Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Cl:25])C(=O)C1>C1COCC1>[Cl:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1nccc1-c1cc(C(=O)OC)oc1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)oc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 3.14 mmol) and NCS (600 mg, 4.49 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 10-20% EtOAc/Hexane) affording the title compound (710 mg, 78%) as a white solid: LC-MS (ES) m/z 289 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[C:26]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC(=O)Cl
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Nc1ccc2cccc(N3CCN(C)CC3)c2c1
Yield: 37.8 %

Procedure:
The title product was prepared following the procedure of example 16 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.182 g, 0.755 mmol) and triethylamine (0.201 mL, 1.51 mmol) and hexanoyl chloride (0.211 mL, 1.51 mmol)in acetonitrile (10 mL) with an overnight reflux. The product was purified by recrystallization from ethyl acetate/hexane to yield 0.097g (37%) of the title compound: mp 144°-146° C. Analysis calculated for C21H29N3O: C, 74.30; H, 8.61; N, 12.38. Found: C, 73.91; H, 8.52; N, 12.22.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=O)C.C[N:24](C)C=O.[NH2-].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:7]([CH3:22])[C:6]=2[C:4]([NH2:24])=[O:3])[CH:10]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(C(N)=O)c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
A solution of 12.4 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid ethyl ester in 70 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.1 mol. of sodium amide (8.0 g. of a 50% suspension in toluene) and then stirred at 100° C. for 2 hours. After cooling, the mixture is poured on to 400 ml. of ice-water and the precipitate is removed by filtration, washed with water and dissolved in methylene chloride. The organic solution is washed with water, dried over sodium sulfate and concentrated to dryness. The residue is dissolved in chloroform and chromatographed on 800 g. of silica gel using chloroform/n-heptane/ethanol (10:10:1) for the elution. The uniform fractions are combined and evaporated. After recrystallization from acetonitrile, there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid amide in the form of yellowish crystals having a melting point of 241°-244° C. (decomposition).
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:8])[CH2:2]2.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[C:10]1([CH:9]=[C:2]2[C:3](=[O:8])[CH:4]3[CH2:7][N:1]2[CH2:6][CH2:5]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CN2CCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)N2CCC1C2

Procedure:
A mixture of 1-azabicyclo [2.2.1] heptan-3-one (2.65 g), benzaldehyde (3.64 ml) and sodium hydroxide (1.15 g) in ethanol (25 ml) was heated at reflux for 40 min. After cooling the solvent was removed in vacuo and the residue partitioned between dichloromethane (300 ml) and water (300 ml). The aqueous layer was further extracted with dichloromethane (2×300 ml). The organic extracts were combined, backwashed with brine (100 ml), dried and concentrated in vacuo to give an orange oil (5.84 g). The oil was purified by FCC, using gradient elution with petrol/ethyl acetate 6:1 to 3:1 to give the title compound as a yellow solid (3.80 g). m.p. 61–63°.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]>>[C:1]([NH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: NCCC(=O)O
Reactant: C=CC(=O)Cl
Product: C=CC(=O)NCCC(=O)O

Procedure:
This amide monomer was prepared from acryloyl chloride and beta-alanine per Example 1 procedure, with the recrystallized (ethyl acetate solvent) product having a melting point of 97°-99° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=1.[Na+:16]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cn1
Yield: 85.6 %

Procedure:
In a flask, 2-chloro-5-(trifluoromethyl)pyridine (54.5 g, 0.3 mol), sodium hydrogen sulfite (125 g, 1.2 mol), ethanol (600 ml) and water (600 ml) were charged and heated under reflux for 198 hours. After evaporating off the solvent, to the solid residue, conc. hydrochloric acid was added. The mixture was evaporated to dryness. The residue was extracted with methanol and filtrated. The filtrate was evaporated to dryness to obtain sodium 5-(trifluoromethyl)pyridine-2-sulfonate (64.0 g). Yield, 86%. Decomposition point, 356°-370° C.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[OH-:21].[Na+]>O1CCCC1>[CH:16]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:21])=[CH:6]1)([CH3:18])[CH3:17]
Reactant: CSc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-methylsulfanyl-1H-indol-3-yl)-ethanone (200 mg, 0.77 mmol) in tetrahydrofuran (1 mL) at 25° C. was treated with a 20% aqueous sodium hydroxide solution (2 mL). The mixture was heated at 100° C. for 24 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (40 mL) and ethyl acetate (40 mL). The solution was treated with a 1N aqueous hydrochloric acid solution. The layers were then shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid (126 mg, 77%) as a white solid: mp 132-133° C.; EI-HRMS m/e calcd for C13H15NO2S (M+) 249.0823, found 249.0819.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:9][CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:8]1[N:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(-c2cccs2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc(-c2cccs2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.175 g of 2-thiophen-2-yl-pyrimidine-5-carboxylic acid methyl ester was dissolved in 3 mL of tetrahydrofuran. The reaction was cooled to 0° C. (ice-water bath) and then 2.39 mL of diisobutylaluminumhydride (1.0 M in tetrahydrofuran) were added dropwise. The reaction was left stirring at 0° C. for 30 minutes, then at room temperature overnight. Water was added, the mixture was extracted with ethylacetate, and the organic layer was dried with magnesium sulphate, filtered and concentrated to afford the crude (2-thiophen-2-yl-pyrimidin-5-yl)-methanol, which was used without purification for the next reactions.
Reaction SMILES: [F-].[K+].I[CH3:4].[Si]([O:12][C:13]1[C:14]([F:22])=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=[O:17])(C(C)(C)C)(C)C.O>CN(C=O)C>[F:22][C:14]1[C:13]([O:12][CH3:4])=[CH:20][C:19]([F:21])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C=O)c1F
Reaction time: 5 h
Yield: 74.4 %

