Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:11]=[N-:12])=[CH:6][CH:5]=1.[NH:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH2:27][CH2:28][NH2:29].C(=O)(O)[O-].[Na+].S(=O)(=O)(O)[O-].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([NH:29][CH2:28][CH2:27][CH2:26][C@H:25]([NH:24][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([OH:32])=[O:31])=[O:23])=[CH:9][CH:8]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 89 %

Procedure:
4-Azidobenzyl (4-nitrophenyl) carbonate synthesized by the method described in the literature (Bioconjugate Chem. 2008, 19, 714.) (Compound tk32) (521 mg, 1.658 mmol) was added to a suspension of Boc-Orn-OH (Compound tk56) (321 mg, 1.382 mmol) and sodium bicarbonate (290 mg, 3.45 mmol) in 1,4-dioxane (3 mL)-water (2 mL). The reaction mixture was stirred at room temperature for 23 hours and then cooled in an ice bath and diluted with ethyl acetate and water, and a saturated aqueous potassium bisulfate solution (2 mL) was added to the resulting mixture. The mixture was extracted with ethyl acetate (×2), and the organic phase was washed with water (10 mL×2) and brine (10 mL) and dried over sodium sulfate. Following concentration under reduced pressure, the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford ((S)-5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk57) (501.3 mg, 89%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH2:8][CH:7]=1.B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:8][CH:7]=1
Reactant: COc1ccc(CCC2CC=C(CCC=C(C)C)CC2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)=CCCC1=CCC(CCc2ccc(O)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of anisole 2F (R=4-Methyl-3-pentenyl) (6 g) in dichloromethane (100 mL) and cooled in an ice bath is added a 1M solution of boron tribromide (3.4 mL). The solution is stirred for one hour, then poured into water. The reaction mixture is extracted with dichloromethane and dried over magnesium sulfate. The solution is concentrated in vacuo. The product is recrystallized from hexane.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:17]1[NH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:19][C:18]=1[C:29]1[CH:30]=[C:31]([O:36][CH3:37])[C:32]([NH2:35])=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[NH:21][C:17]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[C:18]([C:29]3[CH:30]=[C:31]([O:36][CH3:37])[C:32]([NH2:35])=[N:33][CH:34]=3)[N:19]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cc(-c2nc(-c3ccc(F)cc3)[nH]c2Br)cnc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2nc(-c3ccc(F)cc3)[nH]c2C2CCOCC2)cnc1N
Temperature: 90 °C

