Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH3:13]C(=O)CCCCCCCCCCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:13]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: CCCCCCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2c3c(cccc3c1)NCN2

Procedure:
1,8-Diaminonaphthalene of 26.05 g, 32.66 g of 2-tridecanone, 55 mg of p-toluenesulfonic acid monohydrate, and 250 ml of toluene were mixed with stirring. The reaction mixture was refluxed with heating under a nitrogen atmosphere and was allowed to react for 5 hrs. using Dean-Stark trap to remove water from the reaction mixture Thereafter, the mixture was washed with aqueous saturated sodium hydrogen carbonate solution, dried using potassium carbonate anhydride, filtered and solvent was removed under reduced pressure. The product was distilled to obtain 46.50 g of dihydroperimidine intermediate, exhibiting a boiling point of 192 to 213° C./0.3 to 0.4 Torr. The thus prepared dihydroperimidine intermediate of 8.00 g, 1.48 g of squaric acid, 64 ml of n-butanol and 64 ml of toluene were mixed with stirring. The reaction mixture was refluxed with heating under a nitrogen atmosphere and was allowed to react for 3 hrs. using Dean-Stark trap to remove water from the reaction mixture Thereafter, the mixture was filtered, run into petroleum ether and allowed to stand at a temperature of 5° C. for 18 hrs. The product was filtered out, washed with petroleum ether and air-dried to obtain 6.00 g of squarylium dye SS-1. The dye was recrystalized from the mixture of tetrahydrofuran and petroleum ether to refine the product. exhibiting an maximum absorption wavelength (?max) of 802 nm (e=1.8×105) in ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.CN(C)C(=O)C.Cl.Cl[CH2:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[N:6]([CH2:19][C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cn2c(Cl)nc3ccccc32)cs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a mixture of 15.5 pans of 2-chloro-1H-benzimidazole and 235 parts of N,N-dimethylacetamide there were added 22 pans of 4-(chloromethyl)-2-methylthiazole monohydrochloride and 25.4 pans of sodium carbonate. The whole was stirred for 18 hours at 75° C. and was then poured into water. The product was extracted with 4-methyl-2-pentanone and the extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 11.3 parts (42.8%) of 2-chloro-1-[(2-methyl-4-thiazolyl)methyl]-1H-benzimidazole (interm. 1). In a similar manner there was also prepared 2-chloro-1-[(6-methyl-2-pyridinyl)methyl]1H-benzimidazole (interm. 2).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: COC(=O)CCCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCCC#CCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazol-2-one was treated with methyl 7-bromo-5-heptynoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 133°-134° C. , Found: C, 76.9; H, 5.8; N, 6.0%; C29H26N2O3 requires: C 77.3; H, 5.8; N, 6.2%
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl.[CH:17]1([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:19][CH2:18]1.[OH-].[Na+]>C(OCC)(=O)C>[CH:17]1([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[N:27]2[CH2:32][CH2:31][N:30]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=3)=[O:12])[CH2:29][CH2:28]2)[CH2:18][CH2:19]1
Reactant: Cc1ccc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), bis(tricyclohexylphosphine)palladium (II) dichloride (132 mg), tripotassium phosphate (3.8 g) and cyclopropylboronic acid (688 mg) were added toluene (10 mL) and water (500 μL) and the mixture was refluxed for 5 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g). 4-(2-Cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g) was dissolved in chloroform (1 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg). To tetrahydrofuran (2 mL) were added 4-iodobenzoyl chloride (169 mg), 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg) and 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (280 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].C([NH2:22])C1C=CC=CC=1>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Product: Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in schemes 11 and 12) can be treated with a benzylic amine, such as benzyl amine, to displace the chloro moiety. Hydrogenation under standard conditions can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the desired 2,5-diamino-benzenesulfonamide intermediate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCCl>[C:7]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NCCO1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1OCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 2-oxazolidinone (4.68 g; 0.05 mol) in 1,2-dichlorethane (60 ml), there is added benzoyl chloride (5.6 ml, 0.05 mol) and triethylamine (7.0 ml; 0.05 mol), with stirring at ambient temperature for 30 mins. The solution is then concentrated at reduced pressure and ethyl acetate is added, thereafter it is filtered to remove the base hydrochloride; the filtrate is partly evaporated and diluted with n-heptane and the precipitated solid is removed by filtration. After washing with water and drying, it gives 3-benzoyl-2-oxazolidinone (5.94 g; 90%). From absolute ethanol it crystallises in nacar scales with m.p. = 166°-170° C. A portion of the substance in ethanol, with a catalytic amount of sodium ethoxide at room temperature immediately gives ethyl benzoate and, with aniline, benzanilide.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:22])[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:28].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([C:5]1=[CH:6][N:7]([C:23]([CH3:25])([CH3:24])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:22])[C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[C:18]([NH2:19])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C#N)ccc1OC
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C(N)=O)ccc1OC
Temperature: 40 °C
Yield: 93 %

