Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CNC(=O)OCc1ccccc1)C(=O)OCC
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a suspension of diethyl 2-aminomalonate hydrochloride (10.6 g) in tetrahydrofuran are added N-(benzyloxycarbonyl)glycine (10.5 g) and triethylamine (5.1 g). The mixture is cooled to 0° to 5° C., and thereto is added N,N'-dicyclohexylcarbodiimide (10.8 g). The mixture is stirred at the same temperature for 2 hours and then allowed to stand at room temperature overnight. Insoluble substance is filtered off from the reaction mixture. The filtrate is distilled to remove the solvent, and to the residue is added ethyl acetate, and the insoluble substance is filtered off. The filtrate is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate-isopropyl ether to give diethyl 2-[[N-(benzyloxycarbonyl)glycyl]amino]malonate (16.0 g), m.p. 94.5°-95.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1c[nH]cn1
Product: O=C(Cc1c[nH]cn1)N1CCN(c2ccc(OC(F)F)c(OC3CCC3)c2)C[C@@H]1Cc1ccccc1

Procedure:
Prepared by the method outlined for Example 189 using (1H-imidazol-4-yl)-acetic acid and (S)-3-benzyl-1-(3-cyclobutoxy-4-difluoromethoxy-phenyl)-piperazine (Example 4, Compound 92) as starting materials. Product as an oil. LC/MS (Method B) 2.54 min, [M+1]+ 497. Potency class A.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(CCN(N=C(c2ccccc2)c2ccccc2)c2ccc(C)cc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 4-methylphenethylbromide (278 mg, 1.4 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 404 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH:10][C:11](=[O:22])[CH:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:13])[CH:7]=[N:8][CH:9]=1)=O.[OH-].[NH4+:24]>>[CH2:15]([O:14][CH:12]([CH3:13])[C:11]([NH:10][N:6]1[C:5]([C:3]([NH2:24])=[O:2])=[CH:9][N:8]=[CH:7]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cncn1NC(=O)C(C)OCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(OCc1ccccc1)C(=O)Nn1cncc1C(N)=O
Temperature: 60 °C
Yield: 100 %

Procedure:
Compound 9 (8.2 g, 27 mmol) and ammonium hydroxide (100 mL) were mixed and heated to 60° C. for two hours. The reaction mixture was concentrated in vacuo to give compound 10 (7.8 g, 100% yield) as white solid. LC-MS: m/z 289 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc3ccccc3cn2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(CC2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
2.21 g of 3-benzylisoquinoline and 2.88 g of nickel dichloride.hexahydrate were dissolved in 50 mL of methanol at room temperature, and 4.58 g of sodium borohydride was added thereto over 30 minutes, followed by further stirring at room temperature for 4 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=100:1→50:1) to obtain 1.85 g (yield 82%) of a title compound as a light yellow oily substance.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9]C2CCCCO2)[CH:6]=1.[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36](B5OC(C)(C)C(C)(C)O5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>>[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36]([C:2]5[N:3]=[CH:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(B3OC(C)(C)C(C)(C)O3)ccc1-2
Reactant: Brc1cn(CCOC2CCCCO2)cn1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn(CCO)cn3)ccc1-2

Procedure:
Following the procedure for 258, 4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazole was reacted with 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene to give 486. MS (ESI+) 423.1. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 8.11 (s, 1H), 7.73 (d, J=1.0, 1H), 7.68 (d, J=0.9, 1H), 7.58 (dd, J=8.3, 1.7, 1H), 7.44 (d, J=1.7, 1H), 5.95-5.74 (m, 1H), 5.00 (t, J=5.2, 1H), 4.39 (t, J=5.0, 2H), 4.03 (t, J=5.4, 2H), 3.70 (q, J=5.3, 2H), 3.44 (t, J=5.0, 2H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH2:41][CH3:42])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 1-bromobutane (0.322 mL) as starting materials, 5-benzyloxy-N-[(1-butylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-butylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.41 g) was obtained. MS (ESI) m/z: 447 [MH]+
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=3)[CH2:5][CH2:4]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 1 l capacity three-necked flask were added 4-{trans-4'-(hydroxymethyl)cyclohexyl}benzonitrile (75.6 g, 0.35 mol) and pyridine (150 ml), followed by cooling these down to 0° C., dropwise adding a pyridine solution (150 ml) of p-toluenesulfonyl chloride (70.3 g, 0.37 mol) over one hour, agitating these at room temperature for 2 hours, allowing them to stand overnight, adding water (500 ml), extracting with toluene, three times washing with water (300 ml), drying over magnesium sulfate, removing magnesium sulfate, concentrating the residue, passing it through a silica gel column using a chloroform solution, distilling off chloroform, recrystallizing from a mixed solvent of n-heptane with ethyl acetate and drying to obtain white crystals (103.5 g). The NMR spectra of this product accorded with those of the captioned compound and its M.P. was 108.1°-110.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:24][C:23]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=3[F:21])[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of Intermediate 2 (500 mg, 1.82 mmol) in N,N-dimethylformamide (2 mL) was added 2,4-difluorobenzyl bromide (0.23 mL, 1.82 mmol), potassium carbonate (376 mg, 2.73 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (260 mg, 36% yield). MS (M+H): 401
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)=[O:7]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: COCCC(=O)O
Product: COCCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 3-methoxypropionic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (11% yield). 1H NMR (300 MHz, CDCl3) δ 9.44, 8.31, 7.74, 7.63, 7.55, 7.36, 7.02, 4.02-3.98, 3.94-3.89, 3.73, 3.70-3.61, 3.57-3.54, 3.43, 3.33-3.31, 2.73. MS (ES+) m/z 438.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:8])C.Cl.[NH2:19]O>CO>[CH3:1][O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:8][N:19]=1)=[O:17]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(Cl)c2)on1
Yield: 71.3 %

