Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][N:13]1[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCC#Cc1ccccn1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
4-(Pyridin-2-yl)but-3-yn-1-ol (96 mg, 0.65 mmol), isoindoline-1,3-dione (140 mg, 0.97 mmol) and triphenylphosphine polymer bound 3 mmol/g (340 mg, 1.02 mmol) were dissolved in DCM (2 mL) and cooled to 0° C. Di-tert-butylazodicarboxylate (226 mg, 0.96 mmol) dissolved in DCM (0.5 mL) was added dropwise over 30 min. to the reaction mixture followed by THF (0.5 mL) and the reaction mixture was stirred for 16 h at room temperature. After filtration through celite, the organic phase was washed with a solution of NH4OH, brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:7) to yield 130 mg (0.47 mmol, 73%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as an orange solid.
Reaction SMILES: [CH:1]1([CH:7]([NH2:14])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1(=[O:20])[CH2:18][C:17](=[O:19])[CH2:16]1>C(OCC)(=O)C>[CH:1]1([CH:7]([NH3+:14])[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:20][C:15]1[CH2:18][C:17](=[O:19])[CH:16]=1
Reactant: NC(C1CCCCC1)C1CCCCC1
Reactant: O=C1CC(=O)C1
Solvent: CCOC(C)=O
Product: O=C1C=C(O)C1
Product: [NH3+]C(C1CCCCC1)C1CCCCC1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A solution of 4.99 g of dicyclohexylmethylamine (25.0 mmol) in 10 g of ethyl acetate was instilled in a suspension of 2.11 g of 1,3-cyclobutanedione (23.0 mmol) at 20° C. and stirred for 1 hour. After another 30 minutes of stirring at 5° C., the suspension was filtered and dried under vacuum. 5.53 g of the title product with a purity of 94.7 percent (according to HPLC), corresponding to a yield of 81.4 percent, relative to the cyclobutanedione, was obtained. Data for the title compound was:
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.[Cl:15]Cl.P([O-])([O-])([O-])=O.[Al+3:22]>[Fe]>[Cl-:15].[Al+3:22].[Cl-:15].[Cl-:15].[P:2](=[O:1])([OH:13])([OH:9])[OH:3]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: ClCl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Agent: [Al+3]
Product: O=P(O)(O)O
Product: [Cl-]

Procedure:
This demonstrated that there was no loss of P2O5 on firing. The powder was amorphous and was examined on an x-ray diffractometer. SEM/TEM revealed small crystals dispersed here and there in the amorphous matrix. These crystals were identified as an odd phase of AlPO4, which becomes amorphous on bombardment by the electron beam. Typical yield of this reaction was 93%. The calcined powder was white and carbon free because the starting materials contained no iron or chlorine. The product is superior in purity to aluminum phosphate produced by the reaction of aluminum chloride and phosphoric acid.
Reaction SMILES: N(C(OC[CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CCCCNC(OC(C)(C)C)=O.C(Cl)CCl.C1C=C[C:42]2[N:47](O)N=[N:45][C:43]=2C=1.CC(N[O:54][C:55](C1C=CC=CC=1)=[O:56])(C)C>C1COCC1.[Cu](Cl)Cl.CN(C=O)C>[NH2:47][CH2:42][CH2:43][NH:45][C:55](=[O:54])[O:56][CH2:22][C:34]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)NOC(=O)c1ccccc1
Agent: Cl[Cu]Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 137.6 %

