Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]4[C:35](=[O:47])[N:36]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:37]([CH3:40])[C:38]=4[CH3:39])=[O:33])=[CH:27][C:26]=3[F:48])=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:49][CH3:50].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]6[C:35](=[O:47])[N:36]([C:41]7[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=7)[N:37]([CH3:40])[C:38]=6[CH3:39])=[O:33])=[CH:27][C:26]=5[F:48])=[CH:19][CH:20]=[N:21]4)=[CH:16][C:15]=3[O:49][CH3:50])[CH2:5][O:4]2)[CH2:1]1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OC1COC2(CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg, 0.877 mmol) and N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.584 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol, Aladdin). After stirring at rt for 4 hrs, the reaction was warmed to 40° C. and stirred for 16 hrs. The reaction mixture was concentrated in vacuo and chromatographed with a silica gel column (5:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (65 mg, 18%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C>[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=[N:2][OH:3])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C=NO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Hydroxylamine hydrochloride (0.473 g, 6.8181 mmol) and sodium acetate (0.56 g, 6.8181 mmol) was added to a stirred solution of compound of Formula II (0.5 g, 2.2727 mmol) in ethanol (8 mL). The reaction mixture was stirred at room temperature for 50 minutes. Ethanol was evaporated under reduced pressure, which was diluted with water (20 mL) and the organic compound was extracted with ethyl acetate (2×15 mL). The ethyl acetate layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford compound of Formula III. Analysis by 1H NMR spectroscopy gave the following peaks (CDCl3): 9.84 (s, 1H), 8.07 (s, 1H), 6.84-7.24 (m, 3H), 4.79-4.83 (m, 1H), 3.87 (s, 3H), 1.62-2.18 (m, 8H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:25][CH2:26][CH3:27])[CH3:24].[ClH:28]>CN(C=O)C.CO>[ClH:28].[O:25]([C:26]1[CH:2]=[CH:3][CH:4]=[CH:5][C:27]=1/[CH:12]=[CH:13]\[CH2:14][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1)[C:23]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:24]=1
Reactant: CCOCC
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2ccccc2CN1C1CCN(C/C=C\c2ccccc2Oc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0 M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH:19]([NH:21][OH:22])[CH3:20])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[C:26]([O-])(=[O:28])[CH3:27].[Na+].C(Cl)(=O)C>O1CCOCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH:19]([N:21]([OH:22])[C:26](=[O:28])[CH3:27])[CH3:20])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)c(C(C)NO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(C(C)N(O)C(C)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of 500 mg of 1-(4-chlorobenzoyl)-3-[1-(hydroxyamino)ethyl]-5-methoxy-2-methyl-1H-indole (crude product of Example 78) and 230 mg (2.8 mmol) of sodium acetate in 20 ml of 1,4-dioxane and 5 ml of water is added dropwise 90 μl (1.26 mmol) of acetyl chloride. The reaction mixture is stirred for 10 minutes, at which time it is diluted with ethyl acetate and washed twice with water and once with a saturated solution of sodium chloride. The organic phase is further dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by column chromatography, eluting with a gradient of ethyl acetate:methylene chloride (3:7 to 1:1). A second chromatography (silica gel, ether), and finally recrystallization from methanol gives 71 mg (6.3% from oxime) of pure N-[1-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]ethyl]-N-hydroxyacetamide; mp softens at 90° C. then decomposes as the temperature increases.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH2:17]O)[CH:3]=1.C1C=CC(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:33][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate (10 g, 36.8 mmol) in anhydrous THF (100 ml) was added DPPA (8.3 ml, 38.6 mmol) and DBU (5.79 ml, 38.6 mmol). The mixture was stirred overnight and then was partitioned between ethyl acetate and water. The organic layer was washed with brine, and was concentrated in vacuo to a crude oil (14.6 g). Purification was accomplished by silica gel chromatography, eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%) to give tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=3[N:26]=2)[CH2:20][CH2:19]1.Cl[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:19][CH2:20][CH:21]([NH:24][C:25]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:28]4[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=4[N:26]=3)[CH2:22][CH2:23]2)=[CH:44][CH:45]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc(Cn2c(NC3CCN(c4nc5ccccc5[nH]4)CC3)nc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: O=[N+]([O-])O
Product: Fc1ccc(Cn2c(N3CCC(Nc4nc5ccccc5n4Cc4ccccc4)CC3)nc3ccccc32)cc1
Yield: 28.3 %

Procedure:
A mixture of 5.5 parts of N-[1-(1H-benzimidazol-2-yl)-4-piperidinyl]-1-(phenylmethyl)-1H-benzimidazol-2-amine dinitrate, 1.5 parts of 1-(chloromethyl)-4-fluorobenzene, 5 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1.5 parts (28.3%) of N-{1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-4-piperidinyl}-1-(phenylmethyl)-1H-benzimidazol-2-amine; mp. 163.9° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH3:17][C:18](=[CH2:26])[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:17][CH:18]([CH3:26])[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)N1CCCC1
Solvent: Cc1ccccc1
Product: CC(CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)N1CCCC1
Yield: 21.5 %

Procedure:
Following the procedure of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 0.008 mole) and 1-(2-methyl-1-oxo-2-propenyl)pyrrolidine (1.1 g, 0.008 mole) were dissolved in toluene (20 ml) under an argon atmosphere and refluxed for 24 hours. The solvent was removed and the product purified by chromatography on silica, and recrystallized from hexane to yield the product as a white solid (0.65 g), m.p. 125°-126° C.