Procedure:
A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in MeOH (60 ml) was heated at 80° C. for 4 h. After cooling, the mixture was filtered and washed with cold methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (2.0 g, 71%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). Step 2: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw cap vial equipped with stir bar was mixed methyl magnesium iodide (3M in Et2O) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran (0.39 ml, 4.77 mmol) and TEA (1 ml, 7.15 mmol). After cooling to 0° C. a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (300 mg, 1.19 mmol) in toluene (5 ml) was added, followed by stirring at 0° C. for 5 h. The mixture was then quenched with aq 1N HCl (6.5 ml, 6.5 mmol), diluted with toluene (35 ml), sequentially washed with water, sat. aq. sodium bicarbonate,water and brine. The organic phase was concentrated in-vacuo. The isolated residue was dissolved in MeOH (8 ml) and 20% aq. KOH (1 ml) was added, followed by stirring at 45° C. for 30 min and then concentrated in-vacuo. The residue was dissolved in toluene (60 ml), sequentially washed with water, sat. aq. sodium bicarbonate and water. The organic phase was concentrated in-vacuo. The crude residue was purified on silica gel using 2% EA in hex. to isolate the desired compound (156 mg, 60%). 1H-NMR: 7.77 (m, 1H), 7.66 (m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 3: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial equipped with stir bar was mixed 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol), sodium borohydride (34 mg, 0.90 mmol) and MeOH (3 ml), followed by stirring at r.t for 3 h and the quenched with water and brine, extracted with DCM. The combined organic phase was dried (Na2SO4), filtered and concentrated in-vacuo to isolate the title compound. 1H-NMR: 7.69 (m, 1H), 7.59 (m, 1H), 7.37 (m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (br. s, 1H), 1.58 (d, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:13]([N:17]1[CH:21]=[N:20][N:19]=[C:18]1[C:22]1[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=O)[CH:14]([CH3:16])[CH3:15].C[O-].[Li+]>CN(C)C=O>[CH2:13]([N:17]1[CH:21]=[N:20][N:19]=[C:18]1[C:22]1[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26](/[CH:27]=[CH:2]/[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH:29]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: COc1cc(OC)c(-c2nncn2CC(C)C)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2nncn2CC(C)C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-acetyl-benzoic acid (0.12 g, 0.75 mmol) and 5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.24 g, 0.83 mmol) in N,N-dimethylformamide (6 mL) was added lithium methoxide (1.0M in methanol, 3.0 mL, 3.0 mmol). The solution was allowed to stir overnight and additional lithium methoxide (0.11 g, 2.8 mmol). The reaction was quenched with water after 20 hours. The aqueous solution was washed ethyl acetate, acidified to pH 4. The precipitate was filtered, washed with ethanol and dried in vacuo to afford the title compound as a light yellow solid: m.p.>240° C. (dec.). 1H NMR (DMSO-d6) δ 8.59 (s, 1H), 8.18 (d, J=7.9 Hz, 2H), 8.07 (s, 1H), 8.04–8.01 (m, 3H), 7.85 (d, J=15.7 Hz, 1H), 6.84 (s, 1H), 4.06 (s, 3H), 3.92 (s, 3H), 3.66 (d, J=7.2 Hz, 2H), 1.87–1.74 (m, 1H), 0.72 (d, J=6.7 Hz, 6H). MS m/z=436 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([C:10](=O)[CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].S.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:10]1[S:33][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:12][C:11]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(CC(=O)C(CC(=O)c2ccc(Cl)cc2)Cc2ccc(OC)cc2)cc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COc1ccc(Cc2cc(-c3ccc(Cl)cc3)sc2Cc2ccc(OC)cc2)cc1
Yield: 153.3 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 54.5 g (0.133 mole) of 1,2-di-p-anisyl-4-p-chlorophenylbutane-1,4-dione, 100 ml of xylene and 30 g (0.0675 mole) of phosphorus pentasulfide. The autoclave was cooled with a Dry Ice-acetone bath and 130 g (3.81 moles) of hydrogen sulfide was distilled into the autoclave. The vessel was stirred and heated for three hours at 162°-168° C. (1220-1290 psig). After cooling to room temperature the hydrogen sulfide was vented into an aqueous sodium hydroxide solution. Treatment with 150 ml of absolute ethanol to remove unreacted phosphorus pentasulfide gave 77 g of crude product. Recrystallization from 400 ml of absolute ethanol gave 45 g (83.1%) of pure 2,3-di-p-anisyl-5-p-chlorophenylthiophene, m.p. 125°-128° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][CH2:31][NH:32]C(OC(C)(C)C)=O)=[CH:25][CH:24]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH:8]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][CH2:31][NH2:32])=[CH:27][CH:28]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reaction time: 3 h
Yield: 105.7 %