Procedure:
To a solution of Fmoc-Lys(Boc)-OH (500 mg, 1.07 mmol) in solution of 5% DMF in THF (21 mL) were added EDC (245 mg, 1.28 mmol), HOBt (173 mg, 1.28 mmol) and tert-butyl-4-amino benzoate (247 mg, 1.28 mmol) at room temperature. The mixture thus obtained was stirred for 10 minutes and then copper chloride (172 mg, 1.28 mmol) was added to the mixture. The mixture was stirred overnight. The mixture was concentrated to dryness and then the residue was purified by flash chromatography on silica and eluted with 5% methanol in dichloromethane to give compound 1 as a colorless oil (286 mg, 42%). 1H NMR (CD3OD) δ 1.38 (s, 9H), 1.45-1.54 (m, 4H), 1.58 (s, 9H), 1.80 (m, 2H), 3.05 (t, 2H), 4.22 (m, 2H), 4.38 (d, 2H), 7.30 (m, 2H), 7.38 (m, 2H), 7.68 (m , 4H), 7.78 (d, 2H), 7.90 (d, 2H); LC-MS (ES+), 544 (M+H-Boc)+, 667 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH3:44])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H13) according to the general procedure K. Obtained as a light yellow oil (181 mg).
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1C)[CH2:4][NH+:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.O1C[CH:23]1C1C=C2C(=CC=1)C(=O)OCC2.N1(C(OC(C)(C)C)=O)CCNCC1>>[ClH:1].[OH:2][CH:3]([C:11]1[CH:12]=[C:13]2[C:14](=[CH:19][CH:20]=1)[C:15](=[O:18])[O:16][CH2:17][CH2:23]2)[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: [Cl-]
Reactant: O=C1OCCc2cc(C3CO3)ccc21
Reactant: Cc1c(C(O)C[NH+]2CCNCC2)ccc2c1COC2=O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Cl
Product: O=C1OCCc2cc(C(O)CN3CCNCC3)ccc21

Procedure:
6-[1-Hydroxy-2-(piperazin-1-yl)ethyl]-3,4-dihydro-1-H-isochromen-1-one hydrochloride was prepared in an analogous fashion to that described for the synthesis of 1-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-ium chloride starting from 6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one and tert-butyl piperazine-1-carboxylate. LC-MS (IE, m/z): 277 [M+1]+.
Reaction SMILES: NC1N(C2C=C(CC(OCC)=O)C=CC=2)N=C(C2C=CSC=2)C=1.[NH2:24][C:25]1[N:29]([C:30]2[CH:31]=[C:32]([CH:36]([CH3:42])[C:37]([O:39]CC)=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:28]=[C:27]([C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:26]=1.[Cl:48][C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[N:56]=[C:57]=[O:58]>>[Cl:48][C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[NH:56][C:57](=[O:58])[NH:24][C:25]1[N:29]([C:30]2[CH:31]=[C:32]([CH:36]([CH3:42])[C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:28]=[C:27]([C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:26]=1
Reactant: CCOC(=O)C(C)c1cccc(-n2nc(-c3ccsc3)cc2N)c1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: CCOC(=O)Cc1cccc(-n2nc(-c3ccsc3)cc2N)c1
Product: CC(C(=O)O)c1cccc(-n2nc(-c3ccsc3)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1

Procedure:
Using the same general approach as for Example 524, ethyl 2-(3-(5-amino-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)acetate (0.2258 g, 0.450 mmol, 1.00 eq) was transformed to ethyl 2-(3-(5-amino-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)propanoate. This, in turn, was combined with 2,3-dichlorophenyl isocyanate, according to general method A, to afford 2-(3-(5-(3-(2,3-dichlorophenyl)ureido)-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)propanoic acid. Using general method J, this product was combined with 0.5M NH3 in dioxane (4.50 ml, 2.25 mmol, 5.00 eq). to afford 0.1731 g (77%) of pure 1-(1-(3-(1-amino-1-oxopropan-2-yl)phenyl)-3-(thiophen-3-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (DMSO-d6): δ 9.38 (s, 1H), 8.82 (s, 1H), 8.12-8.09 (m, 1H), 7.88-7.87 (m, 1H), 7.62-7.60 (m, 1H), 7.57-7.42 (m, 6H), 7.36-7.31 (m, 2H), 6.89 (brs, 1H), 6.86 (s, 1H), 3.69 (q, 1H, J=7.2 Hz), 1.36 (d, 3H, J=7.2 Hz); MS (ESI) m/z: 500.0 (M+H+), 502.0 (M+2+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCCC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH2:2][CH2:3][CH3:4].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)OCCC)ccc1-c1cccc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)ccc1-c1cccc(OC)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of T13.1 (795 mg, 2230 μmol) and THF (10 mL) at 0° C. was added LAH (1.0 M solution in THF (3345 μL, 3345 μmol)). The reaction was stirred for one hour and then carefully diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide T13.2 (530 mg, 83.0% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:44]=[C:17]2[N:18]([CH:41]([CH3:43])[CH3:42])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:44]=[C:17]2[N:18]([CH:41]([CH3:43])[CH3:42])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)C)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-4-(1-methylethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28].C(N(CC)CC)C>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cn1c(N2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Yield: 70.1 %

