Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13][CH2:12]1.BrB(CC)CC.O>ClCCl>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13][CH2:12]1
Reactant: COCOc1ccccc1C1(c2ccc(C)cc2OC)CC1
Agent: CCB(Br)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)ccc1C1(c2ccccc2O)CC1
Reaction time: 8 h

Procedure:
A solution prepared from 490 mg (1.64 mmol) of 1-(2-methoxymethoxyphenyl)-1-(2-methoxy-4-methylphenyl)cyclopropane and 6.1 ml of a 1 M solution (8.2 mmol) of bromodiethylborane in dichloromethane was stirred overnight under an argon atmosphere. Ten ml of water were added, the phases were separated, and the aqueous phase was extracted twice with 20 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 1-(2-hydroxyphenyl)-1-(2-methoxy-4-methylphenyl)cyclopropane. The proton NMR spectrum was consistent with the assigned structure. This was dissolved in 0.8 ml (8.2 mmol) of a 5 M solution of bromodimethylborane and allowed to stir overnight. Nothing happened. The mixture was cooled to 0° C. and 3.3 ml (3.3 mmol) of a 1 M solution of boron tribromide was added with stirring under an argon atmosphere. After a short reaction period 2 ml of water was added and the mixture was extracted with 2 ml of 5 percent aqueous sodium bicarbonate then with 2 ml of water, dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 350 mg (84 percent of theory) of the title compound as a foamy brown oil. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CCN(C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1
Reactant: OC1CCNCC1
Reactant: Fc1cncc(Cl)c1I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: OC1CCN(c2c(F)cncc2Cl)CC1
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-5-fluoro-4-iodo-pyridine (1 g, 3.885 mmol) in NMP (1 mL) was added DIPEA (753.1 mg, 1.015 mL, 5.828 mmol) and piperidin-4-ol (589.4 mg, 5.828 mmol) and the mixture heated to 120° C. for 4 hours. The mixture was diluted with ethyl acetate (30 ml), washed twice with water (20 ml) and with brine. The organic layer was dried with MgSO4 and concentrated in vacuo to a yellow solid that was purified by column chromatography using DCM and then 2% MeOH/DCM as eluent, yielding 1-(3-chloro-5-fluoro-4-pyridyl)piperidin-4-ol. MS (ES+) 231.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)(Cl)[CH2:10][N+:11]([O-:13])=[O:12]>CO>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])CC(Cl)(Cl)Cl
Reactant: NCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Into 50 ml of methanol was added 8.1 g of 1-amino-3-propanethiol, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, about 1/3-aliquot of a solution of 5.0 g of caustic soda dissolved in 40 ml of methanol was added dropwise thereinto, and the remainder of about 2/3-aliquot of the solution and a solution of 5.4 g of 2,2,2-trichloro-1-nitroethane diluted in 20 ml of methanol were added dropwise slowly over 50 minutes, and the reaction was carried out for one hour. During the dropwise addition, the liquid temperature was maintained at lower than 10° C. (about 8° C.). After the reaction carried out for one hour, the procedure of the post-treatments as described in Example 1 was followed to obtain 4.20 g of tetrahydro-2-(nitromethylene)-1,3thiazine (yield: 86.8%).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(O)CCCCC.N#N.C([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])CCCCC>>[C:2]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: CCCCCCOC(C)(C)C
Agent: N#N
Solvent: CCCCCCO
Product: CC(C)(C)OC(C)(C)C
Reaction time: 18 h