Procedure:
Trifluoroacetic acid (0.25 ml) was added to a solution of 4-anilino-5-bromo-2-{4-[3-(t-butoxycarbonylamino)-1-propynyl]anilino}pyrimidine (Method 25; 30 mg, 0.06 mmol) in DCM (1 ml). The solution was left to stand for 3 hours and volatile material was removed by evaporation. The residue was triturated with diethyl ether to give the product as a trifluoroacetate salt (25 mg, 81%). NMR: 4.0 (m, 2H), 7.2 (m, 2H), 7.4 (m, 2H), 7.5-7.7 (m, 4H), 7.8 (m, 1H), 8.2 (br s, 2H), 8.7 (s, 1H), 9.6 (s, 1H); MS (MH+): 394.3, 396.3.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:12][CH2:13]3)[CH:18]=1)=[O:25])[CH2:31][CH2:30]2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(F)ccc21

Procedure:
100 mg (0.294 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 42 mg (0.31 mmol) 5-fluoro-2,3-dihydro-1H-indole, 100 mg (0.311 mmol) TBTU and 45 μL (0.320 mmol) triethylamine in 10 mL DMF were stirred overnight at RT. The reaction mixture was evaporated down using the rotary evaporator. The residue was dissolved in 3 mL DMF and purified by preparative HPLC-MS. The product fractions were combined and lyophilised.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][P:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:20])[C:16]=1OCC)(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]>>[CH2:2]([O:4][P:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:20])[C:16]=1[NH2:1])(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]
Reactant: CCOc1c(NC/C=C/CP(=O)(OCC)OCC)c(=O)c1=O
Reactant: N
Product: CCOP(=O)(C/C=C/CNc1c(N)c(=O)c1=O)OCC
Reaction time: 72 h
Yield: 68 %

Procedure:
Ethanolic ammonia (235 mL) was combined with [(E)-4[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester (7.15 g, 21.6 mmol) and the solution was left stirring for 3 days and then evaporated. Recrystallization from methanol in ethyl acetate removed a yellow impurity, but flash chromatography (7.5 cm diameter, elution with 5% methanol in dichloromethane) was required to eliminate a more polar contaminant. Recrystallization of this material with methanol in ethyl acetate (final volume=200 mL) afforded [(E)-4-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester as a flocculant white solid (4.43 g, 68%, mp 145°-147° C.); IR (KBr, cm-1): 3280, 3100, 1800, 1640; MS (+FAB): 303 (MH+, 100), 135 (62); 1H NMR (DMSO, 400 MHz): δ 7.5 (br s, 3NH), 5.74-5.68 (m, 1H), 5.57-5.48 (m, 1H), 4.09 (br s, 2H), 4.02-3.91 (m, 4H), 2.64 (d of d, J=21.5 and 7 Hz, 2H), 1.19 (t, J=7 Hz, 6H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1([CH2:19][OH:20])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([OH:18])[CH2:12][NH:11]1>CO.O>[C:1]([NH:8][CH2:9][C:10]1([CH2:19][OH:20])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([OH:18])[CH2:12][NH:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1(CO)NCC(O)C(O)C1O
Solvent: O
Solvent: CO
Product: CC(=O)NCC1(CO)NCC(O)C(O)C1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5.1 ml of acetic anhydride are added to a solution of 6.5 g of crude 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxy-piperidine in 65 ml of methanol/water (1:1) at 0° C. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 18 hours. The solution is concentrated in vacuo, the residue is dissolved in a little water and, to remove the acetic acid formed, the solution is filtered through an anion exchanger in the OH⃝ form and the column is washed with water. The filtrate is concentrated, the residue is dissolved in a little water and the solution is discharged onto a cellulose column 120 cm long and 3 cm wide which contains butanol as the mobile phase. The column is eluted with butanol, 95% pure butanol and 90% pure butanol and the individual fractions are investigated by thin layer chromatography to determine their content of the required compound. The fractions containing the desired product are collected and concentrated. The residue is dissolved in hot methanol and the solution is filtered and concentrated down to a volume of 30 ml. The product crystallises out. The crystallisation is brought to completion by leaving the mixture to stand overnight. The product is filtered off and washed with methanol. 2.7 g of colourless crystals of melting point 196° C. (decomposition) are obtained.