Procedure:
Potassium fluoride (7.79 g, 134 mmol) and iodomethane (4.98 ml, 80 mmol) were added to a stirred solution of 3-tert-butyldimethylsilyloxy-2,5-difluorobenzaldehyde (19.45 g, 67 mmol) in DMF (100 ml) at room temperature. After 5 hr, the mixture was poured into water (100 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica gel) eluting with ethyl acetate/n-hexane (1/10) to give 8.58 g (74%) of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH2:8].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].O>CN(C=O)C>[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:9]=[S:10]
Reactant: COCCOCCN
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCN=C=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2-methoxyethoxyl)ethanamine (0.820 g, 6.88 mmol) in DMF (69 mL) at 0° C. was added dropwise a solution of 1,1′-thiocarbonyldiimidazole (1.349 g, 7.57 mmol) in 21 mL of DMF. The mixture was warmed to RT and stirred for 90 min. The mixture was poured into water (130 mL) and extracted with Et2O (70 mL). The Et2O layer was washed with water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo (325 torr, bath temp: 24° C.) to afford 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (0.678 g, 4.21 mmol, 61% yield) as a yellow oil. The crude material was used in next step.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[OH:17])=[N:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[CH:32]1([O:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:18][C:7]=3[N:8]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3OC3CCCC3)nc2c1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
To a mixture of 0.28 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 0.28 g of potassium carbonate and 2 ml of DMF, a mixture of 0.29 g of cyclopentyl bromide and 2 ml of DMF was added at room temperature. The reaction mixture was stirred while heating at 60° C. for four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.29 g of 2-(3-cyclopentyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 115”).
Reaction SMILES: [Na].[CH:2]1([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].Cl[CH:11]([CH3:15])[C:12](O)=[O:13].S(=O)(=O)(O)O>C(O)C.O>[CH3:15][CH:11]1[O:9][CH:2]2[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[O:8][C:12]1=[O:13]
Reactant: CC(Cl)C(=O)O
Reactant: OC1CCCCC1O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1OC2CCCCC2OC1=O
Reaction time: 5 h

