Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[CH2:17][CH2:18][I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[I-:19].[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][P+:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=2)=[C:11]([F:16])[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(OCc2ccccc2)c(CCI)c1F
Solvent: Cc1ccccc1C
Product: Fc1ccc(OCc2ccccc2)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Product: [I-]
Temperature: 140 °C
Yield: 49 %

Procedure:
To a solution of 1-(benzyloxy)-3,4-difluoro-2-(2-iodoethyl)benzene (720 mg, 1.924 mmol) in Xylene (10 mL) was added Ph3P (1514 mg, 5.77 mmol) and the mixture was heated at 140° C. for 16 h. The mixture was cooled to rt (The product solidified). Solids were then filtered off and washed with toluene and ether, dried under high vac to afford (6-(benzyloxy)-2,3-difluorophenethyl)triphenylphosphonium, iodide salt (600 mg, 0.943 mmol, 49.0% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.87-7.77 (m, 3H), 7.77-7.59 (m, 12H), 7.53-7.44 (m, 2H), 7.40-7.33 (m, 3H), 7.02 (q, J=9.3 Hz, 1H), 6.70 (d, J=9.1 Hz, 1H), 5.15 (s, 2H), 3.81-3.69 (m, 2H), 3.10-2.98 (m, 2H). LCMS (M+H)=510.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[N:16]([Si](C)(C)C)=[N+:17]=[N-]>CC#N.CCOC(C)=O>[N:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:16]=[N-:17]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Nc1ccc(I)cc1
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodobenzenamine (2.38 g, 10.9 mmol) in MeCN (20 mL) at 0° C. was added tert-butyl nitrite (1.95 mL, 1.69 g, 16.4 mmol) and azidotrimethylsilane (1.70 mL, 1.49 g, 12.9 mmol). The reaction mixture was warmed to room temperature and stirred for 6 h, heated to 40° C. for 18 h, and diluted with EtOAc. The aqueous phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give 1-azido-4-iodobenzene which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH2:5]2.[Br:13]Br>C(O)(=O)C>[Br:13][CH:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][C:7]1=[O:12]
Reactant: BrBr
Reactant: O=C1CCc2cc(F)ccc2O1
Solvent: CC(=O)O
Product: O=C1Oc2ccc(F)cc2CC1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 6-fluorochromanone 99.6 g, 0.6 mol) in 500 ml of acetic acid, 96.0 g (0.6 mol) of bromine were added in dropwise at a rate so as to maintain a reaction temperature at 25° C. After stirring the reactants for 2.0 hours at 25° C., the reaction mixture was poured into 1.2 liter of cracked ice with stirring. Resulting precipitate was subsequently filtered, washed with water and then dried on air to give 140 g (95.2%) of the desired compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](Cl)(=[O:25])[C:22](Cl)=O.[CH3:27]N(C)C=O>ClCCl.C(OCC)(=O)C.Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](=[O:10])[CH2:27][C:21](=[O:25])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution (15 mL) of 3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]propanoic acid (5.00 g) in dichloromethane were added oxalyl chloride (7.30 mL) and a catalytic amount of N,N-dimethylformamide under ice-cooling and the mixture was stirred for 30 min. The reaction mixture was concentrated, and the residue was dissolved in tetrahydrofuran (15 mL). Thereto was added triethylamine (9.4% mL) at room temperature, and the mixture was stirred for 30 min. The resulting precipitate was filtered off, enolate separately prepared from acetone (1.08 g) and potassium hydride (2.71 g: 30% wt) in tetrahydrofuran (15 mL) was added to the filtrate at −78° C., and the mixture was stirred for 1 hr. is The reaction mixture was slowly warmed to room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, 1N hydrochloric acid was added and the mixture was stirred for 30 min. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative high performance liquid chromatography, and the title compound (1.60 g, yield 28%) was obtained as colorless amorphous crystals. MS: 337 (MH+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23]>>[F:19][C:20]([F:26])([F:25])[CH2:21][C:22]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:23]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)CC(F)(F)F
Product: O=C(CC(F)(F)F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 3,3,3-trifluoropropanoic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (dd, J=8.1, 1.3 Hz, 1H), 7.98-8.02 (m, 1H), 7.93 (td, J=7.5, 1.3 Hz, 1H), 3.82-3.84 (m, 4H), 3.53-3.60 (m, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 357 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a stirred solution of 1-(bromomethyl)-2-fluoro-3-nitrobenzene (2.00 g, 8.54 mmol) and pyrrolidine (0.91 g, 12.82 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.72 g, 17.08 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The EtOAc solution was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(2-fluoro-3-nitrobenzyl)pyrrolidine (1.20 g, 63%) as a viscous oil. 1H NMR (400 MHz, CD3OD): δ 8.02-7.97 (m, 1H), 7.81-7.76 (m, 1H), 7.36 (td, 1H, J=8.0, 1.2 Hz), 3.81 (d, 1H, J=2.0 Hz), 2.62-2.58 (m, 4H), 1.84-1.80 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:15]=1)[O:12][C:11]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:10][C:9]2=[O:34])=[O:5].C(Cl)Cl>O1CCOCC1>[O:31]1[CH2:30][CH2:29][N:28]([C:11]2[O:12][C:13]3[C:8]([C:9](=[O:34])[CH:10]=2)=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:15][C:14]=3[CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 83.1 %