Procedure:
The product from Example 26E (110 mg, 0.3 mmol) was treated with concentrated sulfuric acid (1 mL). The mixture was heated at 40° C. for 1 hr, diluted with H2O, neutralized with saturated Na2CO3, and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 107 mg (93%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.99 (t, J=7.32 Hz, 3H) 1.40-1.48 (m, 2H) 1.66 (s, 9H) 1.69-1.76 (m, 2H) 2.84 (dd, J=7.63 Hz, 2H) 3.99 (s, 3H) 7.06 (d, J=8.54 Hz, 1H) 7.96 (s, 1H) 8.02 (dd, J=8.85, 2.44 Hz, 1H) 8.51 (d, J=2.44 Hz, 1H); MS (DCI/NH4+) m/z 390 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:7])=[O:6])=[N+:2]=[N-:3].B(F)(F)F.CCOCC.[CH:17]#[C:18][CH3:19]>C(Cl)Cl>[N:1]([CH2:4][C:5]([O:7][C:18]([CH3:19])=[CH2:17])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: C#CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)OC(=O)CN=[N+]=[N-]

Procedure:
Azidoacetic acid (5.35 g, 0.05 mole) and mercuric acetate (1.82 g, 5.7 mMoles) are added to 50 ml of methylene chloride containing 0.1 ml of boron trifluoride etherate. Propyne, which had been passed through Linde Co. Molecular Sieves 4A, is bubbled slowly through the mixture for 3 hours. Sodium bicarbonate (0.5 g) is added and the mixture is filtered through a short Florisil column. The eluent is concentrated in vacuo and the residue obtained is purified by vacuum distillation to give isopropenyl azidoacetate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:10]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)OCO2
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A solution of benzo[d][1,3]dioxole (6.1 g, 50.00 mmol, 1.00 equiv) and N-bromo-succinamide (NBS) (9.3 g, 52.5 mmol, 1.05 equiv) in CHCl3 (25 mL) in a 100-mL round-bottom flask and allowed to react, with stirring, for 3 hr while the temperature was maintained at reflux. The resulting mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate:petroleum ether (1:20)) giving 9.5 g (90%) of 5-bromobenzo[d][1,3]dioxole as yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[O:12][C:11]3[C:10]4[C:14]5[C:19]([NH:20][C:9]=4[CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:18][CH:17]=[CH:16][CH:15]=5.[H-].[Na+].Cl[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]=1>CN(C)C=O.C1COCC1>[C:36]1([C:26]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:29]=[C:24]([N:20]3[C:9]4[CH:8]=[CH:7][C:6]5[C:5]6[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=6[O:12][C:11]=5[C:10]=4[C:14]4[C:19]3=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:25]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc2c(c1)[nH]c1ccc3c4ccccc4oc3c12
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccccc3)nc(-n3c4ccccc4c4c5oc6ccccc6c5ccc43)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 g (50.5 mmol) of 7H-12-oxa-7-azaindeno[1,2-a]fluorene are dissolved in 150 ml of dimethylformamide under a protective-gas atmosphere, and 2.4 g of 60% NaH in mineral oil (60.6 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (14.9 g, 55.6 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 18.4 g (75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.7 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (20 g, 126 mmol) in chlorosulfonic acid (44 g, 378 mmol) was stirred at 100° C. for 48 hours before being poured into ice-water and extracted with EtOAc. The organic extract was dried (Na2SO4) and concentrated, and the residue was triturated with 10% EtOAc-petroleum ether to give 2,4-difluoro-5-nitrobenzenesulfonyl chloride as a brown oil (21 g, 81%) which was used directly in the next step.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:4]1.O=S(Cl)[Cl:16]>C(Cl)(Cl)Cl>[Cl:16][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:4]1
Reactant: CCCC(=O)N1CCCC(CO)C1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N1CCCC(CCl)C1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 1-(3-hydroxymethyl-piperidin-1-yl)-butan-1-one (Starting material 1-01e, 1.33 g, 7.20 mmol) in dry chloroform (10 ml) is cooled down to 0° C. with an ice-water bath. A solution of SOCl2 (1.43 g, 876 μl, 12 mmol) in dry chloroform (10 ml) is added dropwise. The mixture is allowed to stir at reflux for 30 min. The solution is cooled down to rt, SOCl2 (0.48 g, 0.3 ml, 4.1 mmol) is added dropwise and the resulting solution is allowed to stir at reflux for another 30 min. Evaporation of the solvents under reduced pressure gives a brown liquid which is purified by column chromatography on silica-gel (AcOEt/heptane, 35:65), yielding the title compound (1.15 g) in 78% as a colourless liquid: 1H-NMR (CDCl3): The product is a (1:1) mixture of rotamers: δ (ppm) 0.95 (t, 3H, CH3), 1.33-1.54 (m, 2H), 1.58-1.95 (m, 3H), 1.68 (quint., 1H, CH2CH2CH3), 2.32 (dd, 2H, CH2C═O), 2.60 (t, 0.5H), 2.83 (t, 0.5H), 2.99 (m, 2H), 3.36-3.55 (m, 2H), 3.77 (d, 0.5H), 3.93 (d, 0.5H), 4.30 (d, 0.5H), 4.54 (d, 0.5H).
