[CH3:9][C:1]1[CH:6]=[C:5]([CH:4]=[C:3]([CH3:8])[CH:2]=1)[CH:7]=[O:10].[CH3:9][C:1]1[CH:6]=[C:23]([CH:4]=[C:3]([CH3:8])[CH:2]=1)[C:22]([OH:25])=[O:24]
Reactant: CC(=O)O
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Cc1cc(C)cc(C(=O)O)c1
Product: Cc1cc(C)cc(C=O)c1
Yield: 17 %
Yield: 17 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of mesitylene, 1 mmol of N-hydroxyphthalimide and a binary co-catalyst [0.04 mmol of acetylacetonatocobalt Co(AA)2 and 0.005 mmol of acetylacetonatomanganese Mn(AA)2 ]and the resultant mixture was stirred under an oxygen atmosphere at a temperature of 70° C. for 3 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, mesitylene was converted into 3,5-dimethylbenzaldehyde (yield 17%) and 3,5-dimethylbenzoic acid (yield 17%) with a conversion of 60%.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=2)[C:3]=1OS(C(F)(F)F)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:59]=[O:60].[CH2:62]([OH:64])[CH3:63]>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:62]([O:64][C:59]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:14]#[C:15][Si:16]([CH3:18])([CH3:17])[CH3:19])=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:13])[CH2:11][C:2]=1[CH3:1])=[O:60])[CH3:63]
Reactant: CN(C)C=O
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)c2ccc(C#C[Si](C)(C)C)cc2C(C)(C)C1
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc21

Procedure:
Following General Procedure E and using trifluoro-methanesulfonic acid 2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalen-1-yl ester (Intermediate 198, 1.59 g, 3.8 mmol), palladium acetate (0.1 g, 0.45 mmol), 1,3-bis(diphenylphosphino)propane (0.1 g, 0.24 mmol), N,N-dimethylformamide (2.4 mL), ethanol (2.4 mL) and triethyl amine (2.4 mL) followed by flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent the title compound was obtained (0.31 g, 24%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13]>CO>[OH:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1ncccc1O
Solvent: CO
Product: Oc1cccn2cc(C(F)(F)F)nc12
Yield: 17.9 %

Procedure:
A mixture of 2-amino-3-hydroxypyridine (2.18 g, 19.4 mmol), bromo-1,1,1-trifluoroacetone (9.1 g, 42.6 mmol), and molecular sieves (6.3 g, 8–12 mesh beads) in anhydrous methanol (50 mL) was refluxed for 24 h. After the molecular sieves were filtered off and the solvent was evaporated in vacuo, the residue was dissolved in water (150 mL) and the resultant mixture was extracted with diethyl ether (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate and the solvent was evaporated in vacuo to provide the crude 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine. Purification by column chromatography using as eluent a mixture of ethyl acetate and isopropylamine (98:2 v/v) yielded 0.7 g of pure 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine.