Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>C1(C)C=CC=CC=1>[CH2:26]([O:9][C:8](=[O:10])[C@H:6]([CH3:7])[NH:5][CH2:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[OH:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: C[C@H](NCc1ccccc1O)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)[C@H](C)NCc1ccccc1O
Reaction time: 8 h
Yield: 93.4 %

Procedure:
L-alanine (2.9 g) was dissolved in 20 ml of a 2-N sodium hydroxide aqueous solution, and 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were then added thereto in this order. After the mixture was stirred for 1 hour, 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were added thereto again. The mixture was stirred at room temperature for 1 hour, and the insoluble matter was then separated through filtration. The filtrate was extracted with diethyl ether. The pH was adjusted to 6 with hydrochloric acid to obtain 5.8 g of N-(2-hydroxybenzyl)-L-alanine. The resulting N-(2-hydroxybenzyl)-L-alanine (4.6 g) and 8.8 g of 1-dodecanol were added to 150 ml of toluene, and a hydrogen chloride gas was blown thereto up to the saturation. Ten grams of a molecular sieve were added thereto, and the mixture was stirred overnight. After the insoluble matter was separated through filtration, the filtrate was concentrated, and the resulting oil was dissolved in methylene chloride. The mixture was washed with a saturated aqueous solution of sodium chloride. The resulting mixture was dried over magnesium sulfate, and concentrated under reduced pressure to give 8 g of N-(2-hydroxybenzyl)-L-alanine lauryl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:24][N:25](C)[C:26](=O)[O:27][C:28]([CH3:31])(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[OH:35].[C:36]([O:39]CC)(=[O:38])[CH3:37].Cl>C(OCC)(=O)C>[C:28]([OH:35])(=[O:27])/[CH:31]=[CH:37]/[C:36]([OH:39])=[O:38].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)c1
Reactant: CCOC(C)=O
Reactant: CO
Agent: Cl
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(OC)c2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ({5-(2-fluoropyridin-3-yl)-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (303 mg) was dissolved in ethyl acetate (1 mL) and methanol (1 mL) and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) were added. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give the title compound as a free base (149 mg). A solution of the obtained free base (149 mg) in ethyl acetate (2 mL) was added to a solution of fumaric acid (46 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The obtained crystals were recrystallized from a mixed solvent of ethanol-water=9:1 to give the title compound as colorless crystals (yield 138 mg, 44%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][SH:4].[H-].[Na+].[CH2:11](I)[CH3:12]>C1COCC1>[NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][S:4][CH2:11][CH3:12]
Reactant: CCI
Reactant: CC(C)C[C@H](N)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSC[C@@H](N)CC(C)C
Reaction time: 18 h

Procedure:
(S)-2-Amino-4-methyl-1-pentanethiol (6.66 g, 50 mmol) is added over 45 minutes to a well stirred slurry of 60% sodium hydride (2.0 g, 50 mmol) in THF (50 mL) at room temperature under N2. After all of the sodium hydride has reacted, a solution of ethyl iodide (4 mL, 50 mmol) in THF (50 mL) is added and the reaction stirred at 20°-25° C. for 18 hours. THF is removed under reduced pressure and the residue partitioned between diethylether and brine. The ether extract is dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatograp
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2=[O:12].[C:13](Cl)([Cl:15])=[O:14]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:13]([Cl:15])=[O:14])[CH2:7][CH2:6][C:5]2=[O:12]
Reactant: O=C(Cl)Cl
Reactant: O=C1CCNc2ccc(Br)cc21
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)Cl)c2ccc(Br)cc21
Reaction time: 2.5 h

Procedure:
45.2 Parts of 6-bromo-4-oxo-1,2,3,4-tetrahydroquinoline and 200 parts of dioxane were mixed, and 39.4 parts of phosgene was introduced to the stirred mixture while the temperature was maintained at 20°-25° C. over about 30 minutes. After the introduction, the reaction was effected at 40°-45° C. for 2.5 hours, and thereafter the mixture was treated as in Example 37 (a) to obtain 55.9 parts of 6-bromo-4-oxo-1-chloroformyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: CO[CH:3](OC)[N:4](C)[CH3:5].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)[CH:13]=[C:12]([Cl:22])[N:11]=1.[CH3:23]O>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]2[N:17]=[C:18]([N:21]([CH3:23])[CH:3]=[N:4][CH3:5])[S:19][CH:20]=2)[CH:13]=[C:12]([Cl:22])[N:11]=1
Reactant: Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Reactant: CO
Reactant: COC(OC)N(C)C
Product: CN=CN(C)c1nc(-c2cc(Cl)nc(Cl)c2)cs1
Temperature: 10 °C
Yield: 83 %