Reaction SMILES: [ClH:1].[Cl:2][CH:3]=[C:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][O:5]1>>[Cl:2][CH2:3][C:4](=[O:5])[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][Cl:1]
Reactant: CC1(C)CCOC1=CCl
Reactant: Cl
Product: CC(C)(CCCl)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A powerful stream of hydrogen chloride gas is passed from a cylinder into 476 g (3.25 mol) of 2-chloromethylene-3,3-dimethyltetrahydrofuran, while cooling with ice. The gas is absorbed completely, and the internal temperature rises to 30° C. When the reaction mixture is completely saturated with hydrogen chloride, it is subsequently stirred at room temperature for 2 hours. Excess hydrogen chloride is first removed under a water pump, and the mixture is then distilled under a good vacuum. 531 g (90% of theory) of 1,5-dichloro-3,3-dimethyl-2-pentanone of melting point 85°-90° C./0.3 mbar are obtained. ##STR31##
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (448 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane/dichloromethane (6/1 (v/v)), whereby the objective title compound was obtained as a yellow solid (351 mg, yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[CH:1]1([O:7][C:15]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=2[C:13]#[N:14])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OC2C=CCCC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 126c from cyclohex-2-enol and 2,6-dinitrobenzonitrile as a brown solid (90%). MS 245 (MH+).
Reaction SMILES: Br.[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:25]=[C:26]([OH:27])[N:10]=[C:8]([N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[N:9]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: N=C(N)N1CCOCC1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Br
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
Morpholine-4-carboxamidine hydrobromide (0.267 g) and 4-(2-ethoxycarbonylacetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.38 g, 1.27 mmol) were stirred in ethanol (10 mL) and diazobicycloundecane (285 μl) was added. The reaction stirred for 18 hours at room temperature. The ethanol was removed under reduced pressure and water (25 mL) was added. The solution was acidified (to pH=4) with acetic acid. The product was extracted with dichloromethane (4×30 mL). The dichloromethane was removed and crude product was purified twice on silica gel (Combiflash), eluting with 10% methanol in dichloromethane to provide 4-(6-hydroxy-2-morpholin-4-ylpyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 40.5% yield) as a white solid. 1H NMR (300 MHz, CDCl3/TMS): δ=5.63 (s, 1H), 4.25-4.05 (m, 2H), 3.75 (m, 8H), 2.75-2.65 (m, 2H), 2.47-2.35 (m, 1H), 1.00-1.75 (m, 2H), 1.70-1.50 (m, 2H), 1.46 (s, 9H). 13C NMR (75 MHz, CDCl3/TMS): δ=173.35, 166.87, 154.96, 154.06, 98.88, 79.70, 66.72, 45.13, 44.24, 30.64, 28.82, 27.58.
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:33])([CH3:32])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[N:15]=2)=[CH:9][CH:8]=1)=O)C.CC(C[AlH]CC(C)C)C>>[CH2:30]1[CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:16]3[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([CH3:32])([CH3:33])[CH2:4][OH:3])=[CH:8][CH:9]=4)[C:19]([F:20])=[CH:18][N:17]=3)=[CH:23][C:24]=2[O:31]1
Reactant: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(CO)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-pyrimidine-2,4-diamine, N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was reduced with DIBALH to give N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine 1H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.94 (s, 1H), 8.01 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.31-7.27 (m, 3H), 6.98 (dd, 1H, J=2.9 and 8.8 Hz), 6.65 (d, 1H, J=8.8 Hz), 4.65 (t, 1H, J=5.3 Hz), 4.17-4.16 (m, 4H), 3.39 (d, 2H, J=5.2 Hz), 1.20 (s, 6H). 8.9 Hz), LCMS: ret. time: 19.52 min.; purity: 100%; MS (m/e): 411 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:22][OH:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:14][CH:15]=1.O[C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:14][CH:15]=1)[CH2:22][O:23][C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1csc(N2CCOCC2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCOCC2)n1
Reaction time: 15 h
Yield: 59.3 %

Procedure:
To a mixture of {3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (0.93 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.85 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.06 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as crystals (0.83 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (2:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:20][CH3:21])(=O)=O>CC(=O)CC.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:20][CH3:21])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOc1cc(Br)cc(Br)c1
Temperature: 90 °C

Procedure:
A dispersion of 3,5-dibromophenol (0.398 g, 1.6 mmol) and potassium carbonate (0.437 g, 3.2 mmol) in 2-butanone (4 mL) was treated with diethyl sulfate (0.246 g, 1.6 mmol) and the reaction mixture heated at 90° C. for 15 hours. The resulting thick suspension was cooled to room temperature, diluted with dichloromethane and extracted with water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The title compound was obtained as a light brown oil (0.38 g, 86% of theory) which was used in the next step without further purification.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@H:27]([C:76]1[CH:85]=[CH:84][C:83]([OH:86])=[C:82]2[C:77]=1[CH:78]=[CH:79][C:80](=[O:87])[NH:81]2)[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]2[CH:45]=[C:46]([S:50]([C:53]3[CH:54]=[C:55]4[C:60](=[C:61]([CH3:63])[CH:62]=3)[N:59]=[CH:58][C:57]([C:64]([NH2:66])=[O:65])=[C:56]4[NH:67][C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=3)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=2)=[O:43])=[CH:37][CH:36]=1)(C(C)(C)C)(C)C.C(O)(=O)C>C1COCC1>[OH:26][C@H:27]([C:76]1[CH:85]=[CH:84][C:83]([OH:86])=[C:82]2[C:77]=1[CH:78]=[CH:79][C:80](=[O:87])[NH:81]2)[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42]([C:44]2[CH:45]=[C:46]([S:50]([C:53]3[CH:54]=[C:55]4[C:60](=[C:61]([CH3:63])[CH:62]=3)[N:59]=[CH:58][C:57]([C:64]([NH2:66])=[O:65])=[C:56]4[NH:67][C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=3)(=[O:51])=[O:52])[CH:47]=[CH:48][CH:49]=2)=[O:43])=[CH:39][CH:40]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBAF (1.0 M) (1.036 mL, 1.036 mmol) was added to a solution of Intermediate 153 (500 mg, 0.518 mmol), and acetic acid (0.5 mL) in THF (15 mL). The solution was stirred overnight at rt. After which time 7N MeOH/NH4 was added to neutralize the acidic mixture. All solvents were removed in vacuo and the resultant solid was suspended in MeOH (30 mL) and filtered. The solid was treated with a mixture of MeOH/water (1:1) (40 mL) and sonicated for 5 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([N+]([O-])=O)[CH:17]=[CH:18][C:11]=2[S:10]1.C(N(CC)CC)C.[CH3:29][O:30][CH:31]=[CH2:32].[CH:33]1[C:38](=[O:39])[O:37][C:35](=[O:36])[CH:34]=1>CN(C=O)C.O>[CH3:29][O:30][CH:31]=[CH2:32].[CH:33]1[C:38](=[O:39])[O:37][C:35](=[O:36])[CH:34]=1.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[S:10]1
Reactant: NCCCCCCn1sc2ccc([N+](=O)[O-])cc2c1=O
Agent: C=COC
Agent: Cl
Agent: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NCCCCCCn1sc2ccccc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 1.0 g (3 mmol) of the above synthesized N-(6-aminohexyl)-5-nitrobenzoisothiazol-3-one hydrochloride in 25 mL of was prepared and 0.83 mL (5.9 mmol) of triethylamine added. This was added dropwise to a mixture of 0.89 g (6 mmol of anhydride) of Gantrez AN 119 (M.W. 20,000, GAF Corp.) in 15 mL of DMF. After stirring for 30 min, another 0.41 mL (3 mmol) of triethylamine in 45 mL of H2O was added and the mixture stirred for 30 min.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[O:14]C)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1C(C)C)OCCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1c(O)ccc2c1OCCO2
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a solution of 5-isopropyl-6-methoxy-2,3-dihydro-benzo[1,4]dioxine (1.011 g, 4.9 mmol) in 15 ml CH2Cl2 at −78° C. was added BBr3 (7.3 ml, 7.3 mmol). The solution was allowed to warm to room temperature. After 16 hours the solution was cooled to −78° C., quenched with H2O, warmed to room temperature and extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography (7:3 hexane/ethyl acetate) afforded 5-isopropyl-6hydroxy-2,3-dihydro-benzo[1,4]dioxine (0.622 g, 63%) as a pale yellow oil.