Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC#N.C(=O)=O.N1C=CC=CC=1.[CH3:24][NH:25][C:26](=[O:28])[CH3:27]>C(Cl)Cl>[C:1]([N:25]([CH3:24])[C:26](=[O:28])[CH3:27])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CNC(C)=O
Agent: O=C=O
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)N(C)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A dry, 3-necked, round-bottomed flask equipped with a mechanical stirrer under an inert atmosphere is charged with 41.6 g (0.25 mol, ) of cinnamoyl chloride (available from Aldrich Chemical Company, Inc. of Milwaukee, Wis.) and 150 mL of CH2Cl2 (available from Aldrich Chemical Company). The stirred, homogeneous solution is cooled to −40° C. (CH3CN/CO2 bath), and 22.0 mL (0.275 mol) of pyridine (available from Aldrich Chemical Company) is added slowly (keeping solution temperature below −30° C.) in one portion. The reaction mixture is stirred for 20 min at which point a precipitate is observed. To the stirred heterogeneous solution is added 19.0 mL (0.25 mol) of N-methyl acetamide (available from Aldrich Chemical Company) in one portion. The resulting reaction mixture is allowed to warm gradually to room temperature and is stirred overnight. The reaction is diluted with 150 mL of CH2Cl2 and extracted twice with 150 mL of 1 N HCl, twice with 0.1 N aqueous NaOH, and twice with water. The organic layer is dried over Na2SO4, and concentrated by rotory evaporation to give the desired N-cinnamoyl-N-methyl acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.O.O.Cl[Sn]Cl>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1ccnn1C
Yield: 33.1 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.11 g, 9.06 mmol) was treated with SnCl2.2H2O (8.341 g, 36.22 mmol, 4.0 equiv.) in EtOH (50 mL), in a similar manner as described in Example 1.1, providing 4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (1.592 g, 7.8 3 mmol, 87%) as an oil. LCMS m/z (%)=204 (M+H). 1H NMR (400 MHz, CDCl3) δ: 7.51 (d, J=1.8 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.76 (dd, J=2.8, 8.7 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.22 (d, J=1.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.24-3.55 (broad s, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12]CC3C=CC([N+]([O-])=O)=CC=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[Al].Cl>CO.O>[NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Agent: [Al]
Solvent: O
Solvent: CO
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h

Procedure:
p-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (10 gm) was suspended in a mixture of methanol (120 ml) and water (25 ml). Aluminum powder (10 gm) was charged at 30° C., followed by the addition of concentrated HCl (12.5 ml) in a methanol (10 ml) and water (2.5 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0 followed by the addition of activated carbon. After stirring for 10 minutes, the reaction mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried. Yield: 3.9 gm (68%).
Reaction SMILES: [OH:1]CCC[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=C[CH:33]=[CH:32][CH:31]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH:15]=1.[C:20]1([S:26]([O:28][CH2:31][CH2:32][CH3:33])(=[O:1])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCc1cn(-c2cccnc2)c2ccccc12
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCOS(=O)(=O)c1ccccc1
Product: c1cncc(-n2ccc3ccccc32)c1
Reaction time: 14 h

Procedure:
A solution of 1.0 g of 3-(3-hydroxypropyl)-N-(3-pyridyl)indole in 40 ml of dry pyridine at 0° is treated with 0.7 g of benzenesulfonyl chloride and stored at 0° for 14 hours. The solvent is evaporated and the residue is partitioned between ethyl ether and aqueous sodium bicarbonate solution. The organic phase is separated, dried over potassium carbonate and evaporated to yield crude N-(3-pyridyl)indole-3-propyl benzenesulfonate as an oil which is used without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([CH3:18])[CH2:16][NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:18][CH:15]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:17][CH2:16]1
Reactant: CC(CN)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1CNC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 78 %