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53 mg, 0.25 mmol), 5-(5-bromo-2-(4-fluorophenyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine (123 mg, 0.25 mmol; prepared similarly as per Example 2, Steps 2-3), and aqueous 2.0 M Na2CO3 solution (0.5 mL, 1.0 mmol) in DME (3 mL) was sparged with Ar for 5 min. A catalytic amount of Pd(PPh3)4 was added and the mixture was purged with Ar again. Then the reaction was heated to and maintained at 90° C. for 16 h. The reaction mixture was allowed cool to rt and partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was dissolved in dry MeOH (5 mL) and treated with Pd/C (10% w/w, 5.7 mg, 0.005 mmol). The reaction mixture was placed and maintained under a H2 atmosphere for 2 d. The reaction was then filtered through Celite, the filter cake was washed thoroughly with EtOAc. The combined filtrate was concentrated and the resulting residue was purified by flash chromatography (SiO2, 50:50-0:100 hexanes-EtOAc). The isolated material was treated with 3 N HCl at 60° C. for 1 h. The reaction was allowed to cool to rt and was directly purified on reverse phase HPLC, as after freeze drying, provided 6.0 mg of 5-(2-(4-fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine as the TFA salt: LCMS (m/z): 369.0 (MH+), tR=0.44 min
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Br:9])[C:3]=1[Br:10].[Cl:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].C1([O-])C=CC=CC=1>[OH-].[Na+].COCCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][Cl:11])=[C:4]([Br:9])[C:3]=1[Br:10]
Reactant: Oc1ccc(Br)c(Br)c1Br
Reactant: O=C(Cl)c1ccccc1CCl
Agent: [Na+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: COCCO
Product: O=C(Oc1ccc(Br)c(Br)c1Br)c1ccccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
In a two-liter three-necked flask, 40 g of sodium hydroxide was dissolved in 950 ml of methyl glycol at 60° C, and then 331 g (= 1 mole) of tribromophenol was stirred in, and then 189 g (= 1 mole) of o-chloromethyl benzoyl chloride was added, drop by drop, with stirring, over a period of 13/4 hours, at a reaction mixture temperature not exceeding 40° C, into the clear phenolate solution, cooled to 30° to 40° C. Stirring was then continued for one hour at room temperature; the mixture was then cooled to 0° C, the crystallizate was suction filtered and washed free of sodium chloride with water, and dried at 80° C in a vacuum drying chamber. 397 g (= 82% yield) was obtained of o-chloromethylbenzoic acid tribromophenyl ester melting at 180°-110° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][C:5]=2[O:4][N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[N:6]=[C:7]1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2onc(C)c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A suspension of 3-methyl-6-propyl-5H-isoxazolo[5,4-d]pyrimidin-4-one (method 17) (1.698 g, 8.8 mmol), benzylbromide (1.5 g, 8.8 mmol), potassium carbonate (2.43 g, 17.6 mmol) in 10 ml DMF was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc (50 ml×3), the combined organic phases were dried, concentrated, purified by flash column chromatography (elute: hexane-EtOAc=5:1). 1.69 g (68%) of the title compound was obtained as white solid. 1H NMR (DMSO-d6): 0.80 (t, 3H), 1.61 (m, 2H), 2.43 (s, 3H), 2.73 (t, 2H), 5.35 (s, 2H), 7.12-7.35 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]=[CH2:13])[CH:6]=2.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[CH2:23]([O:22][C:20]([NH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]=[CH2:13])[CH:6]=2)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=Cc1ccc2cc(N)c(C(=O)O)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A vial containing the crude 3-amino-7-vinylquinoline-2-carboxylic acid (0.75 g, 3.5 mmol), water (60 mL) and NaOH (7.0 g, 180 mmol) was cooled to −10° C. Benzyl chloroformate (5.0 mL, 33 mmol) was added slowly to the mixture. The mixture was allowed to warm to room temperature and stirred for 1 h. The organic solvent was then removed under reduced pressure. The remaining aqueous layer was neutralized with aq. HCl. The yellow precipitate formed was collected by vacuum filtration, and washed with cold MeOH to give the sub-title compound (1.12 g, 92%) as light yellow powder. LCMS calc. for C20H17N2O4 (M+H)+: m/z=349.1. Found: 349.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(c3cc(N)ccn3)CC2)cc1
Yield: 92.5 %

Procedure:
A solution of N-[4-([1-(4-nitro-2-pyridyl)piperidin-4-yl]methoxy)phenyl]methanesulphonamide (see Preparation 5) (140 mg) in ethanol (50 ml) was hydrogenated at room temperature and 3.5 bar in the presence of 5% palladium on carbon until the required amount of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was evaporated to give the product (120 mg), m.p. 213°-214° (from ethyl acetate/methanol).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:9])=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][C:2]1([C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:4][CH2:5][N:1]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)=CCBr
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CC=C(C)C)CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-tert-Butyl 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (2.29 g, 0.00999 mol) was dissolved in anhydrous THF (30 mL) and the solution was cooled to −78° C. prior to the drop-wise addition of 1.0 M of lithium hexamethyldisilazide in THF (16 mL) over 15 min. After stirring for 1 h, 1-bromo-3-methylbut-2-ene (1.6 mL, 0.014 mol) was added and the resultant solution was stirred for 5 hours at −78° C. The reaction was quenched by the drop-wise addition of saturated NH4Cl (15 mL). After gradually warming to room temperature (RT), the reaction mixture was diluted with EtOAc (100 mL) and water (10 mL). The organic layer was washed with water (15 mL) and the combined aqueous phases were extracted with EtOAc several times. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford the desired product, which was used in the subsequent step without further purification. LC-MS: 198.2 (M−Boc+2H)+ and 320.2 (M+Na)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][NH2:26])=[O:24])[N:22]=1>C(O)(=O)C>[Cl:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][N:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:24])[N:22]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1csc(COc2ccccc2Cl)n1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1csc(COc2ccccc2Cl)n1
Temperature: 100 °C
Yield: 79 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[(2-chlorophenoxy)methyl]-1,3-thiazole-4-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 47 mg of the title compound (79%) as a orange powder in 98.2% purity by HPLC (Rt: 5.07, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH3:33])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=O)[C:24]([CH2:29][O:30][CH3:31])([CH3:28])[CH2:25][O:26][CH3:27])([OH:15])[CH2:6][CH2:5]2>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]([CH2:25][O:26][CH3:27])([CH3:28])[CH2:29][O:30][CH3:31])[CH3:33])([OH:15])[CH2:6][CH2:5]2
Reactant: COCC(C)(COC)C(=O)NCCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Solvent: C1CCOC1
Product: COCC(C)(CNCCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C)COC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69.1 %

