Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a stirred solution of 6-hydroxy-2,3-dihydroinden-1-one (30 g, 0.203 mol) in 300 mL DMF was added K2CO3 (70 g, 0.507 mol), followed by addition of BnBr (38.2 g, 0.225 mol) dropwise at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 20 h. The mixture was diluted with EtOAc (500 mL), then filtered to remove the solid. The filtrate was washed with brine (200 mL×5), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulted solid was recrystallized in ether to give the title compound (44.5 g, 92%) as a white solid. 1H-NMR (600 MHz, CDCl3) δ 7.47-7.46 (m, 2H), 7.44-7.39 (m, 3H), 7.38-7.35 (m, 1H), 7.31-7.30 (m, 2H), 5.12 (s, 2H), 3.11-3.09 (m, 2H), 2.76-2.74 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.[OH2:10].Cl.[NH2:12]O.[OH-].[Na+]>CCO.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:12][OH:10]
Reactant: NO
Reactant: O=Cc1cnccc1Cl
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: ON=Cc1cnccc1Cl
Temperature: 0 °C

Procedure:
4-Chloro-pyridine-3-carbaldehyde (10.0 g, 71 mmol) was dissolved in EtOH (12 ml). H2O (30 ml), ice (30 g) and hydroxylamine hydrochloride (5.40 g, 78 mmol) were added. To the resulting mixture was added over a period of 2 min a solution of 2 N NaOH (88.3 ml, 177 mmol). The resulting yellowish solution was stirred 2.5 h at r.t. before neutralisation with AcOH (pH=6). White crystals precipitated, were collected by filtration and washed with H2O (30 ml). The product was dried 1 h at 50° C. on the high vacuum to yield 9.25 g (84%) of a off white solid. m/z=157.1 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](O)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([Cl:25])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)NC(O)C(Cl)(Cl)Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC(Cl)C(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A stirred solution of Example 37C (20.0 g, 70.8 mmol) in CH2Cl2(300 mL) at 0° C. was treated with pyridine (10 mL). The reaction mixture was treated dropwise with thionyl chloride (10.4 mL, 141 mmol), and the reaction flask was equipped with a calcium chloride drying tube. The reaction mixture was warmed to ambient temperature and stirred for 4 hours. Concentration of the reaction mixture to a reduced volume and addition of diethyl ether (100 mL) resulted in a precipitate which was filtered off, and the filtrate was concentrated and dried under reduced pressure to provide 19.0 g of the desired product as a white solid.
Reaction SMILES: C(C[C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10]C)=[O:9])#N.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([CH2:20][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:22])=[O:21]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(CC#N)cc1C(=O)OC
Agent: Cl
Product: O=C(O)Cc1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
0.78 g of dimethyl 4-cyanomethylphthalate was dissolved in a mixed liquid comprising 15 ml of concentrated hydrochloric acid and 4 ml of acetic acid, followed by stirring under heating at 120° C. for 2.5 hours. The reaction solution was left to cool to room temperature and then extracted by an addition of ethyl acetate and water. The organic layer was post-treated in accordance with a usual method to obtain 0.53 g of the above identified compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].CI.[C:30](OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:7]([CH3:30])[C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(C)=O
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]

Procedure:
12 g nifedipine was introduced into a 100-mL three-neck flask and dissolved in 50 mL tetrahydrofuran under nitrogen. 1.66 g of a 60% dispersion of sodium hydride in oil was then added with stirring. After stirring for a short period of time, 10 mL methyl iodide was added and the reaction was stirred for 1 hour at 38° C. 200 mL ethyl acetate was then added, and the organic layer was thereafter washed several times with water and dried over sodium sulfate. The sodium sulfate was subsequently filtered off and the solvent was then pulled off from the filtrate on a rotary evaporator. The obtained solid was dissolved in 200 mL MIBK, and the addition of hexane to this solution then yielded 8.9 g N-methylnifedipine as yellow crystals. mp=184°-187° C.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:28])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[NH:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[C:6]([O:10][C:11](=[O:28])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[N:17]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[CH2:32][CH2:33][CH3:34])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)NCCCC(=O)Nc1cc(C#N)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(C(=O)CCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A DMF solution (4.0 ml) containing the compound (0.501 g) obtained in Example 46-2 was added with 60% sodium hydride (76.0 mg) and the whole was stirred at room temperature for 30 minutes. The solution was cooled with ice and then 1-iodopropane (0.184 ml) was dropped thereto. The whole was stirred at room temperature for 23 hours. The solvent in the reaction solution was distillated off. The resultant was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (ethyl acetate/chloroform), thereby obtaining the subject compound (0.378 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(S(=O)(=O)c2ccccc2)c2[nH]c3ccc(Cl)cc3c21
Reaction time: 0.5 h