Procedure:
4 Å molecular sieve (10 g) was added to a solution of 1.06 g (10.0 mmol) of benzaldehyde and 1.35 g (10.0 mmol) of 2-phenylpropylamine in toluene (45 ml) and the mixture was refluxed for 4 h. After cooling to RT the mixture was filtered through diatomaceous earth and the filtrate was concentrated to small volume under vacuum. The residue was dissolved in TFA (90 ml) and the solution was heated at 120° C. for 20 h. Then it was concentrated to small volume under vacuum and made alkaline with a 2N aqueous NaOH solution. It was then extracted with EE. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 7:3) of the residue produced 1.74 g (7.8 mmol, 78%) of 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=S)[C:11]([C:20]([O:22]CC)=O)=[N:10]2)=[CH:4][CH:3]=1.[NH2:25][NH2:26]>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:25][NH:26][C:20](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=S
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc2c3cccnc3n(Cc3ccc(Br)nc3)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (120 mg, 0.296 mmol) was suspended in ethanol (15 mL), treated with hydrazine (1.00 mL, 31.9 mmol, 107 equiv) and placed into an oil bath preheated to 80° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])(=[O:12])=[O:11].O[Li].O.Cl>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:11])=[O:12]
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (125 mg, 0.29 mmol) in THF (3 ml) was added a solution of LiOH.H2O (25 mg, 0.59 mmol) in H2O (1 ml). The reaction was stirred at room temperature for 1 hour, acidified with 1M HCl, and was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was triturated with MeOH to yield the title compound (102 mg, 84%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.Cl.[CH:18]1([C:21](=N)OCC)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)C>[CH:18]1([C:21]2[NH:3][C:4]3=[CH:5][S:6][CH:7]=[C:8]3[N:9]=2)[CH2:20][CH2:19]1
Reactant: Nc1cscc1N
Reactant: CCOC(=N)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1scc2[nH]c(C3CC3)nc12
Temperature: 25 °C
Reaction time: 70 h
Yield: 32 %

Procedure:
[step 1] 3,4-Diaminothiophene dihydrochloride (300 mg, 1.60 mmol) was suspended in ethanol (12 mL), triethylamine (0.45 mL, 3.21 mmol) and ethyl cyclopropanecarboimidate monohydrochloride (WO200970485; 528 mg, 3.53 mmol) were added, and the mixture was stirred at room temperature for 70 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to give 2-cyclopropyl-1H-thieno[3,4-d]imidazole (84 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]=[N:10]1.C(=O)([O-])[O-:34].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:34])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]=[N:10]1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc(C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64171.7 %

Procedure:
To a solution of 4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonitrile (0.150 mg) in dimethyl sulfoxide (1.2 mL) is added potassium carbonate (0.03 g) and 50% aqueous hydrogen peroxide (0.2 mL). The reaction mixture is allowed to stir at room temperature for 30 minutes. The reaction mixture is diluted with water (55 mL), cooled to 0° C., and filtered. The resulting solids are washed with cold (−78° C.) hexanes. The white solids are allowed to dry under reduced pressure to give the title compound (0.100 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.9 (d, 2H), 7.6 (d, 2H), 7.5 (m, 5H), 6.9 (d, 2H), 5.0 (s, 2H), 3.3 (p, 1H), 1.5 (d, 6H);′ APCI/MS m/e 481 (M+1), HPLC purity 98.5%.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]1([CH2:29][C:30]([OH:32])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]1([CH2:29][C:30]([O:32][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 68.3 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (4.95 g) in anhydrous dimethylformamide (60 cc), phenylacetic acid (2.05 g) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (2.25 g). After recrystallization in ethyl acetate, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl phenylacetate (4.4 g), m.p. 222°-224° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]=[CH2:10].[CH2:12](O)[CH:13](C)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]=[CH2:10])[CH:13]([CH3:14])[CH3:12]
Reactant: C=CCSCCCC(=O)OC
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCSCCCC(=O)OCC(C)C
Temperature: 25 °C

Procedure:
Into a 25 cc micro flask equipped with spin bar, hot plate (having built in magnetic stirrer), thermometer and reflux condenser are placed 5 grams (0.2874 moles) methyl-4-(allylthio)butyrate; 8.5 grams (0.1149 moles) of isobutanol and 0.05 grams of para-toluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux for a period of 14.33 hours. At the end of the refluxing period, the reaction mass is cooled to room temperature and charged to a distillation flask and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=1.N1CCCC1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:15]3[S:16][CH:17]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)cs1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)cs1
Yield: 61 %

