Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:10]=C)=[CH:4][N:3]=1.[O:12]=[O+][O-].CSC>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:10]=[O:12])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(Cl)nc1NC
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1nc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 95 %

Procedure:
A solution of (2-chloro-5-vinyl-pyrimidin-4-yl)-methylamine (2.50 g, 14.7 mmol) in CHCl3/MeOH (15 mL/15 mL) is bubbled by ozone for 30 minutes and then passed by a stream of argon for 3 minutes at −78° C. The reaction mixture is allowed to warm up to room temperature and treated with dimethyl sulfide (3.24 mL, 44.1 mmol). The reaction mixture is concentrated under reduced pressure to give colorless oil that is purified by flash column chromatography (SiO2, EtOAc/Hx=1/3) over silica gel to give 2-chloro-4-methylamino-pyrimidine-5-carbaldehyde (2.40 g, 95%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:13][Si:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[CH:20]1.C(OCC)(=O)C>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:24]([C:22]2[N:21]=[CH:20][N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:27])([CH3:26])[CH3:13])[CH:23]=2)[OH:25])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C[Si](C)(C)CCOCn1cnc(C=O)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cnc(C(O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-bromopyridine (1.0 g, 6.33×10−3 mol) was cooled to −78° in a dry ice/acetone bath. To this solution, BuLi (3.48 mL, 6.96×10−3 mol, 2M solution in cyclohexane) was added dropwise and the reaction was stirred for 15 minutes. A solution of 1-(2-trimethylsilanylethoxymethyl)-1H-imidazole-4-carbaldehyde (0.955 g, 4.22×10−3 mol) in ether (5 mL) was added dropwise to the reaction and the solution was stirred for 1 hour at −78 C. The reaction was quenched with sat. NaHCO3 (10 mL) and allowed to warm to room temperature. Ethyl acetate was added (100 mL) and the organic layer was washed with water (3×50 mL), dried over MgSO4, filtered and solvent was removed under reduced pressure. The crude product was purified by silcagel column chromatography eluting with a gradient of ethyl acetate:hexane (1:3) to ethyl acetate to ethyl acetate:methanol (9:1). The pure product was isolated as a mixture of isomers (yellow oil, yield 778 mg, 40%). Rf0.5 (ethyl acetate); 1H-NMR (CDCl3) δ −0.09–0.11 (m, 9H), 0.86–0.99 (m, 2H), 3.41–3.57 (m, 2H), 5.22 & 5.26 (2xs, 2H), 5.89 & 6.05 (2xs, 1H), 6.63 & 6.80 (2xs, 1H), 7.25–7.39 (m, 1H), 7.53 & 7.58 (2×s, 1H), 7.79–7.90 (m, 1H), 8.53 & 8.57 (d, 1H), 8.64 & 8.69 (2xs, 1H); ESMS Calcd (C10H18N2O2Si): 226.11, found 227.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH3:15])[CH2:2][CH2:3][CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[Br:39]N1C(=O)CCC1=O>O>[CH2:1]([O:5][C:6]1[C:7]([CH2:15][Br:39])=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOc1ccc([N+](=O)[O-])cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc([N+](=O)[O-])cc1CBr
Reaction time: 8 h

Procedure:
To a stirred and gently refluxing mixture of 256 parts of butyl (5-nitro-o-tolyl)ether, 1 part of benzoyl peroxide and 4800 parts of anhydrous carbon tetrachloride is added, over a one-day period, a mixture of 213.6 parts of N-bromosuccinimide and 1 part of benzoyl peroxide. Upon completion, stirring at gentle reflux is continued overnight. The reaction mixture is cooled and water is added. The organic layer is separated, washed with water, dried, filtered and evaporated. The oily residue is crystallized on standing overnight in 2-propanol, yielding 189.7 parts of (α-bromo-5-nitro-o-tolyl) butyl ether; mp. 64° C.
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[N:15][C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]2O.[C:26]1([O:32][CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:33][O:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13]2
Reactant: COc1ccccc1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: CCCCCON=O
Product: CCOC(=O)C1=NNc2ccc(-c3ccccc3OC)cc2C1

Procedure:
Amyl nitrite (2 ml.) was added to a stirred suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (2 g.) in anisole (250 ml.). The suspension was stirred and heated on a steam bath for 3 hours. The resulting solution was filtered whilst hot and the filtrate was evaporated. The residue was applied to a silica column (100 g. of Kieselgel 60) and eluted with a 10% v/v mixture of dry ethanol and chloroform. The appropriate fractions were evaporated, the residual solid [ethyl 4-hydroxy 6-(methoxyphenyl)cinnolin-3-yl carboxylate] was dissolved in thionyl chloride (50 ml.), and dimethylformamide (5 drops) added. The solution was heated under reflux until gaseous evolution ceased. The solution was then evaporated under reduced pressure, the residue dissolved in dry toluene (20 ml.), and the solution evaporated to dryness. The residue was dissolved in a mixture of dimethylformamide (2 ml.) and ethyl acetate (50 ml.), and sodium borohydride (0.5 g.) was added. The mixture was stirred for 2 hours at room temperature and then added to a mixture of N-hydrochloric acid (10 ml.) and ethyl acetate (50 ml.). The mixture was separated and the ethyl acetate layer was washed with water (3× 20 ml.), dried (MgSO4), and filtered. There was thus obtained the solution of ethyl 6-(methoxyphenyl)-1,4-dihydrocinnolin-3-yl carboxylate (believed to be a mixture of isomers varying in the position of the methoxy radical on the phenyl substituent) which was used as starting material in this Example.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Cl:14])=O.[Br:15][C:16]1[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=1>C(O)C>[Br:15][C:16]1[CH:17]=[N:18][C:19]2[N:20]([CH:2]=[C:3]([C:5]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=3[Cl:14])[N:22]=2)[CH:21]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(CBr)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Yield: 48.2 %