Procedure:
A solution of 6-chloro-4-oxo-1,2,3,4-tetrahydrocarbazole (109 mg, 0.5 mmol) in THF is treated with NaH (60 mg, 60% dispersion in mineral oil, 1.5 mmol), stirred for 30 min., treated with phenylsulfonyl chloride (132 mg, 0.5 mmol), shaken for 8 h and concentrated in vacuo. The resultant residue is dissolved in ethyl acetate, washed with water and reconcentrated in vacuo to afford the title product which is used as is in Example 134.
Reaction SMILES: [CH2:1]=[C:2]([CH:5]=[N:6][C:7]([O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:8])[CH2:3][CH3:4].[Br:14][C:15]1[CH:23]=[C:22]2[C:18](/[C:19](=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)/[C:20](=[O:32])[N:21]2[CH2:24][O:25][CH2:26][CH2:27][Si](C)(C)C)=[CH:17][CH:16]=1.CO>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:23]=[C:22]2[NH:21][C:20](=[O:32])[C:19]3([CH:33]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=4)[CH2:8][C:7](=[O:9])[NH:6][CH:5]3[C:2](=[CH2:1])[CH2:3][CH3:4])[C:18]2=[CH:17][CH:16]=1.[CH3:24][O:25][CH:26]([Si:10]([CH3:11])([CH3:12])[CH3:13])[CH3:27]
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Reactant: C=C(C=NC(=C)O[Si](C)(C)C)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Product: COC(C)[Si](C)(C)C
Temperature: 135 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of 1-(1-ethyl-ethenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (42 mmol) prepared in example 80a in toluene (50 mL) was added E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (2 g, 4.3 mmol) prepared in example 161a. The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After cooling to room temperature, methanol (100 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:Hexane=2:1) gave racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a solid (Yield 350 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]1[C:18](=O)[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].Cl.NO.[N:27]1C=CC=CC=1>C(O)C>[CH2:4]([CH:5]1[CH2:6][N:7]2[CH2:8][CH2:9][C:10]3[C:15]([CH:16]2[CH2:17][CH:18]1[NH2:27])=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH:2]([CH3:3])[CH3:1]
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc2c(cc1OC)C1CC(N)C(CC(C)C)CN1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HG-6 was also synthesized using the following alternative method: tetrabenazine (317 mg, 1 mmol) was dissolved in ethanol (EtOH, 10 ml) and hydroxylamine hydrochloride (70 mg, 1 mmol) was added, followed by the addition of pyridine (1 ml). The reaction was refluxed for 2 hours. After removing solvent, the residue was redissolved in methanol (MeOH, 10 ml). To this solution, MoO3 (80 mg) and sodium borohydride (80 mg) were slowly added. The reaction was stirred at room temperature for 24 hours and quenched with water. The aqueous solution was extracted with methylene chloride (10 ml) twice. The combined organic phase was washed with brine and dried with sodium sulfate. After removing solvent, the residue was purified by chromatography. Two hundred and fifty milligrams of HG-6 (3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-amine) was obtained as white solid (yield: 78%).
Reaction SMILES: Cl[C:2]1(Cl)[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:10]>C(O)(=O)C.C(OCC)C.[Zn]>[CH:9]12[CH2:2][C:3](=[O:10])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=C1C2CCCCC2C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CC2CCCCC12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
(1RS,6SR)-8,8-dichlorobicyclo[4.2.0]octan-7-one (preparation 18) (8.60 g, 44.6 mmol) was heated to reflux in acetic acid (100 ml) with zinc dust (29.0 g, 446 mmol). After 4 hrs the mixture was cooled to room temperature, diluted with diethyl ether (200 ml) and washed with 2N NaOH (2×100 ml) and then with saturated aqueous NaHCO3 (4×100 ml). The ether phase was collected, dried (MgSO4) and the solvent was removed under reduced pressure to give 4.79 g of the title compound as a clear oil.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=2[CH:11]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: N#Cc1nc2ccc(O)cc2s1
Product: C=CCOc1ccc2nc(C#N)sc2c1

