Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](O)=O)[C:2]([CH3:4])=[O:3].[NH2:15][C:16]1[C:17](=[O:38])[N:18]([CH2:35][CH2:36][CH3:37])[C:19](=[O:34])[N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:21]=1[NH2:22]>>[NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[NH:15][C:16]2[C:17](=[O:38])[N:18]([CH2:35][CH2:36][CH3:37])[C:19](=[O:34])[N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[C:21]=2[N:22]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccccc1CC(=O)O
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 2-(acetamino)phenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 8-(2-acetaminobenzyl)-3-[2-(4-aminophenyl)ethyl]-1-propylxanthine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].CCOC(C)=O>CN(C=O)C>[N:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[N+:14]=[N-:15]
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-(bromomethyl)nicotinate from Example G1 (2.0 g, 8.60 mmol) in DMF (15 ml) was added sodium azide (0.84 g, 12.9 mmol). The mixture was stirred at room temperature for 18 h. EtOAc (100 ml) was added and the mixture was washed with water (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80) to give a yellow gum; yield 1.55 g (93%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:14]([CH3:15])=[C:13]2[C:7]([CH2:8][N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:11]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=32)=[CH:6]1.[H-].[Al+3].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:12]2[C:13]3[C:7](=[CH:6][N:5]([CH2:4][CH2:3][OH:2])[C:14]=3[CH3:15])[CH2:8][N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:11]=2[CH:19]=1
Reactant: COC(=O)Cn1cc2c(c1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2c(cn1CCO)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.0 g (9.6 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester in 40 ml of tetrahydrofuran was added dropwise to a solution of 0.8 g (21.0 mmol) of lithuium aluminum hydride in 50 ml of tetrahydrofuran which was cooled to -78° C. When the addition was complete, the reaction mixture was allowed to warm to 0° C. and stirred for 30 minutes. The mixture was treated with 1 ml of water, 1 ml of a 3 N solution of aqueous sodium hydroxide and 3 ml of water. The resulting precipitate was removed by filtration, and the filtrate was concentrated at reduced pressure. The residue crystallized from ether to yield 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-ethanol as pale yellow prisms, mp 149°-152° C. Recrystallization from a mixture of ether and methylene chloride gave white prisms, mp 151°-153° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1cnccc1Cl
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: [K+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cnccc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 4-chloropyridine-3-carbaldehyde (33.44 g), (4-fluorophenyl)boronic acid (39.1 g), tetrakis(triphenylphosphine)palladium (6.73 g), 2 M aqueous potassium carbonate solution (314.4 mL) and 1,2-dimethoxyethane (500 mL) was heated under reflux for 6 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereof, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.04 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([O:21][CH2:22][CH2:23]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1>[CH2:14]([O:21][CH2:22][CH2:23][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Yield: 90.4 %

Procedure:
506 mg (60% in oil, 13 mmol equivalents) of sodium hydride was added to 5.0 mL of tetrahydrofuran, and the mixture was cooled to about 0° C. in an ice bath. 3.2 mL (20.7 mmol equivalents) of diethyl malonate was added thereto (solution A). 2.3 g (10.7 mmol equivalents) of 2-benzyloxy-1-bromoethane was dissolved in 3.0 mL of tetrahydrofuran, this was added dropwise to solution A over 10 minutes, and the mixture was refluxed while heating overnight. After completion of the reaction, a 0.5 mol/L aqueous solution of hydrochloric acid was added dropwise to the reaction liquid, and the mixture was extracted three times with diethyl ether. The combined diethyl ether layers were washed with brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 2.85 g (9.67 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)malonate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[Cl:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11](I)=[CH:10][N:9]=1.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:14][C:12]=2[CH:13]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Temperature: 145 °C