Reaction SMILES: [ClH:1].Cl.CN[C@H]1CCCN([CH2:11][CH:12]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)C1.OC1(C(C2C=CC=C(OC(F)(F)F)C=2)C([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47][C:48](=O)OC(C)(C)C)[CH2:42]2)=O)CCCCC1>>[ClH:1].[ClH:1].[CH3:48][NH:47][C@H:43]1[CH2:44][CH2:45][CH2:46][N:41]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]2([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=2)[CH3:11])[OH:30])[CH2:42]1
Reactant: CN[C@H]1CCCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)C(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@H]1CCCN(C2CCCCC2(O)C(C)c2cccc(OC(F)(F)F)c2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-(2-[(3S)-3-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl ((3S)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}piperidin-3-yl)carbamate. MS m/z 401; HRMS: calcd for C21H31F3N2O2+H, 401.24159; found (ESI, [M+H]+), 401.2419.
Reaction SMILES: [C:1]([O:4][CH2:5][N:6]([CH3:27])[N:7]=[N:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)(=O)C>CO>[CH3:1][O:4][CH2:5][N:6]([CH3:27])[N:7]=[N:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: CC(=O)OCN(C)N=Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Solvent: CO
Product: COCN(C)N=Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(3′-chlorophenyl-amino)-6-aminoquinazoline (100 mg, 0.318 mmol) in acetonitrile (20 mL) kept at 0° C. in an ice bath, nitrosonium tetrafluoroborate (74.3 mg, 0.637 mmol) was added dropwise. The solution was stirred for 20 min and 0.9 mL of a mixture of methylamine 40% (0.075 mL, 0.954 mmol), formaldehyde 37% (0.75 mL, 9.54 mmol), and concentrated HCl (0.1 mL) was added all at once. The diazonium solution was subsequently alkalinized with potassium carbonate (400 mg, 2.86 mmol) and the precipitate was filtered to give a white solid contaminated with excess potassium carbonate. The precipitate was therefore re-suspended in THF and the resulting solution filtered. The organic solvent was further evaporated to give 6-(3-hydroxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline as a pure brown solid (90 mg, 73%). 6-(3-Hydroxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline (100 mg, 0.258 mmol) was dissolved in pyridine (2 mL) after which acetic anhydride (0.055 mL, 0.516 mmol) was slowly added. The solution was further kept on ice for 1.5 h and the pyridine evaporated as an azeotrope with toluene to give 6-(3-Acetoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline as a pure brown residue (105 mg, 95%). 6-(3-Acetoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline (100 mg, 0.260 mmol) was dissolved in anhydrous methanol (2.5 mL) and stirred at room temperature for 24 h. The methanol was then evaporated to provide the title compound 6-(3-methoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline) as a pure brown residue (91 mg, 98%): EI m/z 357.0 (MH+), 253.2 (M-3-methoxymethyl-3-methyl-triazene); 1H NMR (400 MHz, DMSO-d6) d 9.94 (s, 1H, NH), 8.60 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H, J=9.2 Hz), 7.88 (d, 1H, J=6.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.39 (t, 1H, J=6.6 Hz), 7.14 (d, 1H, J=9.2 Hz), 5.17 (s, 2H, CH2), 3.25 (s, 3H, CH3,), 3.24 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:24][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C:14]3=O)=[C:9]2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2].[Cl-:26].O>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[O:24][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[C:14]3[Cl:26])=[C:9]2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2]
Reactant: [Cl-]
Reactant: CCOC(=O)c1cc(=O)c2c3c(ccc2o1)C(=O)CC(C(=O)OC)=N3
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(ccc3c(Cl)cc(C(=O)OC)nc32)o1
Yield: 66 %