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.2 g, 7.2 mmol) was reacted with 4-chloro-thiophene-2-carbaldehyde (1.05 g, 7.2 mmol) and pyrrolidine (0.7 g, 9.9 mmol) to give E/Z-6-chloro-3-(4-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.3 g, 62%)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:5][OH:6])=[O:4].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10]>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][O:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(CO)CO
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)OCC(O)COC(=O)CCC

Procedure:
By following the procedure of Example 1(a) and 1(b) using 13.05 g. of 1,3-dihydroxyacetone, 23.7 g. of pyridine and 31.1 g. of butyryl chloride, 17.9 g. of 1,3-dibutanoyloxy-2-propanol is obtained. The reaction of 12.2 g. of this material and 9.4 g. of valproyl chloride and 4.98 g. of pyridine as described in Example 1(c) yields an oil which is purified by chromatography as described in Example 3. The pure 1,3-dibutanoyl-2-valproyl-glyceride is eluted from the column with petroleum ether/ether (95:5); it is obtained in a yield of 9.1 g.; Rf 0.61 (petroleum ether/ether 3:1); mass spectrum m/e 316 (M+ -42).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:30](Cl)(Cl)=[S:31]>O.C(Cl)Cl>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:30]=[S:31]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Reactant: S=C(Cl)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCO3 (716 mg, 7.16 mmol) in H2O (2 mL) is added CCL4 (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is purified over silica (CH2Cl2) to afford 480 mg (73%) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15 (d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.46 (dd, J=13.8 and 6.0 Hz).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=1)[CH2:13][N:14]=[N+:15]=[N-:16].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:14]([CH2:13][C:12]2[CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=[C:10]([Br:9])[CH:11]=2)[N:15]=[N:16][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(Br)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2cc(Br)cc(C(Cl)=C(Cl)Cl)c2)c1N
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.7 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (546 mg) in 20 ml of ethanol, 6.47 ml of a methanolic solution of NaOH (1N) was added and the resulting mixture was stirred at 60° C. for 20 minutes. A solution of 3-bromo-5-(trichlorovinyl)benzyl azide (1.02 g) in 10 ml of ethanol was added and the reaction mixture heated at 60° C. for two hours. The pH of the solution was adjusted to ~6 with acetic acid and then concentrated to a small volume. Dilution with 50 ml of water afforded a precipitate which was washed thoroughly with water. The precipitate was recrystallized from 8 ml of ethanol to give 466 mg of pure product, m.p. 175°-177° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH2:50][CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[CH2:50]([C@H:41]1[CH2:42][N:43]([CH:46]2[CH2:47][O:48][CH2:49]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[C:14]5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1)[CH3:51]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
A mixture of 105a (220 mg, 0.30 mmol) and LiOH (72 mg, 3.0 mmol) in iPrOH/THF (1:1, 4 mL) and H2O (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 105 (54 mg, 25%) as a white solid. LCMS: [M+H]+ 682. 1H NMR (500 MHz, CDCl3) δ 8.54 (t, J=2.5, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.47 (d, J=1.5, 1H), 7.26-7.24 (m, 1H), 7.18-7.15 (m, 1H), 6.95 (dd, J=2.5, 9.0, 1H), 6.87 (s, 1H), 6.81 (d, J=7.5, 1H), 4.72-4.61 (m, 4H), 4.54 (d, J=11.5, 1H), 4.33-4.30 (m, 2H), 4.20-4.14 (m, 3H), 3.92-3.90 (m, 1H), 3.71 (s, 3H), 3.53 (t, J=5.5, 1H), 3.31 (s, 1H), 3.12 (s, 2H), 2.61-2.56 (m, 5H), 2.44 (s, 2H), 2.35 (s, 1H), 1.91-1.89 (m, 2H), 1.80-1.79 (m, 2H), 1.67 (s, 1H), 1.43-1.37 (m, 1H), 0.82 (t, J=5.5, 3H)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=3[C:9]2=[O:19])=[C:4]([CH3:20])[CH:3]=1.C(Cl)(Cl)=[S:22]>CC(C)=O>[N-:8]=[C:12]=[S:22].[Cl:18][C:15]1[CH:16]=[CH:17][C:10]2[C:9](=[O:19])[N:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[CH3:20])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: S=C(Cl)Cl
Solvent: CC(C)=O
Product: Cc1ccccc1N1C(=O)c2ccc(Cl)cc2C1=O
Product: [N-]=C=S
Reaction time: 1 h
Yield: 148.1 %