Procedure:
Pyruvic acid (0.86 ml, 12.4 mmol) was added to a solution of 2-chloro-5-iodo-pyridin-4-ylamine (Preparation 115, 1.05 mg, 4.13 mmol), palladium acetate (56 mg, 0.25 mmol) and DABCO (1.39 g, 12.4 mmol) in anhydrous DMF (30 ml). The reaction mixture was degassed with argon for 20 min, then heated to 145° C. for 2 h. The solvent was removed in vacuo and the residue taken up in water (200 mL). The suspension was made alkaline (pH 9-10) with dilute NaOH solution (1M) and filtered through Celite. After washing of the filtrate with ethyl acetate (50 mL) and ether (50 mL) the pH was adjusted to 3 with dilute HCl solution (1M). Extraction with ethyl acetate (5×50 mL), drying of the combined extracts (MgSO4) and concentration gave the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:5]1)([CH3:3])[CH3:2].[I:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:14][C:7]1[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1
Reactant: CC(C)n1ccc(-c2cccs2)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of 1-isopropyl-3-(2-thienyl)-1H-pyrazole (27.5 mmol) in 98 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (28.9 mmol) in small portions. The reaction mixture was stirred overnight at room temperature. N-Iodosuccinimide (4.4 mmol) was added and stirring was continued for 24 h. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with ethyl acetate. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 3.70 g 4-iodo-1-isopropyl-3-(2-thienyl)-1H-pyrazole (38% yield).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20](O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:20]3[C:21]4[C:26]([CH:27]=[C:18]([CH3:17])[C:19]=3[CH:9]=[CH:8]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(O)c2ccccc2c1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Product: Cc1cc2ccccc2c2c1C=CC(c1ccccc1)(c1ccccc1)O2

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 3-methyl-1-hydroxynaphthalene was used in place of methyl-1,4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-5-methyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([OH:15])[CH:6]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:13])[CH3:14])=[C:7]([O:15][CH2:26][CH2:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC(C)C)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.5 g (6.69 mmol) of 3-Hydroxy-4-isopropoxy-benzoic acid ethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 1.4 g (7.36 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 6.7 g (equivalent to 20 mmol PPh3) of triphenylphosphine derivatized polystyrene and 3.5 g (20 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/6).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:32][CH3:33])[C:9]3[C:14]([O:15][CH2:16][CH:17]4[S:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)=[CH:13][N:12]=[C:11](Cl)[C:10]=3[N:31]=2)=[N:4][O:5][N:6]=1.[Na+].[I-].C1CCN2C(=NCCC2)CC1.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49].[NH4+].[Cl-]>[Zn].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.CO.C(Cl)Cl.O1CCOCC1>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:32][CH3:33])[C:9]3[C:14]([O:15][CH2:16][CH:17]4[S:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:51]#[C:50][C:48]([CH3:49])([OH:52])[CH3:47])[C:10]=3[N:31]=2)=[N:4][O:5][N:6]=1
Reactant: C#CC(C)(C)O
Reactant: CCn1c(-c2nonc2N)nc2c(Cl)ncc(OCC3CN(C(=O)OC(C)(C)C)CCS3)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OCC3CNCCS3)c21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
A thick-walled pressure vessel was charged with 1,1-dimethylethyl 2-({[2-(4-amino-1,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-thiomorpholinecarboxylate (enantiomer E1) (0.18 g, 1.35 mmol), Zn dust (0.03 g, 0.40 mmol), NaI (0.06 g, 0.40 mmol), DBU (0.61 mL, 4.00 mmol), TEA (0.56 mL, 4.00 mmol), 2-methyl-3-butyn-2-ol (0.48 mL, 5.70 mmol), (Ph3P)4Pd (0.08 g, 0.08 mmol) and dioxane (35 mL). After purging the mixture with nitrogen for 10 min., the vessel was sealed and heated at 80° C. for 2.5 h. After allowing the reaction to cool to ambient temperature, sat NH4Cl was added and the reaction was extracted with EtOAc. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue subjected to flash chromatography (MeOH/CH2Cl2, silica gel). The Boc-protected product was dissolved in 25% TFA/CH2Cl2 (10 mL). After 30 min., the solvent was removed under reduced pressure. The residue was partitioned between 1N NaOH and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate. The solvent was removed under reduced pressure. Flash chromatography (MeOH/CH2Cl2, silica gel) gave 0.22 g (37% yield) of the desired compound. MS (ES+) m/z 444 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.O.C(O)(=O)C.N([O-])=O.[Na+].[BrH:21]>[Cu](Br)Br>[Br:21][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1]