Procedure:
Hydrogen chloride (4M in dioxane) (2.4 mL, 9.6 mmol) was added to a stirred solution of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (440 mg, 0.96 mmol) dissolved in dioxane (3 mL) and DCM (3 mL) at room temperature and the reaction mixture stirred for 4 h. The solvents were evaporated and the residue azeotroped twice with MeCN and dried under vacuum at 50° C. The remaining solid was then extracted with DCM. The DCM was dried over MgSO4 and concentrated to afford methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (286 mg, 83%) as a pale beige solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH:14]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[OH-].[NH4+].[CH2:28](O)[CH3:29]>>[CH2:28]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH:14]=1)=[O:3])[CH3:29].[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)([OH:3])=[O:2]
Reactant: CCO
Reactant: CN1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Product: CN1CCC(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Yield: 42 %

Procedure:
A solution of 0.513 gm (2 mMol) 5-carboxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole in 5.1 mL ethanol was cooled in an ice bath while 0.51 mL sulfuric acid was added dropwise. The resulting mixture was heated at reflux for 5 hours. The now homogeneous solution was poured into 50 mL cold water and was then made basic with saturated ammonium hydroxide. The light yellow precipitate was collected by filtration and then recrystallized from ethanol to provide 0.24 gm (42%) of the desired compound as light yellow crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1CO.N1C=CC=CC=1.S(Cl)([Cl:25])=O.[CH2:27]([Cl:29])Cl>C1(C)C=CC=CC=1>[Cl:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:27][Cl:29]
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1-c1ccccc1CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCc1ccccc1-c1ccccc1CCl
Temperature: 25 °C

Procedure:
To a reaction system comprising a suspension of 2,2'-bis(hydroxymethyl)-1,1'-biphenyl (85.3 grams, 0.398 mole) in methylene chloride (500 mL) at 0° C. containing pyridine (2 mL) was added a solution of thionyl chloride (163 grams, 1.36 moles) in methylene chloride (100 mL) dropwise with stirring. The system was allowed to warm to room temperature overnight and then was stripped to a residue with a stream of nitrogen at room temperature. The residue was dissolved in toluene (100 mL), cooled to 0° C., and quenched by the addition of ice cold, saturated sodium chloride solution (100 mL). The layers were separated, the organic phase was washed with water at 0° C. (1×100 mL), the layers separated, and the organic phase dried with magnesium sulfate. The solvent was evaporated to give a thick oil which was then distilled at 125° C. to 127° C. (0.1 mm Hg) to give 91.9 grams of colorless oil which contained 71.3 g of product dichloride (71% of theoretical yield).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:26]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27].C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)N)=CC=CC=1)=O)CC1C=CC=CC=1>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=2)(=[O:36])=[O:37])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccc1)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Product: O=C(NCCc1ccccc1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 3-nitrophenylsulfonyl chloride, according to the general working procedure 272 mg of 2′-(3-nitrophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained; m.p. 145° C. MS (ES+): m/e=516 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].ClCCl.ClCCl.CO>C1COCC1>[C:22]([NH:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 30.0 g (86.5 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 91.0 ml (63.3 g, 865 mmol) of tert-butylamine in 200 ml of THF was stirred at room temperature for 48 h. The resulting mixture was filtered through glass frit (G3) and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 urn; eluent: dichloromethane and then dichloromethane-methanol=1:1, vol.). Yield 27.4 g (94%). Anal. Calc. for C21H30BNO2: C, 74.34; H, 8.91; N, 4.13. Found: C, 74.49; H, 9.09; N, 3.98. 1H NMR (CDCl3): 8.80 (br. s, 1H, NH), 8.53 (m, 1H, 8-H in naphthyl), 7.88 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.83 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 7.71 (m, 1H, 5-H in naphthyl), 7.47 (m, 1H, 7-H in naphthyl), 7.41 (m, 1H, 6-H in naphthyl), 4.44 (s, 2H, CH2N), 1.49 (s, 12H, CMe2CMe2), 1.41 (s, 9H, tBu).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29][CH3:30]>>[CH3:30][O:29][C:22]1[C:21]2[C:26](=[CH:27][CH:28]=[C:19]([N:7]3[C:8]4[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]4[CH2:15][N:14]5[CH2:13][CH2:12][CH:11]([C:6]3=4)[CH2:17][CH2:16]5)[CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: COc1ncnc2ccc(Br)cc12
Product: COc1ncnc2ccc(-n3c4c(c5cc(C)ccc53)CN3CCC4CC3)cc12