Procedure:
300 mmoles of i-butene, 100 mmoles of 1-hexanol and 2.5 g of Ti-Si-catalyst powder are stirred in a 100 ml autoclave at a pressure of 40 bar N2 and a temperature of 150° C. over a period of 18 h, 62% of n-hexanol were converted into hexyl-t-butyl ether with a selectivity of 92%.
Reaction SMILES: S(OS([O-])=O)([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].O>CN1CCCC1=O>[Cl:10][C:11]1[S:12][C:13]([C:16]2[NH:25][C:24]3[CH:23]=[CH:22][C:21]([S:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:28])=[O:27])=[CH:20][C:19]=3[N:18]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)CS(=O)(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Cl)s1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CS(=O)(=O)c1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
14.4 747 mg (3.93 mmol) of sodium disulfite are added to a solution of 1.15 g (7.86 mmol) of 2-chlorothiophene-5-carbaldehyde and 1.92 g (7.86 mmol) of methyl (3,4-diaminobenzenesulfonyl)acetate in 25 ml of 1-methylpyrrolidone, and the mixture is stirred at 110° C. for 18 hours. Water is added to the reaction mixture, which is extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is stirred with water, and the resultant precipitate is filtered off, giving methyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-acetate as a brown solid; ESI 371.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[C:17]([CH3:30])[C:16]=1[OH:31].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:31][C:16]1[C:17]([CH3:30])=[CH:18][C:19]([C:2]2[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:3]=2)=[CH:20][C:15]=1[CH3:14]
Reactant: CCC(=O)c1cc(Cl)nnc1OC
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(-c2cc(C)c(O)c(C)c2)nnc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2 g of 1-(6-Chloro-3-methoxy-pyridazin-4-yl)-propan-1-one and 1.73 g of tetrakis(triphenylphosphine) palladium (0) are dissolved in 10 ml DME and the solution is stirred for 5 min at RT under argon. 3 g of 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol and 10 ml of a 2M aqueous solution of sodium carbonate are added and the reaction solution is stirred at 95° C. for 4 h. The reaction solution is poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane, followed by purification by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 1.69 g. LC-MS (ES+) 287 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([Cl:14])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (2.27 g, 8.15 mmol) in THF at −78° C. was added methylmagnesium chloride (4.07 ml, 3M solution in THF, 12.23 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 h and then warmed to rt slowly and stirring was continued at rt overnight. The reaction mixture was quenched with 1N HCl and extracted with ether. The organic layer was washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:4 ether:pentane) to give 1-(4-bromo-2-chlorophenyl)-ethanone (1.52 g, 80%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.61 (m, 1H), 7.50-7.44 (m, 2H), 2.64 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[C:18]([S:21]([CH2:24][CH2:25][C:26](O)=[O:27])(=O)=O)[CH:17]=[CH:16]2)=[O:7]>S(Cl)(Cl)=O>[O:27]=[C:26]1[C:19]2[C:20]3[C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:32])([F:33])[F:1])[CH:4]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[CH:17][C:18]=2[S:21][CH2:24][CH2:25]1
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cccc(CCNC(=O)c3cccc(C(F)(F)F)c3)c2c1
Solvent: O=S(Cl)Cl
Product: O=C(NCCc1cccc2ccc3c(c12)C(=O)CCS3)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step B (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a current of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure and the residue is dried with the aid of a vane pump to yield the title product.
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[C@@H:7]([F:8])[CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22].Cl>O1CCOCC1>[CH2:24]([O:23][C:21]([NH:1][C@@:2]1([C:12]([OH:14])=[O:13])[C@@H:7]([F:8])[CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10])=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)Cl
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of (1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (IV) (4.00 g) in dioxane (24 mL) and a saturated aqueous sodium bicarbonate solution (48 mL), allyl chloroformate (0.42 mL) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 20 hours. After addition of 1 mol/L hydrochloric acid to the reaction solution to adjust it to pH 1, the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was filtered off and then the filtrate was concentrated under reduced pressure to give (1S,2S,3S,5R,6S)-2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (A-1-1, 6.23 g) as a colorless amorphous.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[C:13]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[CH:20][C:9]=12>CN1C(=O)CCC1>[CH:15]([O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:9]2[CH:20]=[CH:19][NH:18][C:10]2=[N:11][CH:12]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1cnc2[nH]ccc2c1F
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 200 °C
Yield: 48.8 %

Procedure:
Piperazine (222 mg, 2.6 mmol) was added to 4-fluoro-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.26 mmol) in NMP (1 mL), and the reaction was heated to 200° C. for 1 hour under microwave irradiation. The reaction was concentrated to dryness under high vacuum and then purified by chromatography (SP4, 12+M, water/ACN 100/0→40/60, 20CV) to yield 5-isopropoxy-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (33 mg, 49% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:6]=2[N:5]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:4][CH2:3]1.S(Cl)([Cl:28])=O>ClCCCl>[CH3:1][C:2]1([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([Cl:28])=[O:14])=[CH:12][C:6]=2[N:5]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCN(S(=O)(=O)c2ccccc2)c2cc(C(=O)O)ccc2S1
Solvent: ClCCCl
Product: CC1(C)CCN(S(=O)(=O)c2ccccc2)c2cc(C(=O)Cl)ccc2S1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]-thiazepine-7-carboxylic acid (480 mg, 1.272 mmol) in DCE (20 mL) was added thionyl chloride (2 mL, 27.4 mmol). The reaction was heated to 70° C. and stirred at that temperature for 2 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The solvent was removed under reduced pressure and 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carbonyl chloride (500 mg, 1.263 mmol, 99% yield) was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.Cl.[NH2:10][CH:11]1[CH:18]2[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[C:12]1([CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2.O>O1CCCC1>[NH2:10][CH:11]1[CH:18]2[CH:19]([OH:27])[C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[C:12]1([CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: CC12CCCCCC(C(=O)c3ccc(O)cc31)C2N
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC12CCCCCC(C(O)c3ccc(O)cc31)C2N
Yield: 63.8 %

