Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]2=[O:31])=[N:22][CH:23]=1>CN(C=O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25](=[O:31])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][O:1][C:2]3[CH:9]=[C:8]([CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)[CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:23][N:22]=2)[CH:29]=1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1O
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1OCc1ccc(-n2cc(Cl)ccc2=O)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxy 4-imidazol-1-ylmethyl-benzonitrile (0.050 g, 0.25 mmol) and 5'-bromomethyl-5-chloro-[1,2']bipyridinyl-2-one (Example 10 Step 2) (0.079 g, 0.262 mmol) were dissolved in dry DMF (5 mL), treated with CsCO3 (0.123 g, 0.376 mmol) and stirred at ambient temperature for 18 hr. The reaction mixture was partitioned between EtOAc and aqueous satd NaHCO3 solution, the organic layer washed with H2O, brine, and dried (MgSO4). Chromatography (SiO2, 1-4% CH3OH in CH2Cl2) gave the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([CH2:11][CH2:12][OH:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[C:14]1([C:4]2[N:3]3[N:20]=[N:21][N:22]=[C:2]3[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]=2[CH2:11][CH2:12][OH:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reaction time: 5 h

Procedure:
To a solution containing 27.4 g of 5-chloro-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine-8-ethanol (0.1 mole) dissolved in 250 ml of dimethylsulfoxide is added 13 g of sodium azide (0.2 mole). The resulting reaction mixture is stirred for 5 hours at a temperature of 65°-70° C. and then stirred overnight at room temperature. The reaction mixture is poured in water with stirring. A precipitate forms and the mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is recrystallized from diethyl ether to yield 5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine-6-ethanol having the structural formula ##STR22## and the azido tautomer thereof as a white solid having a melting point of 110° C. and the following elemental analysis:
Reaction SMILES: [CH:1]1([CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]2C)[CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[CH2:31](N(CC)CC)C>CC#N>[CH:1]1([CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=2)[N:5]2[CH2:6][CH2:7][N:8]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([CH3:31])[CH2:10]2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CNCCN1C(c1cccc(C(F)(F)F)c1)C1CC1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: C[C@@H]1CN(C(c2cccc(C(F)(F)F)c2)C2CC2)CCN1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude (2R)-1-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazine (3.15 g, 105.6 mmol) in 25 mL of MeCN was added tert-butyl bromoacetate (2.046 ml, 12.67 mmol), followed by slow addition of triethylamine (2.203 ml, 15.837 mmol). The reaction mixture was stirred at rt overnight. The solution was evaporated to dryness and the residue was submitted to flash chromatography (SiO2, hexane to hexane/EtOAc=100:5 to 100:10 to 100:30) to give tert-butyl 2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetate as a colorless oil.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]2=[CH:5][C:4]=1[C:14]#[N:15].[CH3:16][OH:17]>>[C:14]([C:4]1[CH:5]=[C:6]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]2=[N:8][C:3]=1[O:17][CH3:16])#[N:15]
Reactant: CO
Reactant: N#Cc1cc2c(nc1Cl)CCCCC2
Agent: [Na]
Product: COc1nc2c(cc1C#N)CCCCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
In an atmosphere of argon, metallic sodium (230.0 mg, 0.01 g atom) was dissolved in methanol (10.0 ml) at room temperature, a methanol solution (10.0 ml) of 2-chloro-3-cyano-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (1.03 g, 5.00 mmol) was added dropwise thereto at the same temperature and then the resulting mixture was stirred at 60° C. for 6 hours. After cooling, methanol was evaporated under reduced pressure, the thus obtained residue was mixed with water and extracted with chloroform, and the resulting organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (methylene chloride:hexane=2:1) to obtain the title compound (933.8 mg, 92.5%) as white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[CH:39]1([NH:45][C:16]2[C:17]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=3[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCCCC1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Yield: 54.7 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol) was dissolved in DMF (2 mL). Cyclohexanamine (44.7 mg, 0.45 mmol) was added and the reaction mixture was heated at 85° C. overnight. The reaction mixture was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was purified by flash chromatography using dichloromethane and methanol as eluent yielding tert-butyl 4-(cyclohexylamino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (124 mg, 54.6%). MS (ES+) m/z 504.4 (M+H)+
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1C=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC1C=CC=C(CC([O-])=[O:25])C=1CC([O-])=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Reactant: c1ccc(COCc2ccccc2)cc1
Solvent: ClCCl
Product: O=CCCCCCOCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of alcohol (22, 6-(benzyloxy)hexan-1-01) dissolved in dry DCM, Tempo free radical (0.1 equiv), iodobenzenediacetate (1.1 equiv) were added and stirred at 25° C. On completion of the reaction (by checking TLC), it was quenched with dilute solution of Na2S2O3. The organic layer was extracted in DCM, washed with brine, dried over anhydrous Na2SO4. The solvent was removed in vacuum concentrated and subjected for chromatographic separation. The eluent was allowed to come in a solution of pet ether:EtOAC=95:5 as a colorless liquid. 1H NMR (CDCl3, 200 MHz): δ 9.8 (s, 1H), 7.2-7.4 (m, 5H), 4.5 (s, 2H), 3.5 (t, 2H), 2.4 (t, 2H), 1.6 (m, 4H), 1.4 (m, 4H); 13C NMR (CDCl3, 50 MHz): δ 202.75, 138.50, 128.40, 127.68, 127.50, 72.95, 70.03, 43.86, 29.53, 25.85, 21.91.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH:8]1([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.O1CCNC1=O.[Li]CCCC.[C:38]1([CH2:44][C@H:45]2[CH2:49][O:48][C:47](=[O:50])[NH:46]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH:8]1([CH2:14][CH2:15][CH2:16][C:17]([N:46]2[C@@H:45]([CH2:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:49][O:48][C:47]2=[O:50])=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of pivaloyl chloride (3.57 g, 2.96 mmol) in THF (25 ml) was added to a cold (-78° C.) solution of 4-cyclohexylbutyric acid (5.042 g, 29.62 mmol) and triethyl amine (3.60 g, 35.6 mmol) in THF (100 mL). The resultant white suspension was stirred for 10 min. at -78° C. and then warmed to 0° C. and kept there for 30 min. The reaction mixture was recooled to -78° C. and a cold (-78° C.) metallated oxazolidinone solution in THF (125 ml) [prepared by the addition of n-BuLi (17.65 ml. of 1.65M solution in hexane, 28.2 mmol) to a -78° C. solution of (S)-4-(phenylmethyl)-2-oxazolidinone in THF (125 ml)] was added via a cannula under the positive pressure of argon. The reaction mixture was then warmed to 0° C. and kept there for another 30 min. The reaction was quenched by the addition of saturated NH4Cl (75 ml). The volatiles were removed on rotavapor at reduced pressure and the residue was extracted with CH2Cl2 (3×200 ml). The combined organic phases were washed with 1N NaOH (150 ml) and dried (Na2SO4). The organic layer was concentrated and the residue was purified by flash silica gel chromatography, eluting with hexane:ethyl acetate (3:1) to yield 8.066 g (85%) of (S)-3-(4-cyclohexyl-1-oxobutyl)-4-(phenylmethyl)-2-oxazolidinone: Rf 0.34 (3:1 hexane:ethyl acetate), m.p. 69°-70° C. [α]D25 +47.3° (c 0.97 CHCl3).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=[CH:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>C(O)CC(C)C>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=[CH:23][C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:30][CH2:31]1)=[O:25]
Reactant: O=C(C=Cc1ccco1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccco4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 479 mg. (2 mM) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 412 mg. (2 mM) of 3-(furan-2-yl)-acryloylpiperazine in 10 ml. of isoamyl alcohol was heated under reflux for 4 hours. After ice-cooling, the crystalline substance thus separated was recovered by filtration and washed with ethanol to afford 685 mg. of the desired product as the hydrochloride.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Cl[C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>O1CCCC1.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH3:3]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (5.00 g, 35.8 mmol) in tetrahydrofuran (300 mL) were added triethylamine (9.99 mL, 71.6 mmol) and methyl 4-chloro-4-oxobutyrate (5.39 g, 35.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (5.05 g, yield 65%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])C(OCC)=O)[CH3:2].[Li+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 74.3 %