Procedure:
To a solution of 4.09 g of N-(3-{[2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide in anh. THF (70 mL) was added dropwise at 0° C. for 15 min a 1M solution of borane-THF complex in THF (87 mL). The mixture was stirred for 25 min at rt then for 1.5 h at 65° C. It was cooled down to 0° C., quenched with 1M-NaOH and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude as borane complex was dissolved in MeOH (60 mL) and treated with ethylene diamine (2.37 mL) under microwave conditions (120° C. for 180 s). The mixture was concentrated in vacuo and the resulting residue was taken up in DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The oily crude was purified by CC using EtOAc/MeOH/NEt3 from 95/5/1 to 60/40/1 as eluant to yield 2.74 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-{[3-(3-methoxy-2-methoxymethyl-2-methyl-propylamino)-propyl]-methyl-amino}-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol as yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:46]([O:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C2C(=NC=CC=2)C=C1>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:59][CH2:58][C:57]1[CH:60]=[CH:61][C:54]([O:53][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:55][CH:56]=1)=[O:6]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCc2ccc(OCc3ccccc3)cc2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
2,6-Diamino-nicotinic acid described in Preparation Example A-15 (0.6 g, 3.92 mmol), triethylamine (1.64 mL, 11.8 mmol) and benzotriazole-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (2.6 g, 5.9 mmol) were dissolved in N,N-dimethylformamide (200 mL), 4-benzyloxy-benzylamine described in Preparation Example 1 (1.25 g, 5.9 mmol) was added thereto, and the solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1, then ethyl acetate), the resulting solid was washed with solvent (chloroform:ethyl acetate=2:1), and the title compound (0.37 g, 1.1 mmol, 27%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([NH:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2nnc(Nc3ccncc3)nc21
Reaction time: 144 h
Yield: 30.2 %

Procedure:
A homogenious mixture of 1.8 g (5.0 mmol) of 7-(3,5-dimethoxy-phenyl)-5-ethyl-3-methylsulfanyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one and 3.3 g (35.2 mmol) of 4-aminopyridine was heated at 150° C. for 2 days in a sealed reaction vessel, during which time the sublimed 4-aminopyrdine was reintroduced to the reaction mixture. At the end of 2 days, the sublimed 4-aminopyridine was removed, and the remaining mixture was triturated under 1:9 methanol/chloroform at room temperature and filtered. The solid was suspended in 60 mL of hot chloroform while methanol was added to produce a near homogeneous solution that was filtered and set aside for 6 days. The crystals were collected, washed with chloroform, and dried under house vacuum to give 610 mg (30%) of the title compound as yellow platelets. Mp=316-318° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=O.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>CN(C=O)C.N1CCCCC1.C(O)(=O)C>[CH2:18]([O:17][C:15]([C:14]1[C:12](=[NH:13])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=2)=[O:16])[CH3:19]
Reactant: O=Cc1cc(O)c(O)cc1O
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(O)c(O)cc2oc1=N
Reaction time: 2 h

