Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>O1CCCC1>[N+:11]([C:10]1[C:9]([CH3:14])=[CH:8][C:4]([C:5]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[O:7])=[CH:3][C:2]=1[CH3:1])([O-:13])=[O:12]
Reactant: CC(C)(O)CN
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCC(C)(C)O)cc(C)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 88 %

Procedure:
3,5-Dimethyl-4-nitrobenzoic acid (1 g, 5.12 mmol) is suspended in dry tetrahydrofuran (10 mL) and 1,1′-carbonyldiimidazole (0.91 g, 5.64 mmol) is added. The mixture is stirred for 3 hours then 1-amino-2-methyl-propan-2-ol (patent WO2010/84767, 1 g, 11.22 mmol) is added and the mixture stirred for 30 minutes. The solvent is removed, the residue suspended in EtOAc and washed with 0.2 M aqueous HCl solution, saturated sodium bicarbonate solution and brine, dried and the solvent removed under vacuum to give the title compound (Yield 1.2 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+].[CH3:34][NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>ClCCl.C(N(CC)CC)C.CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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>[CH3:34][NH:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CNc1cccc(B(O)O)c1
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: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
1.0 g (5.5 mmol, 1.0 eq) of methyl 3-(4-hydroxyphenyl)propanoate is dissolved in 8 mL of dichloromethane in the presence of 1 ml of triethylamine. 1.12 mL (6.6 mmol, 1.2 eq) of triflic anhydride are added at 0° C. The reaction mixture is stirred for 1 hour at 0° C. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then filtered on silica gel (1/1 heptane/ethyl acetate). After evaporating off the solvents, the oil obtained is dissolved in 6 mL of an 8/2 mixture of dimethylformamide and of 2M potassium phosphate solution. 1.0 g (6.6 mmol, 1.2 eq) of N-methyl-3-aminophenylboronic acid are added, along with 317 mg of tetrakis(triphenylphosphine)palladium. The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 0.92 g of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate is obtained. Yield=61%
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][C:30]([CH3:45])([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]2=[O:27])=[O:13])[N:10]=1)=O.[Na+:46].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][C:30]([CH3:45])([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]2=[O:27])=[O:13])[N:10]=1.[Na+:46]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(NC(=O)CCl)n2)C(=O)N1S(=O)(=O)[O-]
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]

Procedure:
In 30 ml of water is dissolved 1.158 g of sodium cis-3-{2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer), and under ice-cooling and stirring, 241 mg of sodium monomethyldithiocarbamate is added. The mixture is stirred at room temperature for one hour, after which a further 241 mg of sodium monomethyldithiocarbamate is added. The mixture is further stirred for one hour. The reaction mixture is then washed with ether and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) is a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH:27]2[CH2:29][CH:24]1[CH2:25][CH2:26]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][CH:23]3[CH2:28][CH:27]4[CH2:29][CH:24]3[CH2:25][CH2:26]4)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: NC1CC2CCC1C2
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)NC1CC2CCC1C2
Yield: 71 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-aminonorbornane (21 μL, 0.18 mmol) as the coupling partner. Concentration (no chromatography) yielded 38 mg (71%) of the titled compound. ESI-MS m/z 385 (MH+), 383 (M−H−).
Reaction SMILES: [NH2:1][C:2]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5].Cl>O1CCOCC1>[N:12]1([C:10]2[N:11]=[C:6]([C:4]([C:3]3[C:2]([NH2:1])=[N:29][CH:28]=[C:27]([Br:30])[CH:26]=3)=[O:5])[CH:7]=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(=O)c3cc(Br)cnc3N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCNCC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a suspension of tert-butyl 4-(6-(2-amino-5-bromonicotinoyl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (0.050 g, 0.10 mmol) in 1,4-dioxane (2 ml) was added 4 M HCl in 1,4-dioxane (1 ml) and the resulting mixture was stirred at room temperature for 5 hours. Reaction mixture was then concentrated to dryness in vacuo and the crude product purified by prep-LCMS, then freeze-dried to leave title compound as a yellow solid (13.5 mg, 36%). 1H NMR (DMSO-d6 1.84-1.76 (2H, m), 2.08 (1H, s), 2.71-2.68 (1H, m), 2.89-2.86 (1H, m), 3.72-3.28 (6H, masked signal), 6.89 (10.5H, d), 6.95 (0.5H, d), 7.05 (0.5H, d), 7.10 (0.5H, d), 7.74-7.68 (1H, m), 7.81 (2H, br s), 8.31 (1H, d), 8.54 (1H, d). ES+ 378.15.
