Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:16][C:15]=2[F:34])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:16][C:15]=2[F:34])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: NN
Solvent: C1COCCO1
Product: CSc1nc(NN)c(C(N)=O)c(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 16E (380 mg, 0.74 mmol) in 1,4-dioxane (10 mL) was added hydrazine (185 mg, 3.68 mmol) and the mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated and the residue was recrystallized from ethanol to give the title compound. MS: 495 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[F:27])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3F)c(F)ccc2c1N
Yield: 35 %

Procedure:
Using method B, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.40 mmol) and (2,5-difluorophenyl)boronic acid (519.0 mg, 3.29 mmol) were reacted to afford the title compound (50.5 mg, 35% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bs, 1H), 7.96 (d×d, J=5.3 Hz, J=9.3 Hz, 1H), 7.55 (t, J=9.1 Hz, 1H), 7.13-7.23 (m, 3H), 3.45 (apparent q, J=6.9 Hz, J=13.1 Hz, 2H), 1.65 (apparent sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=361 (M+H) HPLC 2.98 min.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CO>[Pd](Cl)Cl.C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[C:19]([C:20]#[N:21])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h

Procedure:
2M Sodium carbonate solution (200 ml) was added to a stirred mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5° C. The temperature rose to approximately 20° C. and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110°-120° C.) to give 4'-methylbiphenyl-2-carbonitrile which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][C:11]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[N:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Ic1ccccc1
Reactant: Cc1ccc(Nc2ccc(C)cc2C)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2C)c(C)c1
Temperature: 120 °C
Yield: 98.6 %

Procedure:
A mixture of bis(2,4-dimethylphenyl)amine (Compound 14) (9.4 g, 41.8 mmol), iodobenzene (17.14 g, 84 mmol), Pd(OAc)2 (0.47 g, 2.1 mmol), P(t-Bu)3 (0.848 g, 4.2 mmol), sodium tert-butoxide (7.68 g, 80 mmol) in toluene (120 mL) was degassed and heated at 120° C. for 16 hours. The resulting mixture was poured into ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silicagel and purified by flash column using eluent of hexanes. After removal of solvent, an oil (Compound 15) was obtained (12.4 g, in 98.6% yield).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25](O)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CCN=C=NCCCN(C)C.Cl>C1COCC1>[CH2:25]([CH:2]([CH2:1][CH2:7][CH2:8][CH3:9])[C:3]([OH:4])=[O:16])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: CCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) was dissolved in the solution. When the catalyst was fully dissolved, EDC HCl (18.32 g, 95.6 mmol) was added into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]([CH3:13])=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:5][C:6]1[C:7]([CH3:13])=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([NH2:12])=[N:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(N)ncc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(Br)cnc(N)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Nitric acid (0.7 ml) was added dropwise to a solution of 5-bromo-4-methylpyridine-2-amine (2.0 g) in concentrated sulfuric acid (8.7 ml) at 55° C. over 30 minutes, and the mixture was stirred at the same temperature for 3 hours. After further stirring at room temperature for 2 hours, the reaction solution was poured into ice water. A 50% aqueous sodium hydroxide solution was added, and the resulting precipitate was collected by filtration, washed with distilled water and then dried under reduced pressure to give the title compound (2.5 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][O:23][CH3:24])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25](O)=[O:26].[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][O:23][CH3:24])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25]([NH2:28])=[O:26]
Reactant: On1nnc2ccccc21
Reactant: COCN(c1cccc2cc(C(=O)O)n(COC)c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: COCN(c1cccc2cc(C(N)=O)n(COC)c12)S(=O)(=O)c1cccs1
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
To a mixture of 1-(methoxymethyl)-7-[(methoxymethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (3.83 g), 1H-1,2,3-benzotriazol-1-ol (1.51 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.15 g) at room temperature, and the mixture was stirred for 20 min and 28% aqueous ammonia (3.4 mL) was added. The reaction mixture was stirred at room temperature for 3 hr, and water was added. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (3.67 g, yield 96%) as colorless crystals. melting point 203-204° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.O>O1CCCC1>[Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of methyl 2-chloro-3-(1-cyano-1-methylethyl)benzoate (1.67 g, 7.02 mmol) in tetrahydrofuran (24 mL)/methanol (8 mL)/water (8 mL) was added lithium hydroxide•monohydrate (501 mg, 11.9 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 6N hydrochloric acid (2.8 mL) was added dropwise to the residue. The precipitate was collected by filtration, and washed with water to give the title compound (1.43 g, 91%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:12][CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[C:5]([N:4]=2)=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:15][CH:16]=1)=[O:19]
Reactant: Cn1c(CO)nc2cccnc21
Reactant: O=Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Yield: 45.2 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 500 mg of 3-methylimidazo-[5,4-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 374 mg of 4-hydroxybenzaldehyde, 0.76 ml of tributylphosphine, 773 mg of 1,1'-(azodicarbonyl)dipiperidine and 12 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.37 g of the title compound, melting at 124-125° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=1[C:42]([O:44]CC)=[CH2:43].Cl>O1CCOCC1>[C:42]([C:9]1[C:10]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=1[NH2:7])(=[O:44])[CH3:43]
Reactant: C=C(OCC)c1c(CN(C(=O)OC(C)(C)C)C2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1c(CN(C(=O)OC(C)(C)C)C2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 60 °C