Procedure:
The product of step (b) (1.3 g, 3.79 mmole) and phosporyl chloride (0.69 ml) in dry dichloroethane (80 ml) were heated to reflux for 15 minutes. The reaction mixture was then cooled and treated with water. The mixture was extracted with dichloroethane, the organic layer was washed with water, dried, and evaporated to give a brown solid. This was dried in vacuo over P2O5 at 50° C. to give the sub-title compound (0.9 g; 66%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([CH2:31][CH2:32][O:33][C:34]([F:37])([F:36])[F:35])[CH2:24]3)=[C:17]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:16]=[C:15]([CH3:44])[N:14]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:12][C:13]1[C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([CH2:31][CH2:32][O:33][C:34]([F:37])([F:35])[F:36])[CH2:24]3)=[C:17]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:16]=[C:15]([CH3:44])[N+:14]=1[O-:9]
Reactant: Cc1cc(-c2ccccc2)c(COc2ccc3c(c2)CN(CCOC(F)(F)F)C3=O)c(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)c(COc2ccc3c(c2)CN(CCOC(F)(F)F)C3=O)c(C)[n+]1[O-]
Reaction time: 8 h
Yield: 65.8 %

Procedure:
3-Chloroperbenzoic acid (19.3 mg, 0.112 mmol) was added to a solution of 5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)-ethyl)isoindolin-1-one (40 mg, 0.074 mmol, 85% pure) in DCM. After stiffing overnight the reaction mixture was diluted with DCM, sat. aqueous NaHCO3 solution was added. Extraction with DCM, washing of the combined organic layers with water, drying over MgSO4 followed by purification by HPLC provided 2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)methyl)-4-phenylpyridine 1-oxide (23 mg, 64%). ESI-MS [M+H]+=473.1.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C@@H:35]1[NH:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH3:34][C@@H:35]1[N:40]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:39][CH2:38][NH:37][C:36]1=[O:41]
Reactant: C[C@@H]1NCCNC1=O
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H]1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 130 °C

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with (S)-3-methylpiperazin-2-one (21.59 mg, 0.189 mmol, Fluka, St. Louis, Mo.) potassium carbonate (78 mg, 0.568 mmol, Sigma-Aldrich, St. Louis, Mo., St. Louis, Mo.) and acetonitrile (1.26 mL). This mixture was heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by silica gel chromatography (10-100% EtOAc in hexanes) and then by reverse-phase HPLC purification (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give (3S)-3-methyl-4-(((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)-2-piperazinone as a mixture of two diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCOc1ccc(N)cc1
Reactant: N#Cc1ccncc1
Product: CCOc1ccc(NC(=N)c2ccncc2)cc1
Yield: 89.3 %

Procedure:
The title compound was prepared from 4-cyanopyridine (7.58 g, 72 mmol) and 4-ethoxyaniline (10 g, 72 mmol) by following the procedure described in preparation 10 (15.70 g, yield 89.3%, purity 99.4% by HPLC). MS m/z:242.3 (M+).