Procedure:
A solution of 2-bromo-1-(2-chloro-5-nitrophenyl)ethan-1-one (I-2) (30 g, 108 mmol, 1.00 equiv) and 5-bromopyrimidin-2-amine (15 g, 88 mmol, 0.81 equiv) in ethanol (300 ml) was stirred for 12 h at 75° C. and then concentrated under vacuum. The residue was diluted with 200 ml of water and extracted with 3×100 ml of ethyl acetate. The combined organic layers was washed with brine, dried over Na2SO4 and concentrated under vacuum to give 15 g (39%) of 6-bromo-2-(2-chloro-5-nitrophenyl)imidazo[1,2-a]pyrimidine (I-3) as a brown solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][O:7][C:6](=[O:10])[CH2:5]2)[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[CH2:3]1[C:4]2([CH2:9][CH2:8][O:7][CH:6]([OH:10])[CH2:5]2)[CH2:1][CH2:2]1
Reactant: O=C1CC2(CCC2)CCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1CC2(CCC2)CCO1
Reaction time: 1.5 h
Yield: 33.8 %

Procedure:
To a solution of 7-oxaspiro[3.5]nonan-6-one (0.67 g) in tetrahedrofuran (3 mL) cooled at −78° C. was added 1M diisobutylaluminum hydride/tetrahydrofuran (1.0 mL) dropwise over 5 minutes. The reaction solution was stirred at that temperature for 1.5 hours. Water (40 μL) was added to the reaction solution. After allowing the temperature to rise to room temperature, a 15% aqueous sodium hydroxide solution (40 μL) and water (120 μL) were successively added to the solution. After stirring the solution at room temperature for 10 minutes, diethyl ether (2 mL) and anhydrous magnesium sulfate (0.17 g) were added. The solution was stirred for additional 30 minutes. The reaction solution was then filtered with Celite. The filtrate was concentrated under reduced pressure to give the title compound (230 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](N)=[CH:19][C:18]=1[CH3:25])(=[O:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:12][C:9]2[CH2:10][CH2:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:19][C:18]=1[CH3:25])(=[O:15])[CH3:14]
Reactant: NC1=NN(c2ccccc2)CC1
Reactant: CC(=O)Oc1c(C)cc(N)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C)cc(NC2=NN(c3ccccc3)CC2)cc1C
Yield: 46.7 %

Procedure:
4,5-Dihydro-1-phenyl-1H-pyrazol-3-amine (0.16 g), 4-amino-2,6-dimethylphenyl acetate (0.2 g), and toluene-4-sulfonic acid (0.02 g) were refluxed in toluene under nitrogen for 8 hours. Evaporation and chromatography (silica, dichloromethane/ethyl acetate [95:5]) of the residue gave the title product (0.15 g), as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl 4-hydroxybenzoate: MS (APCI) m/z 446 (M+).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH3:13].[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21].ClC(OC)=O>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.[Cu]I.C(N(CC)CC)C.CN(C=O)C>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:21]#[C:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:5][C:4]=1[CH3:13]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C
Temperature: 100 °C
Yield: 19.9 %