Procedure:
3.93 g (0.033 mol) of dimethylformamide dimethyl acetal are added to a mixture of 7.38 g (0.03 mol) of [4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-amine and 50 ml of methanol at 20° C., while stirring, and the mixture is stirred at 50° C. for a further 2 hours. Thereafter, the reaction mixture is cooled to 10° C. and filtered with suction. The residue is washed with 10 ml of cold methanol and then dried at 45° C. under reduced pressure. 7.5 g (83% of theory) of N-[4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-N,N'-dimethylformamidine are obtained in this manner in the form of a solid substance of melting point 145° C.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][NH2:4].Cl.[NH2:16][C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOC(OC(OCC)=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([NH:16][C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])[CH2:3][NH2:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a room temperature suspension of Boc-Dap-OH (6.31 g, 22 mmol) in anhydrous CH2Cl2 (100 mL) was added HCl×Phe-OMe (5.2 g, 24.2 mmol), DEPC (6.7 mL, 44 mmol) and DIEA (11.5 mL, 65.9 mmol). This reaction mixture was stirred for 16 h, diluted with ethyl acetate (500 mL) and washed sequentially with 0.1 M HCl (2×300 mL), H2O (300 mL), saturated NaHCO3 (2×300 mL) and H2O (300 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. This crude oil was purified by silica gel flash column chromatography using a 20-100% ethyl acetate/hexanes gradient. Boc-Dap-Phe-OMe was obtained as white foam (8.85 g, 19.7 mmol, 90% yield).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].[NH2:14][C:15]1[C:16]([CH3:30])=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1.N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-]>>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:23])([CH3:24])[CH3:22])[CH:18]=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:16]=1[CH3:30])=[O:9])=[N+:2]=[N-:3]
Reactant: Cc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: Cc1ccc(C(=O)Nc2cc(C(C)(C)C)cc(NS(C)(=O)=O)c2C)cc1N=[N+]=[N-]

Procedure:
3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methyl-phenyl)-4-methyl-benzamide was prepared from 3-azido-4-methyl benzoic acid (US 04/102492) and N-(3-Amino-5-tert-butyl-2-methyl-phenyl)-methanesulfonamide in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:9][CH3:10])[CH:6]([CH3:7])[O:5][CH:4]1[CH3:8].[CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[C:13]([OH:24])[CH:12]=1.[OH-:25].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[CH3:7][CH:6]1[C:3]([CH2:2][O:24][C:13]2[CH:12]=[CH:11][C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:2][C:3]4([CH2:9][CH3:10])[CH:6]([CH3:7])[O:25][CH:4]4[CH3:8])=[CH:19][CH:18]=3)=[CH:15][CH:14]=2)([CH2:9][CH3:10])[CH:4]([CH3:8])[O:5]1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: [OH-]
Reactant: CCC1(CCl)C(C)OC1C
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CCC1(COc2ccc(-c3ccc(OCC4(CC)C(C)OC4C)cc3)cc2)C(C)OC1C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
While stirring, 3-chloromethyl-3-ethyl-2,4-dimethyl-oxetane, 4,4′-bisphenol, and tetrabutylphosphonium bromide were heated to 80° C. An aqueous potassium hydroxide solution was dripped. The resulting mixture was heated to approximately 110° C. to start reflux. While refluxed, the reaction was allowed to proceed over 8 hours. After the reaction, the reaction mixture was cooled to room temperature. Subsequently, pure water was added and the resulting mixture was well stirred. Thereafter, deposits were collected by filtration. The resulting deposits were washed with water, followed by washing with methanol. Subsequently, drying was performed employing a vacuum dryer, whereby a targeted compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:16](I)=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([Cl:18])[CH:3]=1.O=[C:20]([CH3:24])[C:21]([OH:23])=[O:22].N12CCN(CC1)CC2>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([O:9][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[C:16]2[C:2](=[CH:3][C:4]=1[Cl:18])[NH:1][C:20]([C:21]([OH:23])=[O:22])=[CH:24]2)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1cc(I)c(N)cc1Cl
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc2cc(C(=O)O)[nH]c2cc1Cl
Temperature: 100 °C
Reaction time: 5 h
Yield: 198.9 %