Procedure:
0.51 g of 4-nitrophenethyl bromide, 0.5 g of 1,3-dimethyl-6-[1-piperazinyl]-2,4(1H,3H)-pyrimidinedione (Compound b) and 0.5 ml of triethylamine were suspended in 5 ml of isopropanol, and the resultant suspension was heated under reflux for 8 hours. The solvent was distilled off from the resultant reaction mixture under reduced pressure, and the residue was then dissolved in chloroform. After washing with water, the washed organic layer was dried over anhydrous sodium sulfate. In addition, the dried organic layer was treated under reduced pressure, and the solvent was then distilled off. Afterward, the residue was purified through a silica gel column chromatograph (chloroform/methanol=50/1 to 20/1 in volume ratio) to obtain 0.58 g of 1,3-dimethyl-6-[4-(2-[4-nitrophenyl]ethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [N+](C1C=CC(C[CH:9]2[C:14]([Cl:15])=[C:13]([C:16]([O-:18])=[O:17])[N:12]3[C:19](=[O:38])[CH:20]([NH:21][C:22](=[O:37])[C:23]([C:29]4[N:30]=[C:31]([NH:34][CH:35]=[O:36])[S:32][CH:33]=4)=[N:24][O:25][CH2:26][CH2:27][CH3:28])[C@H:11]3[S:10]2)=CC=1)([O-])=O.CO.O>[C].[Pd].O1CCCC1>[CH:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([C:23](=[N:24][O:25][CH2:26][CH2:27][CH3:28])[C:22]([NH:21][CH:20]2[C:19](=[O:38])[N:12]3[C:13]([C:16]([OH:18])=[O:17])=[C:14]([Cl:15])[CH2:9][S:10][C@H:11]23)=[O:37])[N:30]=1)=[O:36]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(Cl)C(Cc3ccc([N+](=O)[O-])cc3)S[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 85.5 %

Procedure:
A suspension of 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.4 g.), 10% palladium carbon (1.0 g.), methanol (24 ml.), water (3.6 ml.) and tetrahydrofuran (48 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature. After removing insoluble substance by filtration, the filtrate was concentrated in vacuo. Water and ethyl acetate were added to the residue, and adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration, and the aqueous layer was separated. Ethyl acetate was added to the solution, adjusted to pH 2.0 with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution and extract were combined together, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diethyl ether and collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a suspension of the 254 (26.8 mg, 0.84 mmol) in THF (1.6 ml) was added 2-phenylacetyl isothiocyanate (23 mg, 0.13 mmol). The mixture was stirred for 1 hr transferred onto a chromatography column and eluted sequentially with EtOAc/MeOH (9:1) and EtOAc/hexane (1:1), to afford title compound 255a (30 mg, 72% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17]1([CH2:23][CH:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[C:17]1([CH2:23][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 45.0 g of 1-bromo-4-(trifluoromethyl)benzene in 300 mL of THF cooled to -78° C. was added 77.0 mL of 2.5M n-butyl lithium in hexane dropwise. An exothermic reaction to -55° C. was observed. The reaction was then stirred for 20 minutes after which time phenyl acetaldehyde (23.5 mL, 0.2 mol) was added dropwise. The reaction was then stirred for an additional hour with gradual warming to room temperature. The mixture was then partitioned between ether and water, dried over anhydrous magnesium sulfate and concentrated to 52.6 g of a yellow oil. The crude oil was dissolved in 600 mL of methylene chloride and 100 g of pyridinium dichromate was added in several portions over 20 minutes and the mixture was then stirred at room temperature overnight. The reaction was then diluted with ether and filtered through magnesium sulfate and concentrated. The crude product was dissolved in hot n-butyl chloride, insoluble material was filtered off and the mixture was cooled to 0° C. Filtration and drying of the precipitate afforded 12.7 g of the title compound as a white solid, mp 127°-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]=[CH2:19])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:21]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]3[CH2:21][CH2:19]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C=COCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: CCOCC
Solvent: ICI
Product: Clc1ccc(Br)cc1Cc1ccc(COC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(vinyloxymethyl)benzyl)benzene (0.7 g, 2.07 mmol) and Et2Zn (5.18 mL, 5.18 mmol, 1.0 M in hexane) in dry ethyl ether (10 mL) was added diiodomethane (0.42 mL, 5.18 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and then with brine (20 mL), and then dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE=1:200) to obtain intermediate CV (0.6 g) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 7.33˜7.24 (m, 5H), 7.18 (d, 2H), 4.55 (s, 2H), 4.07 (s, 2H), 3.40˜3.37 (m, 1H), 0.69˜0.49 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[C:2]2/[C:1](=[O:11])[C:10]3[C:5]([CH2:4][CH2:3]/2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1/C(=C/c2ccc(Br)cc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.9 %