Reaction SMILES: [CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](=[O:31])[CH:17]=[C:16]1[CH2:32][N:33]1C(=O)C2C(=CC=CC=2)C1=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(Cl)(Cl)Cl.CO>[NH2:33][CH2:32][C:16]1[N:15]([O:14][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:18](=[O:31])[CH:17]=1
Reactant: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN3C(=O)c4ccccc4C3=O)cc2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-((1-(benzhydryloxy)-5-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl)isoindoline-1,3-dione (Intermediate 292, 1.66 g, 2.90 mmol) in chloroform (20 mL) and methanol (10 mL) at room temperature was added hydrazine monohydrate (0.284 mL, 5.80 mmol). The reaction mixture was stirred overnight at room temperature. Another 1 eq of hydrazine monohydrate was added. After 3 hours still see starting material. Added another 1 eq of hydrazine monohydrate. After 2 hours the reaction mixture was filtered to remove solids. The filtrate was concentrated. The residue was triturated with MeOH and ether and the solids filtered off. This was repeated twice more. The resulting solid was triturated once with chloroform and MeOH and the solids removed by filtration. The filtrate was concentrated to afford a yellow foam (1.01 g, 79%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[N:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:23]=1[C:24]#[N:25].[I:32]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[Cl:21][C:22]1[N:29]=[C:28]([Cl:30])[C:27]([F:31])=[C:26]([I:32])[C:23]=1[C:24]#[N:25]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1c(Cl)nc(Cl)c(F)c1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of diisopropylamine (15.9 g, 157 mmol) in THF (400 ml) at −78° C. was added n-butyllithium (2.5 M hexanes, 154 mmol), and the solution was stirred at −78° C. for 30 minutes. The lithium diisopropylamide solution was then added slowly dropwise to a −78° C. solution of 2,6-dichloro-5-fluoronicotinonitrile (10.0 g, 52.3 mmol) and iodine (26.5 g, 104 mmol) in THF (175 ml). Upon completion of the addition, the reaction was allowed to warm slowly to room temperature, and stirred at room temperature for 12 hours. An aqueous 10% Na2S2O3 solution (500 ml) was added and the reaction was extracted with EtOAc (3×300 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated to give the title compound (14.5 g, 87%) as a brown solid that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27]C(=O)OC(C)(C)C)=[N:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[CH3:19])#[N:2]>C(O)(C(F)(F)F)=O>[NH2:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][N:14]3[CH3:19])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)cnc3C#N)cccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
The crude tert-butyl (1S,2R)-2-(5-cyano-6-(1-methyl-1H-indol-4-ylamino)pyrazin-2-ylamino)cyclohexylcarbamate (153 mg) was dissolved in TFA (4 mL). After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2S)-2-aminocyclohexylamino)-3-(1-methyl-1H-indol-4-ylamino)pyrazine-2-carbonitrile (18 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][N:6]([C@@H:8]2[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:9]2[O:10][C:11](=[O:13])[CH3:12])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=1)CCC.[F-].[K+]>O1CCCC1.C(OCC)(=O)C.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>[CH2:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:2][C:3]2[N:4]=[N:5][N:6]([C@@H:8]3[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:9]3[O:10][C:11](=[O:13])[CH3:12])[CH:7]=2)=[CH:37][CH:38]=1)[CH3:43]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(CBr)nn2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
A solution of 4-(bromomethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,2,3-triazole 32 (500 mg) (See Federico G. H. et al., J. Med. Chem. (1979) 29, 496), tri-n-butyl(4-ethylphenyl)tin 33 (604 mg) and tetrakis(triphenylphosphine)palladium (0) (59 mg) in tetrahydrofuran (10 ml) was stirred under heating at 70° C. for 12 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then, an aqueous potassium fluoride solution was added thereto and the mixture was stirred at room temperature for one hour. Insoluble materials were filtered off, and the filtrate was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-50:50) to give 4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,2,3-triazole 34 (90 mg) as a colorless solid. APCI-Mass m/Z 518 (M+H). (2) From the above tetraacetate compound 34, the desired 4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)1,2,3-triazole 35 was prepared in a manner similar to Example 106-(3) as a colorless solid.