Procedure:
To a stirred suspension 2 g. of lithium aluminum hydride (LAH) in 250 mL of tetrahydrofuran (THF) was added a slurry of 1 g. (0.003 mole) of 13-amino-6,7,8,9,10,11-hexahydro-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-12(5H)-one hydrochloride dihydrate in 50 mL of THF over a period of 1 hour. The reaction mixture was refluxed for 25 hours and then cooled and excess LAH was decomposed by careful addition of 2 mL of water. The reaction mixture was filtered and the filtrate washed with aqueous ammonium chloride, dried (anhydrous Na2SO4) and evaporated under reduced pressure to afford a white residue which was recrystallized from acetone-ethanol (5:1) to afford 500 mg (68% yield) of the title compound, mp 232°-235° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]#[N:23])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COS(C1C=CC(C)=CC=1)(=O)=O>CC(C)=O>[CH3:1][N:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)[C:22]#[N:23]
Reactant: O=C([O-])[O-]
Reactant: N#CNc1ccc(OCc2ccccc2)cc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C#N)c1ccc(OCc2ccccc2)cc1

Procedure:
Potassium carbonate (9.6 g) was added to a solution of 4-benzyloxyphenylcyanamide (6.3 g) in acetone (450 ml) with stirring. A solution of methyl-4-toluene sulphonate (9 g) in acetone (50 ml) was added and the mixture stirred for 7 hours. The solvent was removed by evaporation and the residue suspended in water and extracted into dichloromethane. The extract was dried (Na2SO4) and the solvent removed by evaporation to give a residue which was triturated with a 1:1 mixture of ethylacetate and hexane to give N-methyl-4-benzyloxyphenylcyanamide (m.p. 116° C.).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.[CH2:15]([N:17]([CH2:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:16]>>[CH2:24]([N:17]([CH2:15][CH3:16])[C:18]1[CH:23]=[CH:22][C:21]([C:10]([C:5]2[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=2[C:7]([OH:9])=[O:8])=[O:11])=[CH:20][CH:19]=1)[CH3:25]
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCN(CC)c1ccccc1
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
In this example a mol-for-mol combination of phthalic anhydride (I) and N,N-diethylaniline (T) are reacted, as disclosed previously, to yield the keto acid (II). The keto acid is similarly reacted with N-vinyl carbazole to yield the title compound. The title compound imparts a blue-yellow color to paper coated with a phenolic resin or silton clay or a combination of the two. A reflectance spectrum of the blue-yellow color has an absorption peak at 630 nanometers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:30]
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1sccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1sccc1Cl
Reaction time: 4 h
Yield: 41.5 %

Procedure:
The intermediate 5-chloro-2-(1H-tetrazol-5-yl)aniline (200 mg, 1.0 mmol) and diisopropylethylamine (310 uL, 1.7 mmol) were taken up in 5 mL of dichloromethane. To the solution was added 3-chlorothiophene-2-carboyl chloride (221 mg, 1.2 mmol). The solution was stirred for 4 hours, at which point starting material was no longer detected by LCMS analysis. Dichloromethane (10 ml) was then added to solution. This solution was extracted 3 times with an aqueous solution of 0.1 N NaOH. The aqueous extractions were combined and concentrated HCl was added to until pH=1. The resulting precipitate was filtered and washed with acetonitrile to yield final product (141.1 mg, 41%). 1H NMR (400 MHz, d6-DMSO): 11.89 (s, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.05 (d, 1H), 7.45 (d, 1H), 7.30 (d, 1H). MS (EI) for C12H7Cl2N5OS: 340.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23](I)=[C:22]([CH3:27])[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])=[C:22]([CH3:27])[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(C)c3)cn2)CC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4F)c(C)c3)cn2)CC1