Procedure:
To 4-bromo-2-methyl-5-nitrophenyl methyl carbonate (500 mg, 1.72 mmol), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol), and CuI (3 mg, 0.02 mmol) were added DMF (5.0 mL), triethylamine (5.0 mL), and N,N-dimethylprop-2-yn-1-amine (717 mg, 919 μL, 8.62 mmol) under nitrogen atmosphere. The reaction mixture was heated under microwave irradiation at 100° C. for 15 min, resulting in product formation with partial loss of the carbonate group. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL), water, and brine. The solution was dried over Na2SO4, filtered, and dried down to a red oil. The oil was dissolved in cold (0° C.) dichloromethane (4 mL) and triethylamine (132 μL, 1.71 mmol) then treated dropwise with methyl chloroformate (132 μL, 1.71 mmol). After 5 min the reaction was quenched with water and the aqueous layer extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-60% ethyl acetate/hexanes) provided 4-(3-(dimethylamino)prop-1-ynyl)-2-methyl-5-nitrophenyl methyl carbonate (100 mg, 20% yield). LC/MS m/z 293.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[C:17]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2C2=CCOCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2C2CCOCC2)C1
Temperature: 30 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of (115) (938 mg, 2.96 mmol) and wet Pd—C (50%, 400 mg) in MeOH (30 mL) was stirred under H2 (40 psi) at 30° C. overnight. Then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated to give the desired compound (116) (897 mg, 2.81 mmol, yield 95%). ESI-MS (M+1): 320 calc. for C17H25N3O3 319.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:33](=[O:35])[CH3:34])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)N(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: -15 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}amino)ethanol (prepared as described in Example 36/30 mg, 0.07 mmol) was dissolved in DMA and the mixture was cooled to −15° C. Acetic anhydride (6 μL, 0.07 mmol) was added and the mixture was stirred for 1 hour. Water was then added and the precipitated solid was filtered and dried to give the title compound (22 mg, 67%); NMR Spectrum (mixture of rotamers): (major isomer) 2.08 (s, 3H), 3.49 (t, 2H), 3.56-3.59 (m, 2H), 3.80 (t, 2H), 4.40 (t, 2H), 4.90 (t, 1H), 5.28 (s, 2H), 7.26 (d, 1H), 7.37 (t, 1H), 7.58 (d, 1H), 7.84-7.98 (m, 2H), 8.16 (d, 1H), 8.28 (s, 1H), 8.30 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 498 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: CSc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na2CO3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh3)4 (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600 mL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50° C. to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@@H:24]([CH2:32][OH:33])[NH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([C:7]([N:23]2[C@H:24]([CH2:32][OH:33])[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)=[O:9])[CH:10]=1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To an ice cooled solution of 5-bromo-2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)benzoic acid (45.0 g, 127.8 mmol) in DCM (450 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (20.8 g, 102.27 mmol), HATU (72.7 g, 191.2 mmol), DIPEA (55.7 mL, 319.6 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with DCM (750 mL), washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 50 g (79%). Rf=0.44 (55% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-7.00 (m, 4H), 6.80-6.40 (m, 1H), 5.10-3.80 (m, 7H), 3.50-2.40 (m, 3H), 2.40-2.10 (m, 3H), 1.30-1.00 (m, 3H); ES-MS: m/z 498.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:29]3[C:28]([CH3:27])=[N:32][N:31]=[N:30]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3nnnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:32])([F:31])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[CH:28]=[CH:29][N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([F:31])([F:32])[F:15])=[CH:20][CH:21]=2)[C:26]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)F)cc1
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 25.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.68 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.70 g of 1-[4-(2,2,2-trifluoroethoxy)phenyl]-2(1H,3H)-imidazolone, 0.30 g of 1-[-(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1methylpropyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2(1H,3H)-imidazolone was obtained as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].OCC1C=CC=C(CO)C=1C([O-])=O.[C:31]([NH:38][CH:39](O)[CH2:40][CH2:41][CH3:42])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CCCC(O)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: COC(=O)c1c(O)cccc1OCCCCN
Agent: O=C([O-])c1c(CO)cccc1CO
Solvent: ClCCl
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
(2RS)-(4-{2-Benzenesulfonylamino-2-[4-(2-methoxycarbonyl-3-hydroxy-phenoxy)butylcarbamoyl]ethyl}-2-bromophenyl)difluoromethylphosphonic acid diethyl ester (Compound 3A) was prepared from the sulfonamide acid obtained in Example 2B following a procedure similar to Example 2C except that 2-(4-amino-butoxy)-6-hydroxybenzoic acid methyl ester was used instead of phenbutylamine. The 2-(4-amino-butoxy)-6-hydroxy-benzoic acid methyl ester was prepared by taking a solution of 2,6-dihydroxymethylbenzoate (1.0 g, 5.95 mmol), 1.5 equivalents N-Boc aminobutanol and 1.5 equivalents of triphenylphosphine (2.34 g, 8.93 mmol) in 40 mL of CH2Cl2 and adding 1.5 equivalents of DIAD (1.80 g, 8.93 mmol). Stirring continued for 1.5 hours at room temperature. Evaporation to dryness followed by column chromatography (30% EtOAc/hexanes) gave 2-(4-tert-butoxycarbonylamino-butoxy)-6-hydroxy-benzoic acid methyl ester. This compound was cooled to 0° C. in an ice/brine bath. HCl gas was bubbled into the solution for 2 minutes and stirring was continued for 1 hour. Evaporation to dryness followed by precipitation with ether and filtration gave 2-(4-aminobutoxy)-6-hydroxybenzoic acid methyl ester as the HCl salt. Compound 3 was prepared from Compound 3A following the procedures in Example 2D. MS (ion spray):m/z 733.4/735.4 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 9.91 (br s, 1H), 8.15 (d, 1H, J=9.2 Hz), 7.94 (br s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.46 (m, 5H), 7.21 (d, 1H, J=8.0 Hz), 7.15 (t, 1H, J=8.0 Hz), 6.47 (m, 2H), 3.95 (m, 1H), 3.85 (m, 2H), 3.72 (s, 3H), 2.85 (m, 3H), 2.65 (m, 1H), 1.49 (m, 2H), 1.35 (m, 2H).