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the minor product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.20 (m, 4H) 2.42 (s, 3H) 2.89-2.96 (m, 1H) 3.09-3.30 (m, 4H) 4.23 (s, 3H) 4.33 (s, 2H) 6.91-7.04 (m, 2H), 7.22 (s, 1H) 7.87 (dd, J=9, 2 Hz, 1H) 8.06-8.13 (m, 2H) 8.83 (s, 1H); MS (DCI/NH3) m/z 385 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].C(N(CC)CC)C.[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[N:15][C:14]([Cl:19])=[C:13](Cl)[N:12]=1>CN(C)C=O>[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[N:15][C:14]([Cl:19])=[C:13]([S:2][CH3:1])[N:12]=1
Reactant: N#Cc1nc(Cl)c(Cl)nc1N
Reactant: CS
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(N)c(C#N)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dimethylformamide (1.5 ml) there was dissolved 2-amino-3-cyano-5,6-dichloropyrazine (200 mmg, 1 mM) and then cooled in an ice bath. Through the solution there was then bubbled methanethiol gas for 5-10 minutes. The reaction mixture was then stirred overnight at room temperature. Triethylamine (0.14 ml) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was then placed under a nitrogen atmosphere to remove solvent and excess methanethiol. The product was passed through a silica gel column, eluting with dichloromethane. The product was recrystallized from hexane/ether (139 mg). Elemental Analysis for C6H5N4ClS: :
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[Si:22]([O:29][NH2:30])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[Si:22]([O:29]/[N:30]=[C:11]1\[NH:10][C@@H:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Br:20])[CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\1=2)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/O[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (588 mg, 4.0 mmol), Hg(OAc)2 (640 mg, 2.0 mmol) and toluene (5 mL) was heated at 100° C. for 2 h. The mixture was cooled to r.t. and filtered through celite. Filtrate concentrated and the resulting oily residue was triturated with dry methanol to afford a pale yellow solid. Filtered and dried to afford ((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-tert-butyldimethylsilyloxime (384 mg, 80%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H) 0.97 (s, 9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd, J=16.36, 4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05 (td, J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd, J=8.72, 5.94 Hz, 1H). MS (ES) [M+H] calculated for C20H28BrFN5OSi, 480.12; found 480.30.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([CH3:15])=[CH2:14])=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:2]2[CH:3]=[C:4]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([Cl:8])=[CH:10][CH:11]=3)([CH3:15])[CH3:14])[CH:5]=[CH:6][C:1]=2[OH:7])([CH3:15])[CH3:14])=[CH:11][CH:10]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Product: CC(C)(c1ccc(Cl)cc1)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Yield: 66.2 %

Procedure:
The title compound is prepared according to the procedure of Example 3 by reacting 19 g of phenol with 80 g of 4-chloro-α-methylstyrene to give 53.4 g of the title compound as a white solid. The structure is confirmed by 1Hnmr and mass spectroscopy.
Reaction SMILES: CO[C:3]1[CH2:4][C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:12].[NH4+:13]>CCO>[ClH:12].[CH3:10][C:5]1([CH3:11])[CH2:6][CH2:7][CH2:8][NH:9][C:3](=[NH:13])[CH2:4]1
Reactant: COC1=NCCCC(C)(C)C1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CCO
Product: CC1(C)CCCNC(=N)C1
Product: Cl
Yield: 61.6 %