Procedure:
5′-(2′-Fluoro-2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 2-fluorophenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C27H28N3O3F [M+H]+: 462.2188. Found: 462.2186.
Reaction SMILES: [Cl-].[Ca+2:2].[Cl-].[P:4]([O-:8])([O-:7])([OH:6])=[O:5].[OH-].[Na+]>>[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:2].[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:2].[Ca+2:2]
Reactant: O=P([O-])([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: O=P([O-])([O-])[O-]

Procedure:
An aqueous solution of calcium chloride (18 mM) was added, dropwise and under magnetic stirring, to an aqueous solution on dibasic hydrogen phosphate (10.8 mM). The pH of both solutions was adjusted beforehand to 9.5 with NaOH. CaP NPs were obtained by filtration of the suspension through a 0.22 μm filter. CaP NPs were stored at 4° C. before use. CaP/ZOL-NPs complexes (CaPZ NPs) were prepared by mixing a CaP NPs dispersion with an aqueous solution of ZOL at different ZOL concentrations (10 mg/ml of ZOL in water or 50 mg/ml of ZOL in phosphate buffer at pH 9.5), at a volume ratio of 50:1.
Reaction SMILES: [CH2:1]1[CH2:33][O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:2]1.CO.[Na].Cl>O.O1CCCC1>[CH2:1]1[CH2:33][O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(OCCCNc2ccc(NCc3ccc4c(c3)OCCO4)cc2)cc1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCCCNc2ccc(NCc3ccc4c(c3)OCCO4)cc2)cc1
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To methyl 4-[3-[N-[4-(3,4-ethylenedioxybenzylamino) phenyl]amino]propoxy]benzoate (2.1 g) were added methanol (100 ml), tetrahydrofuran (20 ml) and 2N sodium hydroxyide (12 ml), and the mixture was stirred at 45°-50° C. overnight. To the reaction mixture was added water (150 ml), then, after the mixture was neutralized with 2N hydrochloric acid, the resulting precipitate was collected by filtration, washed with water and ethanol to give 4-[3-[N-[4-(3,4-ethylenedioxybenzylamino)phenyl]amino]propoxy]benzoic acid (0.4 g). mp. 246°-247° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:9]1([S:15][CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[CH3:16][S:15][C:9]1[CH:14]=[CH:13][C:12]([C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: CC(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CSc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Acetyl chloride (8.2 g, 0.105 mol) is added to a suspension of AlCl3 (16 g, 0.12 mol) in dichloroethane (50 ml) cooled to 0° C.; the mixture is stirred for 15 min and a solution of thioanisole (12.4 g, 0.1 mol) in dichloroethane (20 ml) is then added dropwise; the temperature is kept below 20° C. by cooling (30 min). The mixture is stirred for a further 1 h and allowed to stand at RT overnight. The Lewis acid complex is decomposed by addition of ice water (100 ml) with cooling, the organic phase is separated in a separating funnel, and the aqueous phase is extracted a further 2 times with dichloroethane (100 ml). The combined extracts are dried over Na2SO4 sicc. and concentrated to ¼ of the starting volume. The red-brown residue (15.2 g) is washed with diethyl ether (20 ml) and hexane (20 ml): 12 g of light red (brick-red) substance result.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH2:12][CH:13]3OC=CO3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:19]([NH:22][CH2:23][CH2:24][NH2:25])(=[O:21])[CH3:20]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:25]([CH2:24][CH2:23][NH:22][C:19](=[O:21])[CH3:20])[CH:13]=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CCC1OC=CO1)c1ccc2c(c1)OCO2
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc2c(c1)OCO2
Yield: 91.2 %

Procedure:
1-(1,3-Benzodioxol-5-yl)-3-(1,3-dioxol-2-yl)-1-propanone (1.7 g) was added under argon and while stirring to a solution of 1.4 g of N-acetylethylenediamine in 20 ml of acetic acid. The reaction mixture was refluxed overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 80 ml of methylene chloride and washed with a mixture of 50 ml of saturated sodium hydrogen carbonate solution and 10 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 50 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 2.6 g of brown oil, was chromatographed on 50 g of silica gel with ethyl acetate/hexane (2:1) as the eluent. 1.7 g (95%) of N-[2-[2-(1,3-benzodioxol-5-yl)-pyrrol-1-yl]-ethyl]acetamide were isolated as a yellow oil. MS: m/e=272 (M+).