Procedure:
2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester (10.3 g, 32.6 mmol) in DMSO (200 mL) containing LiCl (2.9 g, 68.4 mmol) and water (0.6 mL, 33.3 mmol) was set stirring and heated to 100° C. After 5 h the mixture was cooled to room temperature and added to water (750 mL). The product was extracted with two portions of EtOAc. The organics were combined, washed with water, dried (MgSO4) and evaporated to give 5.9 g (75%) of a clear yellow oil. TLC (silica, 25% EtOAc/hexanes): Rf=0.50. 1H NMR (400 MHz, CDCl3): 8.21 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.3 Hz, 2H), 7.47 (d, J=2.3 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.12 (s, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][OH:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)C[C@H]2C[C@H]21
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an ice-cooled solution of (1R,3S,5R)-3-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.480 g, 2.15 mmol) in pyridine (5 mL) was added 4-toluenesulfonyl chloride (0.490 g, 2.58 mmol). The reaction mixture was stirred at RT for 6 h and then diluted with Et2O. The organic phase was washed with 1N HCl (3×), aqueous NaHCO3 (3×) and NaCl, then dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 4:1) to afford the title compound as a colorless wax. TLC, Rf (c-hexane/EtOAc 4:1)=0.2. MS (LC-MS): 390.0 [M+Na]+, 757.0 [2M+H]+. tR (HPLC conditions k): 4.07 min.
Reaction SMILES: [C:1]1([C:7]([CH:9]([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:10]([O-:12])=[O:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](O)(=O)[CH3:19].CCOC(C)=O>C1(C)C=CC=CC=1.N1CCCCC1>[O:17]=[C:15]1[CH2:14][CH2:13][CH:9]([C:10]([O:12][CH2:18][CH3:19])=[O:11])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16]1
Reactant: CC(=O)CCC(C(=O)[O-])C(=O)c1ccccc1
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(=O)C=C1c1ccccc1
Temperature: 25 °C
Yield: 758.3 %