Procedure:
tert-Butyl (4-amino-2-chloro-5-iodobenzyl)carbamate (1.18 g, 3.08 mmol) (known from WO-A-2006/101321) was initially charged under argon in N,N-dimethylformamide (12 ml). 2-Oxopropionic acid (0.88 g, 10.02 mmol), 1,4-diazabicyclo[2.2.2]octane (1.12 g, 10.02 mmol) and palladium acetate (0.034 g, 0.15 mmol) were added. The reaction mixture was stirred at 100° C. for 5 h. After cooling, the solution was filtered through Celite and the filtercake was washed with ethyl acetate. The filtrate was washed with hydrochloric acid (0.1 M) and saturated sodium chloride solution, the organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. 1.99 g of crude product were obtained, which were converted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]2[O:11][CH2:12][CH2:13][O:14][C:3]=12.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH2:12]1[CH2:13][O:14][C:3]2[C:4](=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=2[NH:1][C:15]([CH3:16])=[O:17])[O:11]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(N)c2c1OCCO2
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(C)=O)c2c1OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4'-amino-2',3'-ethylenedioxyacetophenone (310 mg, 1.60 mmol) in 2.3 mL of pyridine under nitrogen was cooled in an ice/water bath and 6.9 mL of acetic anhydride was added drop-wise. The mixture was allowed to warm to room temperature and then stirred for 16 hours. The mixture was concentrated by rotary evaporation and the residue was stirred into water. The residue was isolated by filtration and washed with water. Drying gave 2',3'-ethylenedioxy-4'-(methylcarbonylamino)acetophenone (289 mg, 1.23 mmol), m.p. 142°-144° C.
Reaction SMILES: [CH2:1]([C:3]([S:11][CH2:12]Cl)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].P([S-])(=S)([O-])[O-].[P:19]([SH:27])([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[S:20].CCOCC>C(N(CC)CC)C>[P:19]([S:27][CH2:12][S:11][C:3]([CH2:1][CH3:2])([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[S:20])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]
Reactant: CCC(C)(SCCl)c1ccccc1
Reactant: CCOP(=S)(S)OCC
Agent: [O-]P([O-])(=S)[S-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOP(=S)(OCC)SCSC(C)(CC)c1ccccc1
Temperature: 25 °C

Procedure:
To 0.091 mole of chloromethyl α-ethyl-α-methylbenzyl sulfide and 16.9 grams (0.091 mole) of the phosphorodithioate of the formula (C2H5O)2PSSH in 100 ml. of ether is added 9.2 grams of triethylamine, dropwise, maintaining the temperature at 25° C. The mixture is stirred for several hours and then washed with water and 5% sodium hydroxide solution. Evaporation of the solvent from the dried (magnesium sulfate) solution gives 31.3 grams (95%) of a colorless liqiuid. This material is chromatographically purified on a silica gel dry-column using 10 volume percent methylene chloride in hexane as the eluant.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>CN(C)C=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ccccn1
Temperature: 100 °C