Procedure:
The product of EXAMPLE 64 (260 mg, 1.7 mmol) in 10 mL of EtOH was reacted with ammonium chloride (88 mg, 1.7 mmol) by the method of EXAMPLE 27 to yield 185 mg (55%) of the title material.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][S:17][CH:16]3[N:13]([C:14](=[O:27])[CH:15]3[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]=2[C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:9][N:10]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][S:17][CH:16]3[N:13]([C:14](=[O:27])[CH:15]3[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]=2[C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (1.51 cc) in dry tetrahydrofuran (10 cc) is added dropwise, in 5 minutes, to a solution, cooled to 0° C., of 3-(2-aminothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in dry tetrahydrofuran (150 cc), and a solution of triethylamine (2.8 cc) in dry tetrahydrofuran (5 cc) is then added. The reaction mixture is stirred for 1 hour 30 minutes at about 0°-5° C. and is then treated with further acetyl chloride (1.51 cc) in tetrahydrofuran (10 cc). After 1 hour 50 minutes at 5° C., the reaction mixture is filtered and the filtrate is concentrated to 50 cc and diluted with ethyl acetate (250 cc). The organic phase is washed with a saturated sodium bicarbonate solution (100 cc), with distilled water (100 cc) and with a half-saturated sodium chloride solution (100 cc) and is then dried over magnesium sulphate and concentrated to dryness. Crude 3-(2-acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicylo[4.2.0]oct-2-ene (10 g) is obtained in the form of a brown froth. Crystallisation from acetonitrile (25 cc) gives pure 3-(2-acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.9 g) in the form of a whitish crystalline powder whose characteristics are identical to those of the product obtained in variant (A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]([O:39][Si](CC)(CC)CC)[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([Cl:31])=[N:20][N:21]3C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.NC1C=C([C@@H](O[Si](CC)(CC)CC)CN(C(OC(C)(C)C)=O)CCOC2C=C3C(C(Cl)=NN3C(OC(C)(C)C)=O)=CC=2)C=CC=1F.[C:96]1([S:102](Cl)(=[O:104])=[O:103])[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1.C(Cl)Cl.C(O)C(N)(CO)CO>C(Cl)Cl.N1C=CC=CC=1>[Cl:31][C:19]1[C:18]2[C:22](=[CH:23][C:15]([O:14][CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][S:102]([C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)(=[O:104])=[O:103])[CH:3]=3)[OH:39])=[CH:16][CH:17]=2)[NH:21][N:20]=1.[ClH:31]
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(Cl)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1ccc(F)c(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(Nc1cc([C@@H](O)CNCCOc2ccc3c(Cl)n[nH]c3c2)ccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Tert-butyl 6-(2-((2-(3-amino-4-fluorophenyl)-2-(triethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-3-chloroindazole-1-carboxylate-CH2Cl2 solution [0.5 mL; solution obtained by dissolving (R)-tert-butyl 6-(2-((2-(3-amino-4-fluorophenyl)-2-(triethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-3-chloroindazole-1-carboxylate (480 mg) which can be prepared according to the method described in Reference example 70, etc. in dehydrated CH2Cl2 (3.52 mL)] was added with dehydrated pyridine (42 μL), benzenesulfonyl chloride-CH2Cl2 solution [0.5 mL; solution obtained by dissolving benzenesulfonyl chloride (466.3 mg; manufactured by Wako Pure Chemical Industries, Ltd.) in dehydrated CH2Cl2 (4 mL)] and dehydrated CH2Cl2, and the mixture was shaken (600 min−1) overnight at room temperature. To the reaction solution, PS-Trisamine [300 mg (3.6 mmol/g); manufactured by Argonaut] was added and the mixture was shaken (600 min−1) for 5 hours at room temperature. The reaction solution was filtered and the solvent was evaporated by blowing nitrogen gas to the filtrate. The resulting residue was purified by column chromatography (“COLUMN-I”; methanol). The resulting purified product was dissolved in 1,4-dioxane (0.2 mL), added with 4 mol/L-hydrochloric acid-1,4 dioxane solution (1.5 mL), and then shaken (600 min−1) overnight at room temperature. To the reaction solution, nitrogen gas was blown to evaporate the solvent, and the resulting residue was added with MTBE to obtain suspension. Nitrogen gas was blown to the suspension to evaporate the solvent, and as a result, the title compound was obtained as a hydrochloride (40.7 mg).