Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[N:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:27]>O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[N:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)nc1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
3-Chlorophenylboronic acid (CAN 63503-60-6, 0.61 g, 3.9 mmol), 1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 53 mg, 0.065 mmol) and potassium carbonate (CAN 584-08-7, 0.54 g, 3.9 mmol) was added to a solution of 6-bromo-5-methyl-pyridine-2-carboxylic acid (0.7 g, 3.2 mmol) in water (30 mL). The mixture was stirred at 100° C. overnight. The reaction mixture was adjusted to pH=3 and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give product (0.55 g, 56.9%); MS (EI): m/e 248.1 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:46][C:47](=[N:49]O)[CH3:48].CN(C)C=O>O>[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([O:27][N:49]=[C:47]([CH3:48])[CH3:46])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)=NO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=NOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 47.9 %

Procedure:
First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic acid (compound a-2), 49 mg of acetone oxime, and 2 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 2 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of acetone O-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetyloxime (compound a-98).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][N:27]([CH3:47])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:26])[CH3:47])=[N:33][CH:34]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Product: CN(C)CCCOc1ccc(-c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Yield: 33 %

Procedure:
Similarly, reaction of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole and N,N-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxy}-1-propanamine, as in Example 47, gave N-[3-({5-[2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]-2-Pyridinyl}oxy)propyl]-N,N-dimethylamine in 33% yield: mp (CH2Cl2/hexanes) 140-141° C.; 1H NMR (DMSO-d6) δ 9.07 (d, J=2.2 Hz, 1H), 8.53 (dd, J=8.8, 2.5 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.80 (t, JHF=52.8 Hz, 1H), 7.52 (dt, J=7.8, 1.0 Hz, 1H), 7.50 (dd J=8.1, 1.0 Hz, 1H), 7.42 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 4.39 (t, J=6.6 Hz, 2H), 3.85-3.84 (m, 4H), 3.78-3.76 (m, 4H), 2.39 (t, J=7.1 Hz, 2H), 2.17 (s, 6H), 1.89 (quintet, 2H); Anal. Calcd. for C26H29F2N7O: C, 61.3; H, 5.7; N, 19.2. Found: C, 61.0; H, 5.5; N, 19.1%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH3:16][N:17]([CH3:30])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[C:21]([S:18]([N:17]([CH3:30])[CH3:16])(=[O:19])=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a 20 mL vial were 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (50 mg, 0.19 mmol), (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid, K2CO3 (43 mg, 0.19 mmol), and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.009 mmol), and a stir-bar. The vial was sealed with a teflon lined cap and sparged with N2. The vial was then charged with freshly sparged DMSO (2 mL) and then stirred 16 hours at 80° Celsius. The reaction mixture was then cooled to rt, filtered, and purified by HPLC to give the title compound (36 mg, 40%). MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 2H), 8.06-7.96 (m, 2H), 7.72-7.67 (m, 1H), 7.64-7.59 (m, 1H), 7.43-7.39 (m, 1H), 7.32-7.26 (m, 2H), 2.49 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([OH:28])[CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:46]I.O>C1COCC1>[CH:29]1([C:26]([C:16]2[CH:17]=[C:18]([CH3:25])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)([O:28][CH3:46])[CH3:27])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc(C(C)(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(c1cc(C)c(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol (18 mg, 0.028 mmol) in THF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 8 mg, 0.202 mmol) at room temperature. After stirring for 5 minutes methyl iodide (12.2 mg, 0.086 mmol) was added and the solution was stirred at room temperature