Procedure:
To a solution of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.190 g, 0.528 mmol) in N,N-dimethylformamide (5 ml) was added 2-tri-n-butylstannylpyridine (0.265 g) followed by dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.187 g). The mixture was heated at 100° C. for 9 h. The solvent was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with 4% methanol in dichloromethane. The residue was then loaded onto a cartridge of strong cation-exchange resin. Elution with methanol gave non-basic impurities. Further elution with 2M ammonia in methanol gave crude product. Further purification by preparative thin-layer chromatography on silica gel using 4% methanol in dichloromethane as eluant and crystallisation of the residue from toluene/isohexane afforded 3-[4-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as yellow needles: δH (400 MHz, DMSO) 7.46 (1H, m), 7.53 (1H, d, J 7), 7.61 (1H, dd, J 11 and 9), 7.86-7.91 (2H, m), 7.95-7.99 (1H, m), 8.24 (1H, dd, J 7 and 2), 8.30 (1H, s), 8.74-8.76 (1H, m), 9.27 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(I)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 5-iodopyridin-2-amine (25.5 g), 4-methylbenzene-1-sulfonyl chloride (23.2 g) and pyridine (250 mL) was stirred at 100° C. overnight. The reaction mixture was poured into water (1.2 L) and stirred. The resulting solid was collected by filtration. The obtained solid was washed with water and diethyl ether and dried in vacuo to give the title compound (37.4 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:23][CH:24]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCOCc1ccccc1
Reactant: OCCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Product: OCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
is prepared from 4,4-bis(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol (example 1c) and benzyl 2-bromoethyl ether by PTC reaction according to the method described in the example 1a.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][CH:25]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=2)=[CH:28][CH:29]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
solution of 3,5-dibromo-1-methyl-2-pyridone (267 mg, 1.0 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (568 mg, 1.0 mmol) in DMF (7 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). bis(triphenylphosphine)palladium dichloride (80 mg, 0.11 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 40 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane (40 mL) and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (1×10 mL), 5% potassium fluoride (2×10 mL) and brine (1×5 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 45 g of silica gel eluting with 3:7 ethyl acetate:hexane to give 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxyl)carbonyl]-L-phenylalanine methyl ester (140 mg, 30%). FAB MS: 465 (M+H (1 Br)).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:42])[C:5]1[N:9]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=3)[N:11]=2)[C:8]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:7]=2[N:6]=1.I[CH3:44]>CN(C=O)C.O>[F:42][CH:4]([F:3])[C:5]1[N:9]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([N:28]([CH3:44])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][CH:27]=3)[N:11]=2)[C:8]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:7]=2[N:6]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N(C)C(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
NaH (95%, 11 mg, 0.435 mmol) was added to a suspension of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenylcarbamate (Example 74) (120 mg, 0.217 mmol) in DMF (3 mL) at 0° C. After stirring at 0° C. for 15 min, iodomethane (0.020 mL, 0.321 mmol) was added. The reaction mixture was warmed to room temperature, stirred for additional 17 hrs, and then diluted with H2O. The resulting precipitate was collected by filtration and dried to give tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl(methyl)carbamate (104 mg, 85%): mp (CH2Cl2/MeOH) 205-208° C.; 1H NMR (CDCl3) δ 8.42 (d, J=8.8 Hz, 2H), 8.09 (dd, J=8.4, 0.6 Hz, 1H), 7.63 (t, JHF=53.5 Hz, 1H), 7.45-7.40 (m, 3H), 6.86 (d, J=7.8 Hz, 1H), 4.13 (m, 2H), 4.07 (s, 3H), 4.00 (m, 2H), 3.86 (m, 4H), 3.35 (s, 3H), 1.50 (s, 9H); Anal. Calcd. for C28H31F2N7O4: C, 59.25; H, 5.5; N, 17.3. Found: C, 59.0; H, 5.3; N, 17.2%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH:23]([OH:25])[CH3:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][C:23](=[O:25])[CH3:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)CNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)CNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
To a solution of oxalyl chloride (37 mL, 2 M solution in CH2Cl2, 74 mmol) in CH2Cl2 (60 mL) at −78° C. under argon was added DMSO (7.8 g, 100 mmol). The mixture was stirred at −78° C. for 20 min, and to this mixture was added a solution of 1-benzyloxycarbonylamino-2-propanol (2) (12.9 g, 61.8 mmol) in CH2Cl2 (40 mL). The mixture was stirred at −78° C. for 1 h, and then Et3N (21 mL) was added to the mixture. The mixture was warmed to room temperature and washed with 1 N hydrochloric acid followed by aqueous sodium bicarbonate solution. The organic solution was dried over Mg2SO4 and concentrated to afford 1-benzyloxycarbonylamino-2-propanone (10.2 g, 81%) as a solid, which was used without further purification in the next step. 1H NMR (CDCl3): □ 7.32 (m, 5H), 5.50 (s, 1H), 5.06 (s, 2H), 4.07 (s, 2H), 2.1 (s, 3H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[ClH:22].[ClH:22].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(CCCc2ccccc2)CC1
Yield: 219.3 %

Procedure:
The procedure described in Example 17(a) was followed, using 36.0 g of (3-phenylpropyl)piperazine, 25.0 g of potassium hydroxide, 125 ml of dimethyl sulfoxide and 28.0 g of 1-bromo-3-chloropropane, to give 46.0 g (73% of theory) of 1-(3-phenylpropyl)-4-(3-chloropropyl)piperazine dihydrochloride.