Procedure:
A mixture of 2-(phenylcarbonyl)-5-oxohexanoate(3.87 g, 14.8 mmol), acetic acid(130 mg, 2.17 mmol) and piperidine(127 mg, 1.49 mmol) in toluene(5 ml) was refluxed for 5 hr. After cooling down to room temperature, AcOEt was added to the reaction mixture and washed with dil. HCI, water and brine and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 4.02 g of ethyl 4-oxo-2-phenylcyclohex-2-enecarboxylate(y=94.7%) as a brown oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.50(2H, dd, J=3.0 and 6.4 Hz), 7.40-7.48(3H), 6.47(1H, s), 4.11(2H, q, J=7.0 Hz), 3.96(1H, dd, J=3.7 and 3.7 Hz), 2.60-2.70(1H, m), 2.35-2.55(3H), 1.12(3H, t, J=7.0 Hz).
Reaction SMILES: [O:1]1[CH2:12][CH:2]1[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][CH:2]([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7]
Reactant: CCOP(=O)(CC1CO1)OCC
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(CC(O)Cn1cncn1)OCC
Yield: 38 %

Procedure:
A mixture of diethyl 2,3-epoxypropylphosphonate (14.55 g), 1,2,4-triazole (5.18 g), potassium carbonate (10.35 g) and methyl ethyl ketone (220 ml) was heated under reflux for four hours. The supernatant liquid was decanted from a sticky residue and evaporated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (using a Waters LC 500 apparatus, silica as solid phase, and ethanol: ether in the proportion of 1:2 by volume as the liquid phase) to give diethyl 2-hydroxy-3(1,2,4-triazol-1-yl)propylphosphonate (7.5 g) as a pale yellow viscous oil. The identity of the product was confirmed by examination of its infra-red; mass; and proton, P31 and C13 nuclear magnetic resonance spectra, which were all consistent with the structure assigned.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][N:40]1[C:44]([Sn](CCCC)(CCCC)CCCC)=[CH:43][N:42]=[CH:41]1>CN(C=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>[CH3:39][N:40]1[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:27][CH2:26]4)[CH:20]=[N:19][CH:18]=2)=[CH:43][N:42]=[CH:41]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cncc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 183.9 %

Procedure:
A solution of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (147 mg, 0.251 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (Synthonix, Inc., Wake Forest, N.C.; 0.099 mL, 0.327 mmol), and Pd(PPh3)4 (14.53 mg, 0.013 mmol) in DMF (2.0 mL) was heated under argon at 100° C. for 2.5 h. The reaction was cooled to RT, concentrated onto silica gel, and chromatographically purified (ISCO, 12 g silica gel column, 0-10% MeOH/DCM, 20 min, 254 nm) to provide crude (4R)-tert-butyl 4-(6-(5-(1-methyl-1H-imidazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (270.3 mg; contaminated with PPh3 and DMF) as a yellow-orange foam: MS (ESI, pos. ion) m/z: 586.2 (M+1). This material was used without further purification in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ccc(Cl)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(Cl)cn1
Temperature: 25 °C
Yield: 0.8 %

Procedure:
A solution of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-chloropyridin-2-yl)but-3-yn-2-ol (518 mg, 2.85 mmol), bis(triphenylphosphine)palladium(II) dichloride (400 mg, 0.57 mmol) and triethylamine (0.5 mL) in DMSO (0.5 mL) was irradiated under nitrogen in a 10-mL sealed tube with microwave radiation for 2 h at 100° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the crude product (50 mg) was purified by preparative HPLC to give 2 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-chloropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (400 MHz, DMSO) delta 8.61 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.98-7.82 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (d, J=5.2 Hz, 3H), 6.44 (s, 1H), 5.06 (t, J=5.6 Hz, 1H), 4.61 (t, J=4.8 Hz, 2H), 3.83-3.80 (m, 2H), 1.82 (s, 3H); LC-MS: m/z=+451 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:34])=[CH:26][CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(O)ccc54)ccc3o2)n1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-tert-butyl-2-{5-[(3-cyano-5-hydroxyindol-1-yl)methyl]benzofuran-2-yl}thiazole (158 mg), methyl iodide (0.1 ml) and sodium carbonate (0.1 g) in N,N-dimethylformamide (1.5 ml) was stirred for 3 days at room temperature. The resulting mixture was diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[(3-cyano-5-methoxyindol-1-yl)methyl]benzofuran-2-yl}thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.12 mol) in DMF (100 mL) was added K2CO3 (26.3 g, 0.19 mol). The reaction mass was stirred at 80° C. for 1 h followed by addition of methyl iodide (12.3 mL, 0.19 mol). The reaction mass was further stirred at 80° C. for 5-6 h. The reaction mass was filtered and the obtained filtrate was concentrated. The residue was further diluted with water and obtained solid was filtered off to afford 20.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.83 (s, 3H), 3.97 (s, 3H), 7.38 (d, J=9.3 Hz, 1H), 8.41 (dd, J=2.4 Hz & 2.4 Hz, 1H), 8.47 (s, 1H); MS (m/z): 212.44 (M+H)+.