for 18 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organics were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give an oil (17 mg). This material was purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10% ethyl acetate in heptane) to yield the title compound (11 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.75 (s, 1H) 7.70 (s, 2H) 7.39 (s, 1H) 7.01 (s, 1H) 5.19 (d, J=17.42 Hz, 1H) 5.0 (d, J=17.42 Hz, 1H) 4.74 (q, J=16.72 Hz, J=16.18 Hz, 2H) 4.17 (s, 3H) 3.0 (s, 3H) 2.42 (s, 3H) 1.99 (d, J=12.40 Hz, 1H) 1.72 (m, 2H) 1.58 (s, 3H) 0.99 (m, 8H). MS calc. 637.5, found 638.5 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15]/[CH:16]=[CH:17]/[CH2:18][C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C/C=C/CC(=O)NCCc2ccccc2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: COc1ccc(CCNCC/C=C/CCNCCc2ccccc2)cc1OC
Temperature: 0 °C
Yield: 35.8 %

Procedure:
The product of step (c) (6 g., 14.6 mmoles) and lithium aluminium hydride (1M solution in ether, 60 ml, 60 mmoles) in dry dichloromethane (200 ml) were heated at reflux under nitrogen for 5 hrs. The suspension was cooled and poured slowly into an ice-cold 10% aqueous solution of sodium hydroxide. The organic phase was separated, washed with brine and evaporated. Recrystallisation of the residue from 2-propanol afforded the sub-title compound (2.0 g) mp 270°-272°.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH:14]1[CH2:19][CH2:18][O:17][C:15]1=[O:16].[CH3:20][S:21]SC>O1CCCC1>[CH3:13][C:14]1([S:21][CH3:20])[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CC1CCOC1=O
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSC1(C)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Under an argon atmosphere, n-butyllithium (1.7 M in hexane, 1800 ml, 3.06 mole) was added slowly to a stirred solution of diisopropylamine (309.4 g, 3.06 mole) in tetrahydrofuran (1800 ml) at -78° C. Upon completion of addition, the reaction mixture was allowed to stir for 30 minutes at which time alpha-methyl-gamma-butyrolactone (278.0 g, 2.78 mole) was added dropwise, also at -78° C. The reaction mixture was stirred 30 minutes then dimethyl disulfide (392.8 g, 4.17 mole) was added dropwise. After stirring for 30 minutes at -78° C., the reaction mixture was warmed to ambient temperature during a one hour period. The reaction mixture was quenched with 5% aqueous hydrochloric acid (1500 ml) and then diluted with ethyl acetate (2000 ml). The layers were separated, and the organic layer was washed with aqueous 10% hydrochloric acid (1×200 ml) and then saturated aqueous sodium bicarbonate (1×100 ml). The organic layer was dried and concentrated under reduced pressure. The residue was distilled to yield 234.6 g of alpha-methyl-alpha-methylthio-gamma-butyrolactone as a colorless oil, b.p. 104°-105° C./8 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.F[C:25]1[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[N:1]1([C:25]2[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#Cc1ncccc1F
Reactant: c1nnn[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ncccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of tetrazole (1.0 g; 14 mmol) in DMF (150 mL) was added 40% aqueous tetrabutylammonium hydroxide (7.8 g; 12 mmol). The solvent was removed under reduced pressure. To ensure removal of all the water from the tetrabutylammonium hydroxide solution, the residue was redissolved in DMF and the solution was evaporated under reduced pressure. This procedure was repeated a total of three times. The residue was then dissolved in DMF (60 mL) and 3-fluoro-2-cyanopyridine (1.5 g; 12 mmol) was added. The reaction was stirred at ambient temperature under inert atmosphere for four days, at which time hplc analysis indicated about 65% conversion of the 3-fluoro-2-cyanopyridine to new products. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient elution of 1:4 to 100:0 EtOAc:hexanes to give 3-(tetrazol-1-yl)cyanopyridine as a white crystalline solid (TLC Rf=0.5, 1:1 EtOAc-hexanes; hplc retention time=2.04 min, method X; 1H NMR (CDCl3) δ 9.42 (s, 1H), 8.94 (dd, J=1.3, 4.6 Hz, 1H), 8.31 (dd, J=1.3, 8.4 Hz, 1H), 7.87 (dd, J=4.6, 8.4 Hz, 1H).