Procedure:
A mixture of tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(tetrahydro-2H-pyran-4-yl)carbamate (Int-8f, 35 mg), 4N HCl in dioxane (0.3 mL) and dioxane (2 mL) was heated at 60° C. for 10 min. Concentration afforded crude tert-butyl (6-acetyl-7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(tetrahydro-2H-pyran-4-yl)carbamate (Int-8g), which was then heated under microwave conditions with N2H4.H2O (200 uL) and NMP (1.5 mL) first at 100° C. for 30 min and then at 200° C. for 1h. Purification with prep-LC provided N-((3-methyl-6-(quinolin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-amine (26),
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2]>[Pd].CO.O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
A mixture of 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.20 g) and 10% palladium on carbon (0.25 g) in methanol (15 ml) and 1,4-dioxane (15 ml) was stirred under hydrogen (3 atm) at room temperature for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-aminopyridine (1.10 g).
Reaction SMILES: [CH:1]([P:3](=[O:6])([OH:5])[OH:4])=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10]>>[CH2:8]([NH:7][CH2:1][P:3]([OH:4])([OH:5])=[O:6])[C:9]([OH:11])=[O:10]
Reactant: O=CP(=O)(O)O
Reactant: NCC(=O)O
Product: O=C(O)CNCP(=O)(O)O
Yield: 90 %

Procedure:
Reaction of formylphosphonic acid and glycine was carried out under the conditions described in Example 6 except that the pH was adjusted to 10.0 before commencement of the reduction reaction. Analysis indicated a 90.0% yield of glyphosate salts.
Reaction SMILES: S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[CH2:42]([O:49][C:50](=[O:66])[CH2:51]N=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Br[CH2:68][C:69]1[CH:81]=[CH:80][C:72]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])=[CH:71][CH:70]=1>ClCCl.CCOCC>[CH2:42]([O:49][C:50](=[O:66])[CH2:51][CH2:68][C:69]1[CH:70]=[CH:71][C:72]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])=[CH:80][CH:81]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
Tetrabutyl ammonium sulfate (3.0 g, 9 mmol) was added to a biphasic mixture consisting of 10% aqueous sodium hydroxide (75 mL), 2-[(diphenylmethylene)amino]acetic acid benzyl ester (3.05 g, 9.3 mmol) and 1,1-dimethylethyl 4-bromomethylbenzoate (3.0 g, 9 mmol) in dichloromethane (58 mL). After several hours of vigorous stirring at room temperature, the reaction mixture was diluted with ether (300 mL) and the layers were separated. The organic layer was washed with water (3×30 mL), dried (K2CO3) and filtered. Concentration provided an oil that was purified by HPLC on silica gel (the columns were pre-treated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate to give rac.-2-](diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester, (1.7 g, 3 mmol) in 36% yield.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]1[CH2:20][CH2:19][CH2:18][C@@:14]1([CH3:21])[C:15]([OH:17])=[O:16])=O)(C)(C)C.C(N(CC)CC)C>ClCCCl>[CH3:21][C@@:14]1([C:15]([OH:17])=[O:16])[CH2:18][CH2:19][CH2:20][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CS(=O)(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@@]1(C(=O)O)CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid (252 mg, 2.6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)-2-methylproline (500 mg, 2.2 mmol) and 1,2-dichloroethane (2.53 g), and the mixture was stirred at 25° C. for 3 hours. When triethylamine (265 mg, 2.6 mmol) was added thereto, a solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes and further stirred at 25° C. for 2 hours. Thereafter, the solid was then separated by filtration under reduced pressure. The solid was washed with 1,2-dichloroethane (0.2 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (197 mg, yield of 69%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[CH2:33][OH:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH2:33][OH:34])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: OC[C@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 55.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.6 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([CH2:16][NH2:17])[CH2:11]2)=[CH:6][CH:5]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH:35]([CH3:37])[CH3:36])[CH2:31][C:32](O)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]([CH:35]([CH3:37])[CH3:36])[CH2:31][C:32]([NH:17][CH2:16][CH:12]2[O:13][CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:18])[F:19])=[CH:9][CH:8]=3)[CH2:11]2)=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: CC(C)N(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CC(=O)NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
(4-(4-(Trifluoromethyl)phenyl)morpholin-2-yl)methylamine hydrochloride (99 mg, 0.34 mmol), 2-[(4-fluoro-benzenesulfonyl)-isopropyl-amino]-acetic acid (96 mg, 0.35 mmol), BOP reagent (154 mg, 0.35 mmol) and TEA (0.2 mL) were combined in 5 mL of dichloromethane. The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was washed with sodium bicarbonate solution and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (11 g silica gel, ethyl acetate in hexanes 0% to 50%) to give the desired compound as a white solid (133 mg, 74%). [MH]+=517.9.
Reaction SMILES: COC(=O)C[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7].C[O-].[Na+].CO.IC[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CS(C)=O.O>[CH2:46]([O:45][C:43](=[O:44])[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])[CH3:47]
Reactant: COC(=O)CCS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: CCOC(=O)CI
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 0.25 h