Procedure:
To a slurry of 150 mg (0.52 mmol) of 2-(4-amino-2-methylphenyl)-5-chlorobenzo[c]azoline-1,3-dione in 2 mL of acetone, was added 41 uL (0.54 mmol) of thiophosgene. The yellow slurry dissolved whereupon a white precipitate formed. After 1 h, this solid was collected by filtration and dried to give 127 mg (74%) of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:15]([Cl:16])=[CH:14][C:8](C(N=[N+]=[N-])=O)=[C:7]([O:17][CH3:18])[CH:6]=1)(=[O:3])[CH3:2].ClCCl.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N-:35]=[C:36]=[O:37]>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:15]([Cl:16])=[CH:14][C:8]([NH:35][C:36]([N:32]2[CH2:33][CH2:34][N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:30][CH2:31]2)=[O:37])=[C:7]([O:17][CH3:18])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N=[N+]=[N-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)c(Cl)cc1NC(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of the 4-acetylamino-5-chloro-2-methoxy benzoyl azide (e7) (1.35 g) in dry toluene (30 ml) was heated to 90° for 30 minutes with stirring under dry nitrogen until the evolution of nitrogen ceased. A dichloromethane solution of 1-benzylpiperazine (0.9 g) was then added to the cooled suspension of the isocyanate (e8) and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was then poured into petrol (200 ml) and the precipitated solid filtered off. Recrystallisation from toluene give the N-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide (e9) (1.4 g) m.p. 174°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19]
Reactant: Oc1ccc(F)cc1F
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 4-bromo-3-fluoro-2-nitroaniline (0.100 g, 0.426 mmol) [Combi-Blocks, AN-2785] and cesium carbonate (0.167 g, 0.511 mmol) in dimethyl sulfoxide (0.47 mL) was treated with 2,4-difluorophenol (0.083 mL, 0.512 mmol) and stirred at 20° C. for 30 min and heated at 110° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (140 mg, 95%) as an orange/brown oil. LCMS calculated for C12H8BrF2N2O3 (M+H)+: m/z=345.0, 347.0. found: 344.9, 346.9.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:7]1([Zr+2:12]C2(CCCC)C=CC=C2)[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:4][CH2:5][CH3:6].[C:22]([OH:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[CH2:3]([C:7]1([Zr+3:12])[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1([Zr+2]C2(CCCC)C=CC=C2)C=CC=C1
Reactant: CC(C)(C)C(=O)O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)[O-]
Product: CCCCC1([Zr+3])C=CC=C1
Yield: 78 %

Procedure:
To a solution of bis(n-butylcyclopentadienyl)zirconium dichloride (1.001 g, 2.477 mmol ) and pivalic acid (0.760 g, 7.451 mmol ) in toluene (25 ml) at 25° C. was added triethylamine (0.871 g, 8.610 mmol ) with stirring. A white precipitate formed immediately which was removed by filtration. The title compound was isolated as a light orange oil in 78% yield by evaporating the solvent under vacuum. The title compound such prepared exhibit purity above 95% based on MNR results. 1H NMR (toluene-d8) δ 6.22 (m,2H), 5.97 (m,2H), 2.61 (t,J=7.7 Hz, 2H), 1.51 (m, 2H), 1.29 (m, 2H), 1.11 (s, 27H), 0.87 (t, J=7.2 Hz 3H).