Procedure:
25.3 gm (1.1 mol) of sodium were dissolved in 500 ml of ethanol under dry nitrogen. 116 gm (1 mol) of 1,2-cyclohexane-diol were added to the solution at room temperature. Then, the ethanol was completely removed under vacuum. 163 gm (1.2 mol) of the ethyl ester of 2-chloropropionic acid were added to the mono-sodium salt of 1,2-cyclohexane-diol so obtained, at 50° C., and the mixture was allowed to stand for 5 hours at 80° C. to react further. Then, the reaction mixture was decomposed with water and acidified with sulfuric acid. The organic phase was separated and the aqueous phase was extracted twice with ether. After combining the organic phases, these were washed neutral with water and sodium bicarbonate solution, dried over sodium sulfate and reduced under vacuum. The crude product obtained was distilled under high vacuum. 76 gm of 4-methyl-2,5-dioxabicyclo-[4,4,0]-decan-3-one were obtained with the following analytical data:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N:14]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20])=[N+:15]=[N-:16]>C(Cl)Cl>[N:14]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:2]([CH2:3][CH3:4])[CH3:1])=[O:20])=[N+:15]=[N-:16]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCNC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methylethanamine (2.65 mL, 1 equiv, 30.9 mmol) and DIEA (7.0 mL, 1.3 equiv, 40.2 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (5.0 g, 30.9 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The contents of the reaction were poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (7.14 g, 96.1%). This material was purified on an ISCO flash chromatography system with ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (5.09 g, 89.4%). 1H NMR (CDCl3, 400 MHz): δ 1.42 (s, 6H), 2.40 (s, 2H), (dq, J=2.4 & 8.8, 2H). LRMS (ESI+) for C8H16N4O (184.1); Found: 185 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][C:7]=2[CH:36]=1)#[N:2].[CH3:37]I.[H-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:37])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: CCOC(=O)C(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-2-ethoxy-2-oxoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-B) (139.5 mg, 0.285 mmol) in DMF (2.850 mL) were added successively MeI (0.080 mL, 1.282 mmol) and NaH (34.2 mg, 0.855 mmol) at 0° C. After stirring for 2.5 hrs at this temperature another additional aliquot of MeI (0.045 mL, 0.57 mmol) were added to the mixture. The mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with a saturated aq. solution of ammonium chloride at 0° C. and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic layers were concentrated to give crude product that was purified via FCC: Heptane/AcOEt:100/0 to 50/50 to obtain the title compound. MS (ESI+) m/z 504.38 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[O:26]=[S:2]1(=[O:1])[CH:3]=[CH:4][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of methyl (5R)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate (Step 2, 0.73 g, 1.87 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.27 g, 5.6 mmol) in dioxane (9 mL) is heated to 100° C. for two days. The solution is cooled and treated with 20 mL of 10% aqueous Na2SO3 and stirred for 30 minutes. The solution is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with satd NaHCO3 and saline and dried (MgSO4), filtered and concentrated. The crude residue is purified by column chromatography (0→5% ethyl ether-dichloromethane) to provide the title compound (0.28 g, 38%); 1H NMR (300 MHz, CDCl3): δ 3.31-3.35 (m, 2H), 3.89 (s, 3H), 4.00-4.15 (m, 3H), 4.25 (t, 1H), 5.11 (m, 1H), 5.45 (d, 1H), 6.54 (d, 1H), 7.29 (d, 2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of hydroquinone (33.00 g, 0.30 mol) and potassium carbonate (45.6 g, 0.33 mol) in dry DMF (250 mL) was stirred at 40° C. for 30 minutes. Allyl bromide (5.20 mL, 0.06 mol) was added and the reaction was stirred overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with hexane/ethyl acetate (4:1) to afford 4-allyloxyphenol.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][N:29]=[C:28]3[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=3)[C:44](O)=[O:45])[CH2:37][CH2:36]2)[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH2:55].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[S:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH:55][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[C:41]([N:38]2[CH2:37][CH2:36][N:35]([C:28]3[C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:23]5[CH:22]=[N:21][N:20]([C:1]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=6)[C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)[CH:24]=5)[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH2:40][CH2:39]2)[CH:42]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)c1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Reaction time: 12 h
Yield: 115.1 %

Procedure:
118 mg 3-{4-[6-(1-trityl-1H-4-pyrazolyl)-4-quinazolinyl]piperazin-1-yl}benzoic acid (compound in Example 828), 18 mg 1,3-thiazol-2-amine, 20 mg triethylamine and 89 mg benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate were dissolved in dichloromethane and stirred for 12 hours. The reaction solution was concentrated and purified by silica gel column chromatography, to give 150 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](Cl)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: NN1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Part D: Crude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonyl chloride (919 mg, ˜2.39 mmol), 1-aminopiperidine (0.469 g, 4.69 mmol) and triethylamine (0.363 g, 3.59 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature. The mixture is washed with a saturated aqueous NaHCO3 solution (3×20 mL), dried over Na2SO4 and concentrated in vacuo and further purified by column chromatography (ethyl acetate, silicagel) to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (356 mg, 26% yield (based on ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate). Mass Spectrometry (MS): 449.
Reaction SMILES: CC1NC(C)=CC=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:8]=1.C(O)C.Cl.[NH2:30]O.Cl>O>[NH:22]1[CH2:23][CH2:24][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[N:8]=[C:7]([NH2:30])[CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: Cc1cc(-c2cccc(-c3ccc(C4CCNCC4)cc3)n2)c(C)[nH]1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 100 mg (0.302 mmol) 4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 10 mL ethanol, 1 mL water, and 417 mg (6.04 mmol) hydroxylamine hydrochloride. The reaction was refluxed 20 hours cooled, and poured into dilute aqueous hydrochloric acid, then washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (77 mg, 100%) was converted to the hydrochloride salt using HCl in, ether to afford a tan solid, 32 mg (32%), mp dec. above 150° C.