Procedure:
A solution of 3-[4-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (200 mg, 0.4 mmol) in DMSO (5 mL) was treated a 15% solution of sodium methoxide in methanol (150 μL, 0.42 mmol). After 15 minutes, the mixture was cooled (water bath) and ethyl iodoacetate (50 μL, 0.42 mmol) was added followed by removal of the water bath. After 18 hours, the mixture was diluted with EtOAc (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-6% methanol in dichloromethane. The material from the column was twice triturated with ether, filtered and dried under vacuum to afford the title compound as a tan solid.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N([O-])=O.[Na+].[I-:18].[K+].II>O.S(=O)(=O)(O)O>[I:18][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: [I-]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(I)c(Cl)cc1C(=O)O
Yield: 59.6 %

Procedure:
A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid (12.25 g , 60.8 mmol) in water (136 mL ) and concentrated sulfuric acid (34 mL) was cooled to 0° C. in a flask fitted with an overhead stirrer. A solution of sodium nitrite (4.62 g , 66.9 mmol) in water (26 mL) was added dropwise while keeping the internal temperature around 0° C. Potassium iodide (11.11 g , 66.9 mmol) and iodine (4.246 g , 33.5 mmol) were dissolved in water (130 mL) and added dropwise to the stirred reaction mixture. After 2 hours the reaction was extracted with ethyl acetate. The organic extracts were then washed with 10% sodium thiosulfate and brine, then dried over magnesium sulfate, filtered and evaporated to dryness to yield 11.32 g of the title compound, m.p. 150–151° C. This material was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:11][C:12](=[O:42])[C:13]([NH:38][C:39](=[O:41])[CH3:40])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:21]=1)[C:14]([O:16]CC)=[O:15])[CH3:10].Cl>C(OCC)(=O)C>[CH2:9]([O:11][C:12](=[O:42])[C:13]([NH:38][C:39](=[O:41])[CH3:40])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:21]=1)[C:14]([OH:16])=[O:15])[CH3:10]
Reactant: CCOC(=O)C(Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1)(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1)(NC(C)=O)C(=O)O
Reaction time: 8 h

Procedure:
Sodium hydroxide, 1N, (20.5 mL, 20.5 mmol, 1.10 equivalents) was added to a dioxane solution of 2-acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (8.99 g, 18.6 mmol, 1.0 equivalents) at room temperature over 30 minutes and the reaction was stirred overnight. The reaction was diluted with ethyl acetate (200 mL) and acidified to pH=1-1.5 with 1 N hydrochloric acid. The organic portion was washed with brine (200 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give 8.589 of a 1:1 mixture (by 1H NMR) of 2-Acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonic acid monoethyl ester [MS (Cl) m/z 356.3 (M-99)] and the decarboxylated title compound [MS (CI) m/z 412.3 (M+1), 312.2 (M-99), 410.3(M−1)].