Procedure:
To a solution of 2,4,5-trihydroxybenzaldehyde (2.94 g) and ethyl cyanoacetate (1.62 g) in DMF (20 ml) were added 20 drops (Pasteur pipette) of piperidine and eight drops of acetic acid and the solution kept at 80° C. under nitrogen for two hours. The product was filtered and washed with DMF and ethyl ether. Yield: 2.00 g.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25]([Cl:27])=[N:24][CH:23]=[N:22][C:21]=3[N:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.O>ClCCl>[Cl:27][C:25]1[C:26]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[CH:17][CH:16]=3)=[CH:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: CC(C)n1cc(-c2ccc(N)cc2)c2c(Cl)ncnc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)n1cc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzenesulphonyl chloride (0.27 g) in dichloromethane (5 ml) was added dropwise with stirring to a solution of 5-(4-aminophenyl)-4-chloro-7-isopropylpyrrolo[2,3-d]pyrimidine (0.40 g) and triethylamine (155 mg) in dichloromethane (15 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for one hour and then warmed to ambient temperature and stirred at this temperature for 18 hours. Water (20 ml) was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with sodium bicarbonate, dried, filtered and evaporated to give N-[4-(4-chloro-7-isopropylpyrrolo[2,3-d]pyrimidin-5-yl)phenyl]benzenesulphonamide
Reaction SMILES: C([O:3][C:4](=[O:37])[C@:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[S:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[O:28][C:29]=2[CH3:30])=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>CO>[CH3:30][C:29]1[O:28][C:27]([C:31]2[S:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[N:26][C:25]=1[CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C@@:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:37])=[O:3])=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@](CC)(Cc1ccc(OCCc2nc(-c3ccc(C)s3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@](Cc1ccc(OCCc2nc(-c3ccc(C)s3)oc2C)cc1)(Oc1ccccc1)C(=O)O
Temperature: 55 °C
Reaction time: 18 h

Procedure:
(S)-2-(4-{2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyric acid ethyl ester (201 mg, 0.40 mmol) in MeOH (8 mL) was treated with 2N NaOH (8 mL) and warmed to 55° C. After 18 h, the mixture was concentrated under reduced pressure and then acidified with 5N HCl to pH=1. The solution was extracted with EtOAc and then the organic phases dried (MgSO4), filtered and concentrated to a white foam (158 mg, 81%) that was dried in a vacuum oven at 50° C. for 24 h: 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=3.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.83 (d, J=7.6 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 6.71 (dd, J=3.6, 0.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.18 (A of Abq, J=13.6 Hz, 1H), 3.00 (B of Abq, J=13.6 Hz, 1H), 2.90 (t, J=6.8 Hz, 2H), 2.49 (s, 3H), 2.31 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[CH3:8])[CH:2]=1.[Cl:10][C:11]1[N:19]=[C:18]([N:20]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[N:17]=[C:16]2[C:12]=1[NH:13][C:14](=[O:31])[NH:15]2>>[Cl:10][C:11]1[N:19]=[C:18]([N:20]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[N:17]=[C:16]2[C:12]=1[NH:13][C:14](=[O:31])[N:15]2[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8]
Reactant: N#Cc1ccc2ncn(-c3nc(Cl)c4[nH]c(=O)[nH]c4n3)c2c1
Reactant: CC(O)c1cccnc1
Product: CC(c1cccnc1)n1c(=O)[nH]c2c(Cl)nc(-n3cnc4ccc(C#N)cc43)nc21
Yield: 26 %

Procedure:
Yellow oil (26% yield based on 73% conversion). Synthesized using 1-pyridin-3-yl-ethanol and 3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.27 (s, 1H), 9.20-9.00 (br m, 1H), 8.86 (d, 1H), 8.88-8.77 (m, 1H, overlapping with 8.86 ppm), 8.68 (s, 1H), 8.13 (br s, 1H), 7.87 (d, 1H), 7.68 (d, 1H), 6.17 (q, J=7.1 Hz, 1H), 2.19 (d, J=7.3 Hz, 3H); MS (EI) m/z 417.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](N)=[O:20])=[CH:14][CH:13]=1)=[O:11].S(=O)(=O)(O)[OH:23].N([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:20])=[O:23])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
10.7 g of 4-(2,3-dichlorophenylcarbamoyl)phenylacetamide was dispersed in 100 ml of acetic acid, and 17.5 ml of sulfuric acid was added. Then, a solution obtained by dissolving 3.2 g of sodium nitrite in 17.5 ml of water, was dropwise added to bring the reaction temperature to a level of 20° C. ±5° C. Thereafter, the mixture was stirred at room temperature for two hours, and then poured into 400 ml of ice water. The resulting crystals are collected by filtration, thoroughly washed with water and then dried to obtain 9.8 g of desired 4(2,3-dichlorophenylcarbamoyl)phenyl acetic acid. The yield was 91.3%, and the melting point of this compound was from 184° to 185.5° C.