Procedure:
A 250 mL flask was charged with tetralone (3.22 g, 22 mmol) and 4-bromobenzaldehyde (5.3 g, 28.6 mmol). This was dissolved in warm tetrahydrofuran (12 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (100 mL). The reaction was stirred for 4 days at room temperature. The mixture was concentrated and reduced to approx 10% vol. The residue was filtered and washed with MTBE (3*50 mL), dried, to afford a light yellow powder (6.61 g, 96%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)[CH3:15].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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.CCOC(C)=O>[C:12]([C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:19]2[CH:18]=[N:17][N:16]([CH2:14][CH3:15])[CH:20]=2)[N:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: COC(=O)c1c(C#N)ccnc1Cl
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCn1cc(-c2nccc(C#N)c2C(=O)OC)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
A mixture of methyl 2-chloro-4-cyanonicotinate (207 mg, 1.053 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (201 mg, 0.905 mmol) and tetrakis(triphenylphosphine)palladium(0) (122 mg, 0.105 mmol) in DME (2 mL), and saturated aq Na2CO3 (2 mL) was stirred at 80° C. for 3 h under N2 atmosphere. Water and EtOAc were subsequently added. The organic phase was washed with H2O and brine, dried over MgSO4, and evaporated to yield the title compound (265.3 mg, 98%). [M+H] calc'd for C13H12N4O2, 257; found, 257.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:23]([O-])=O)[CH3:2]>C(O)C.O.C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[NH2:23])[CH3:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCC)c([N+](=O)[O-])cc23)c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCC)c(N)cc23)c1
Temperature: 70 °C
Yield: 73.9 %

Procedure:
7-ethoxy-N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine (8 g, 0.024 mol) was dissolved in a mixture of 80 ml ethanol, 80 ml H2O and 10 ml acetic acid. The reaction was heated to 70° C., then Fe (5.4 g, 0.096 mol) was added. The reaction mixture was heated to reflux for 4 hours. The resulting clear reaction solution was concentrated under reduced pressure to remove solvent. The pH of the residue was adjusted to 9 with 4N aqueous NaOH, and was washed with 200 ml EA/MeOH (50/1) until TLC show no product can be detected in the organic layer. The combined organic layers were concentrated, grey solid was precipitated and filtered to afford 7-ethoxy-N4-(3-ethynylphenyl)quinazoline-4,6-diamine as grey solid 5.4 g (74.2% yield).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:4]1.CI.[CH3:19]COCC>O1CCCC1>[CH3:19][CH:12]([C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:3][N:4]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1nsc2ccccc12
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1nsc2ccccc12
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (1.25 g, 60% in oil, 31.3 mmol) in tetrahydrofuran is added to a solution of methyl 1,2-benzisothiazole-3-acetate (6.0 g, 29.0 mmol) in tetrahydrofuran. After stirring for 30 minutes, the reaction mixture is treated with methyl iodide (2.0 mL, 32.0 mmol), stirred for one hour and quenched with ice. The aqueous mixture is neutralized with hydrochloric acid (pH5-pH6) and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a brown oil. Chromatography of the oil using silica gel and 10% to 25% ether in hexanes solutions gives the title product as an amber oil which is identified by NMR spectral analyses.