Reactant: Br
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-fluoro-5-nitroaniline (25.90 g), 47% aqueous hydrogen bromide (100 ml), water (200 ml) and acetic acid (200 ml) was added dropwise an aqueous sodium nitrite (11.56 g) solution (100 ml), and the mixture was stirred at 0° C. for 1 h. This mixture was added at 0° C. to a solution of copper bromide (CuBr: 27.30 g) dissolved in 47% aqueous hydrogen bromide (100 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent: hexane). Crystallization from hexane gave the title compound (4.01 g) as colorless needle crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.[C:12]1(C=O)C2C=CC=CC=2C=1.[F-].[K+]>C(Cl)Cl>[OH:7][CH:5]1[C:4]2=[CH:9][CH:10]=[CH:11][CH:2]=[C:3]2[CH2:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=CC1=Cc2ccccc21
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: OC1Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Chloroperoxybenzoic acid (0.66 g) was added to a solution of benzocyclobutene aldehyde (0.2 g) in methylene chloride (10 mL) at 0° C. The mixture was stirred for 30 minutes at 0° C. and then warmed to room temperature. Stirring was continued for 12 hours at room temperature. Potassium floride (0.3 g) was added and stirring continued for an additional two hours. The reaction mixture was filtered, washed with sodium bisulfite solution and the solvent was removed by flash column chromatography. Liquid chromatographic analysis found a yield to hydroxy benzocyclobutene of approximately 55 percent and no benzocyclobutene carboxylic acid, with the balance comprising unidentified materials characterized as undesired product.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][C:15]1[C:24]([CH2:25][P:26]([O:30]C)([O:28]C)=[O:27])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[C:20]([Cl:32])[CH:21]=2)[N:16]=1)[C:10]([O:12]C)=[O:11])=O)(C)(C)C>Cl>[NH2:8][C@H:9]([CH2:14][C:15]1[C:24]([CH2:25][P:26]([OH:30])([OH:28])=[O:27])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[C:20]([Cl:32])[CH:21]=2)[N:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@@H](Cc1nc2cc(Cl)c(Cl)cc2cc1CP(=O)(OC)OC)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@H](Cc1nc2cc(Cl)c(Cl)cc2cc1CP(=O)(O)O)C(=O)O
Yield: 58 %

Procedure:
Methyl (R)-α-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate (0.26 g, 0.5 mmol) was refluxed in 6M HCl (20 ml) for 4 h. The solvent was removed in vacuo and the residue was coevaporated 3 times with acetonitrile. The resulting powder was treated with water and chloroform, filtered off and finally recrystallized from methanol to give 0.11 g of (R)-α-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinolinepropanoic acid. 1H NMR (D2O, 400 MHz): δ 3.15 (d,2H), 3.56 (dd,1H), 3.64 (dd,1H), 4.41 (m,1H), 7.91 (s,1H), 8.00 (s,1H), 8.02 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]([CH:21]=[C:22]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:24]([NH2:25])[CH2:23]1)[CH:18]([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]([CH:21]=[C:22]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:24]([NH:25][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:23]1)[CH:18]([CH3:20])[CH3:19])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC1=CC=C(N)CC1=CN(C(=O)OC(C)(C)C)C(C)C
Reactant: Fc1cnc(Cl)nc1Cl
Product: COC1=CC=C(Nc2nc(Cl)ncc2F)CC1=CN(C(=O)OC(C)(C)C)C(C)C

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxy-aniline were reacted to produce N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine R940320. 1H NMR (DMSO-d6): δ 10.01 (1H, s), 8.34 (1H, d, J=3.6 Hz), 7.52 (2H, m), 7.08 (1H, d, J=8.7 Hz), 4.33 (3H, m), 3.90 (3H, s), 1.50-1.30 (9H, m), 1.18 (6H, d, J=6.9 Hz); purity 95%.