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[N:27]=[C:26](C(F)(F)F)[CH:25]=[CH:24][N:23]=1>CO.CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:10][S:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: NS(=O)(=O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(Nc1ncccn1)N1CCCCC1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a slurry of the piperidine sulfonamide from part F (6.3 g, 12.0 mmol) in methanol (25 mL) was added ammonium formate (2.2 g, 34.5 mmol). The system was purged with nitrogen for 10 minutes. The nitrogen stream was removed and palladium on carbon (1.2 g of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five minutes, cooled, filtered through Celite under nitrogen, and concentrated in vacuo. The residue (4.5 g, 10 mmol) was dissolved in dry dimethylformamide (20 mL) and potassium carbonate (4.14 g, 30 mmol) and 2-chloro-4-trifluoromethylpyrimidine (2.4 mL, 20 mmol) were added. The reaction was stirred at seventy degrees Celsius for three hour and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-pyrimidinyl piperidine sulfonamide as a white solid (4.51 g, 76%).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[N:26]=1.C(N(CC)CC)C>C(#N)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.[Cu]I>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:22]3[S:23][CH:24]=[C:25]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[N:26]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1csc(Br)n1)C(=O)OCC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC[C@H](NC(=O)c1csc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OCC
Yield: 67.5 %

Procedure:
To a 100 mL 14/20 round bottom flask under an argon atmosphere were added 0.316 g (1.17 mmol) of 2 -pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine suspended in 10 mL of acetonitrile, followed by the addition of 0.47 g (1.2 mmol) of diethyl N-(2-bromo-4-thiazolylcarbonyl)-L-glutamate, 0.14 g (0.12 mmol) of tetrakis(triphenylphosphine)palladium (0), 0.046 g (0.24 mmol) of copper (I) iodide, and 0.35 mL (2.5 mmol) of triethylamine with an additional 10 mL of acetonitrile. The reaction was heated to reflux for 2 hours The volatiles were removed in vacuo, and the residue purified using silica gel flash chromatography, eluting with a step gradient of 100% chloroform to 2% methanol/chloroform to give 0.46 g (67%) of diethyl N-{2-[2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl]-4-thiazolylcarbonyl}-L-glutamate as an off-white solid, m.p. 201-202° C. (dec). Rf =0.28 (4% methanol/chloroform). 1H NMR (300 MHz, DMSO-d6) δ 1.12-1.29 (m, 15H), 2.05-2.15 (m, 1H), 2.37 (t, J=7.2 Hz, 2H), 3.98-4.13 (m, 4H), 4.45-4.49 (m, 1H), 8.47 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.84 (d, J=8.1 Hz, 1H), 9.07 (d, J=1.9 Hz, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:9][CH2:10][C:11]3[N:12]([C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:31][N:32]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NC(=S)CN=C2c1ccccc1Cl
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)-n1c(nnc1-c1ccccc1)CN=C2c1ccccc1Cl
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 8-nitro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 9-nitro-1-phenyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH-].[Na+].[C:3]1([N:9]2[N:13]=[N:12][C:11]([C:14]([O:16]CC)=[O:15])=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(O)C>[C:3]1([N:9]2[N:13]=[N:12][C:11]([C:14]([OH:16])=[O:15])=[N:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nnn(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nnn(-c2ccccc2)n1
Temperature: -5 °C
Yield: 49 %

Procedure:
To 0.8 mL ethyl glyoxylate in toluene (50%) was added 130 mL ethanol solution of sulfonyl hydrazide (0.69 g, 4.0 mmol). The resulting mixture was stirred for 1 hr at room temperature in an open flask before 130 mL of chilled distilled water was added. A white precipitate (sulfonylhydrazone) was generated, which was collected by filtration. The filtrate was subsequently dissolved in 50 ml pyridine to derive solution A. Separately, to a 10 mmol solution of aniline in a 1:1 mixture of ethanol and water (20 mL cooled to −5° C.) was added 3.0 mL of concentrated HCl. To the resulting acidic aniline solution, 4 mL solution of sodium nitrate (0.690 g, 10 mmol) was added drop-wise generating the phenyl-diazonium salt solution (solution B). Both solutions were cooled to −5° C. and solution B was added drop-wise to solution