Reaction SMILES: [O-]CC.[Cu+2:4].[O-]CC.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10]>O1CCCC1>[C:8]([O-:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[Cu+2:4].[C:8]([O-:13])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)O
Agent: [Cu+2]
Agent: CC[O-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.50 Grams (0.009 mol) of copper (II) ethoxide was introduced into a 50 ml. round bottom flask having a magnetic spinning bar, in an argon atmosphere in a dry box. A solution of 1.84 g (0.02 mol) of methacrylic acid, prepared in 20 ml of anhydrous tetrahydrofuran was then added to it. The contents of the flask were agitated overnight (20 hr) by means of a magnetic stirrer at ambient temperature under argon. All volatile matter was then removed in vacuo (about 0.1 mm Hg) for 12 hours. The resulting solid was analyzed for its metal content.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7](=[O:18])[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:4]=2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[CH:29]2.ClC1N=CC2N(C3C=CC=CC=3)C(=O)[C@@H](C)N(C3CCCCC3)C=2N=1.C1(N)CCCC1>>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:2]3[N:11]=[CH:10][C:9]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:7](=[O:18])[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:4]=4[N:3]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Cl)nc21
Reactant: Nc1ccc2[nH]ncc2c1
Agent: C[C@@H]1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1C1CCCCC1
Agent: NC1CCCC1
Product: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Nc3ccc4[nH]ncc4c3)nc21

Procedure:
This compound was prepared from 2-chloro-8-(3-methylbutyl)-5-phenyl-5,8-dihydropteridine-6,7-dione and 5-aminoindazole, according to procedures similar to the preparation of example 18 from (7R)-2-chloro-8-cyclohexyl-7-methyl-5-phenyl-7,8-dihydropteridin-6(5H)-one. Examples 306 and 307 was prepared according to procedures similar for the preparation of Example 305, using corresponding starting materials and intermediates. For example, for synthesis of example 307, cyclopentanamine was used in the step a of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:38]=[C:37]([CH3:39])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH3:36])[CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:38]=[C:37]([CH3:39])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([N:28]([CH3:36])[CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)(=[O:26])=[O:27])=[CH:23][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)N(C)CCN5CCCC5)cc4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N(C)CCN4CCCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.297 mmol, 1.0 equiv) was dissolved in 10 mL anhydrous DCM and placed under an argon atmosphere. 4 mL of BBr3 (0.1 M) was added via syringe and the reaction was stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHCO3 until pH=7. The mixture was filtered and washed with water and Et2O to give 4-[7-(2-chloro-5-hydroxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a dark green solid (120.5 mg, 74% yield). Rf=0.61 1H NMR (DMSO-d6): δ 1.90(m, 2H), 2.01 (m, 2H), 2.72 (s, 6H), 3.06 (m, 2H), 3.30 (t, J=5.6 Hz, 2H), 3.38 (t, J=6.0 Hz, 2H), 3.59 (m, 2H), 6.89 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.96 (d, J=2.9 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.9 Hz, 2H), 7.92 (d, J=0.9 Hz, 1H), 8.21 (d, J=1.7 Hz, 1H), 8.30 (d, J=9.0 Hz, H), 11.50 (s, 1H). MS (ES+) m/z=553 LC retention time 2.41 min. Elemental for C27H30Cl2N6O3S 5H2O Calculated: C, 47.72; H, 5.93; N, 11.37. Found: C, 46.59; H, 5.67; N, 11.42.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[NH:17][N:16]=[CH:15]3)=[CH:6][CH:5]=1)([OH:3])=O.S(Cl)(Cl)=O.CN(C=O)C.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH-:37]>C1(C)C=CC=CC=1.C1COCC1>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH:37][C:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[NH:17][N:16]=[CH:15]3)=[CH:6][CH:5]=1)=[O:3]
Reactant: CN(C)CCC[NH-]
Reactant: O=C(O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)CCCNC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Temperature: 42 °C
Reaction time: 8 h

Procedure:
Trans-6-(2-(4-Carboxyphenyl)ethenyl]-1(2H)-phthalazinone (46 g), thionyl chloride (315 ml) and DMF (2 ml) were mixed and heated slowly to 42° C. and maintained at 42°-48° C. until the gas evolution subsided. The reaction mixture was diluted with toluene and filtered to give the crude acid chloride (52 g). The crude acid chloride (25 g) was dissolved in THF (1250 ml) and 3-dimethylaminopropylamide (250 ml) was added dropwise. After stirring overnight at room temperature the precipitate was filtered, washed with ether (2 l) and then dried to give the amide (13.5 g). The amide was purified via the hydrochloride salt, mp 287° C.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:25]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:22]=[CH:23][CH:24]=3)[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)cccc1C1CCNCC1
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (548 mg, 1.643 mmol), 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (544 mg, 1.725 mmol) and Pd(Ph3P)4 (190 mg, 0.164 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (1.000 mL) was added tripotassium phosphate (1395 mg, 6.57 mmol), The solution was sealed and irritated in Biotage MW at 120° C. for 20 min. The mixture was directly dried with silica gel and purified by column chromatography to afford 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]piperidine (D122) (169 mg). MS (ES): C24H28ClN3OS requires 441.2. found 442.2 (M+H+).
Reaction SMILES: Cl[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CC(Cl)c2cc(C#N)ccc2O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-chloro-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran(3g) and sodium azide (0.9g) in N,N-dimethylformamide (20 ml) was stirred for 3 days at room temperature. Water was added and the mixture extracted with ethyl acetate, the organic phase was separated and further washed with water, then dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent in vacuo gave the title compound (3.03g) as a solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]([O:20]C)=[O:19])=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:1]1([C:7]2[C:8]([C:18]([OH:20])=[O:19])=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1noc(-c2ccccc2)c1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a thick suspension of methyl 4,5-diphenylisoxazole-3-carboxylate (306 mg, 1.09 mmol) in MeOH (8 mL), THF (2 mL) and water (2 mL) at rt was added LiOH, hydrate (46.0 mg, 1.09 mmol) and the reaction mixture was allowed to stir at rt for 1 hr. During this time, the reaction became homogeneous. The MeOH and THF were removed in vacuo and the remaining aqueous mixture was acidified to pH ˜1 with 1N HCl. The mixture was then extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford 4,5-diphenylisoxazole-3-carboxylic acid (290 mg, 1.09 mmol, 100% yield) as a yellow solid. HPLC retention time=1.72 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.