Reaction SMILES: CN(C)CCN.[CH2:7]([O:9][N:10]1C(=O)C2=CC=CC=C2C1=O)[CH3:8].C(O)(=O)C.[C:25]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH2:26][CH2:27][CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:25](=[N:10][O:9][CH2:7][CH3:8])[CH2:26][CH2:27][CH3:28])[CH:35]=1
Reactant: CCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CCCC(=NOCC)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 22 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-ethoxyphthalimide (287 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-butyryl-4-chlorophenyl)trifluoromethanesulfonamide 29A (330 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1), the solvent evaporated under reduced pressure and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-[4-chloro-2-(1-ethoxyiminobutyl)phenyl]trifluoromethanesulfonamide 193 (82 mg, 22%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 12.10, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.47, d, J=2.4 Hz, 1H; 7.32, dd, J=2.4 and 8.8 Hz, 1H; 4.27, q, J=7.2 Hz, 2H; 2.78, m, 2H; 1.59, sextet, 2H; 1.37, t, J=7.2 Hz, 3H; 1.02, t, J=7.6 Hz, 3H. HRMS (M+) 372.0514.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c(OC)c1
Yield: 73.6 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2,4-dimethoxyphenyl)benzamide (203.4 mg, 0.40 mmol) and acetic anhydride (0.046 ml, 0.49 mmol), the procedure of Inventive Example 94 was repeated to obtain 161.2 mg (73.6%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:2]([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: CN1CCC(C(Cl)c2ccc(Cl)cc2)CC1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CCC(C(c2ccc(Cl)cc2)N2CCNCC2)CC1
Yield: 62 %

Procedure:
A mixture of 4-(chloro(4-chlorophenyl)methyl)-1-methylpiperidine (1.2 g, 4.66 mmol) in butanone (10 ml), anhydrous piperazine (1.58 g, 18.45 mmol), anhydrous K2CO3 (0.63 g, 4.61 mmol) and KI (0.76 g, 4.61 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2:CH3OH:NH4OH 90:10:0.5) afforded desired product in 62% yield.
Reaction SMILES: CC(C)=O.N[C:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]([NH:21][CH3:22])=[O:20].Cl>O>[CH3:22][N:21]1[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[C:19]1=[O:20]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C=C(N)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cn1c(-c2ccccc2)cc2onc(-c3ccccc3)c2c1=O
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, there is added 54 liters of acetone to 5.4 kilograms (16.9 mole) of 5-(2-amino-2-phenylethenyl)-N-methyl-3-phenyl-isoxazole-4-carboxamide at room temperature. To the resulting suspension, there is added 10.8 liters of approximately 5N hydrochloric acid while maintaining the temperature below 25° C. The mixture is then stirred overnight at 25° to 28° C. The resulting suspension is diluted with 16 liters of water at room temperature, and after mixing for 15 minutes, the solids are then filtered off and washed three times with a mixture of acetone/water (2:1). The resulting solids are then dried under reduced pressure at 45° C. to obtain 3.86 kilograms of 5-methyl-3,6-diphenyl-isoxazolo[4,5-c]pyridine-4(5H)-one; m.p. 145° to 148° C. The mother liquor is then concentrated under reduced pressure maintaining the temperature below 50° C. The mother liquor is then cooled to 20° C., the solids filtered off and washed three times with acetone/water (2:1) to obtain a second crop of 290 grams of 5-methyl-3,6-diphenyl-isoxazolo[4,5-c]pyridine-4(5H)-one; m.p. 140° to 145° C.; Yield 81%.