A over a period of 30 minutes. Following addition, the reaction mixture was allowed to warm up to room temperature over 45 min and subsequently extracted with ethyl acetate three times. The organic layer was subsequently washed with a 0.1 N HCl solution, dried over sodium sulfate, and concentrated. The crude mixture was purified via a silica gel chromatography using a stepwise gradient of ethyl acetate/hexane to afford ethyl 2-phenyl-2H-tetrazole-5-carboxylate as a pink-purple powder. Following purification, sodium hydroxide (7.5 mmol; 0.6 g dissolved in 2 mL of water) was added to a 50 mL solution of ethyl 2-phenyl-2H-tetrazole-5-carboxylate in ethanol. The reaction mixture was refluxed overnight and allowed to cool to −5° C. The mixture was acidified with 1.2 mL of dilute HCl solution. The resulting solution was extracted five times with ethyl acetate to yield the titled compound (0.37 g, 49%): 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=7.5 Hz, 2H) 7.60 (m, 3H); 13C NMR (75.4 MHz, CDCl3) δ 158.6, 158.3, 135.9, 130.7, 130.2, 120.3; HRMS (EI) calcd for C8H6N2O2 162.0424 [M−N2]+, found 162.0423.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH:20]([Mg]Cl)([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1.O>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[CH:20]([CH3:22])[CH3:21])[N:3]=[CH:2]1
Reactant: CC(C)[Mg]Cl
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(1H-Imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (6.50 g) was dissolved in THF (120 ml) and the mixture was cooled to −10° C. A solution (2.0 M; 38.7 ml) of isopropyl magnesium chloride in THF was slowly added dropwise and the mixture was stirred for 30 min. To the reaction mixture was added saturated aqueous solution of ammonium chloride and the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and after drying, concentrated. The obtained residue was purified by silica gel column chromatography (eluate, chloroform:methanol=20:1→10:1) and recrystallized from ethyl acetate to give the title compound (5.04 g) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[S:13][CH3:14].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:18])=[O:11])=[CH:5][C:4]=1[S:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1SC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Cl)cc1SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-3-(methylthio)phenylacetic acid (10.2 g, 47.3 mmol) in THF (300 mL) was added oxalyl chloride (6.6 g, 52 mmol, 1.1 equivalent) followed by a catalytic amount of N,N-dimethylformamide (DMF) (~0.5 mL). The reaction mixture was stirred at ambient temperature for 3 h and then concentrated under reduced pressure to give the title compound as a yellow oil. The product was used without purification.
Reaction SMILES: C[Si](C)(C)N1C(=O)C2=CC=CC=C2C1=O.C[Si](C)(C)[O:18][C:19]([CH:21]([N:25]1[CH:28]([S:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH:27]([NH:41][C:42](=[O:51])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:26]1=[O:52])[C:22]([CH3:24])=[CH2:23])=[O:20]>CC(N(C)C)=O>[C:19]([CH:21]([N:25]1[CH:28]([S:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH:27]([NH:41][C:42](=[O:51])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:26]1=[O:52])[C:22]([CH3:24])=[CH2:23])([OH:20])=[O:18]
Reactant: C=C(C)C(C(=O)O[Si](C)(C)C)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)N1C(=O)c2ccccc2C1=O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 1.8 g (5 mmoles) of phenoxymethylpenicillin-S-sulphoxide and 6.6 g (30 mmoles) of N-trimethylsilylphthalimide in 35 ml of dimethylacetamide was heated at 100° C for 2 hours. The reaction mixture (containing 1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one) was evaporated to dryness, treated with 30 ml of dichloromethane and filtered. The filtrate was concentrated and purified by chromatography on a silica gel column impregnated with 1% acetic acid, using a 4:1 (v/v) mixture of toluene and acetone with 0.5% acetic acid as an eluent. There was obtained 1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one. Yield: 1.11 g (2.24 mmoles) or 45%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1cccnc1

Procedure:
Following General Procedure F and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared as a solid having a melting point of 62°-64° C. The reaction was monitored by tlc on silica gel (Rf=0.48 10% methanol/dichloromethane) and purification was by silica gel chromatography.