Procedure:
In greater detail, 2-cyano-6-methoxybenzothiazole is used as a starting material and reacted with pyridine hydrochloride to yield 2-cyano-6-hydroxybenzothiazole. Next, the 2-cyano-6-hydroxybenzothiazole is reacted with allyl bromide to yield 6-allyloxy-benzothiazole-2-carbonitrile.
Reaction SMILES: OC(COC1C=CC=CC=1)CC(O)=O.O[CH:16]([CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]([OH:20])=[O:19]>>[O:24]([CH2:23][CH2:22][CH2:21][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CC(O)CCCOc1ccccc1
Agent: O=C(O)CC(O)COc1ccccc1
Product: O=C(O)CCCCCOc1ccccc1

Procedure:
Also, in Macromolecules, 29, 3432-3435 (1996), it is reported that using Pseudomonas oleovorans, PHA containing 3-hydroxy-4-phenoxybutyric acid and 3-hydroxy-6-phenoxyhexanoic acid as units is produced from 6-phenoxyhexanoic acid, PHA containing 3-hydroxy-4-phenoxybutyric acid, 3-hydroxy-6-phenoxyhexanoic acid and 3-hydroxy-8-phenoxyoctanoic acid as units is produced from 8-phenoxyoctanoic acid, and PHA containing 3-hydroxy-5-phenoxyvaleric acid and 3-hydroxy-7-phenoxyheptanoic acid as units is produced from 11-phenoxyundecanoic acid. Yields of polymers in this report are extracted and are shown in the following.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccncc1
Reactant: NC(=O)c1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: O=c1[nH]c(-c2ccncc2)nc2ccccc12
Yield: 85 %

Procedure:
To a flask of anthranilamide (1 mmol) was added 4-pyridine carboxaldehyde (1 mmol) to form a paste. Followed by the careful addition of 2,3 dichloro-5,6-dicyano-1,4-benzoquinone, (0.5 mmol), the well blended mixture was microwaved in a beaker with silica for 9 min. To the resultant solid was added methanol with subsequent sonication. The collected filtrate was concentrated and dried in vacuo to afford the desired product as a brown solid (85% yield). 1H NMR (400 MHz, d6-DMSO): δ 12.80 (br s, 1H), 8.80 (d, 2H), 8.20 (d, 1H), 8.12 (d, 2H), 7.88 (t, 1H), 7.80 (d, 1H), 7.60 (t, 1H). MS (EI) for C13H9N3O: 224 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH:16]12[NH:24][CH:20]([CH2:21][CH2:22][CH2:23]1)[CH2:19][C:18](=O)[CH2:17]2.Cl.C(O)(=O)C>>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][C:18]1[CH2:17][CH:16]3[NH:24][CH:20]([C:19]2=1)[CH2:21][CH2:22][CH2:23]3
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CC2CCCC(C1)N2
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Temperature: 25 °C

Procedure:
In a 30 mL microwave reaction tube were combined 4-(trifluoromethoxy)phenyl-hydrazine hydrochloride (1062 mg, 5.0 mmol; Maybridge), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (878 mg, 5.0 mmol; Accela ChemBio), and 1 N HCl in acetic acid (15 mL, 15 mmol; Aldrich). The reaction mixture was microwaved at 150° C. (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to ˜pH 12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.33-1.52 (m, 2H), 1.64-1.78 (m, 2H), 1.89-2.06 (m, 2H), 2.68 (d, J=17 Hz, 1H), 3.25-3.34 (m, 1H), 3.62 (t, J=5 Hz, 1H), 4.43 (t, J=3 Hz, 1H), 6.93 (ddd, J=9, 2, 1 Hz, 1H), 7.22 (d, J=1 Hz, 1H), 7.31 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]([CH3:25])[C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>CN(C)C=O>[CH3:18][N:19]([CH3:25])[C@H:20]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Nc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(c2nccc(N)n2)C1
Temperature: 220 °C
Yield: 64.1 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (539 μl, 3.09 mmol) and (3S)—N,N-dimethyl-3-pyrrolidinamine (294 μl, 2.316 mmol) in N,N-dimethylformamide (DMF) (2 ml) was heated to 220° C. via a microwave reactor for 30 min. The reaction mixture was purified by RP-HPLC to yield 2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinamine (205 mg, 0.989 mmol, 64% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C.[CH2:14]([NH:17][C:18]([NH2:20])=[S:19])[CH:15]=[CH2:16]>CC(C)=O>[ClH:1].[CH3:12][C:11]1[C:2]([S:19][C:18](=[NH:20])[NH:17][CH2:14][CH:15]=[CH2:16])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=CCNC(N)=S
Reactant: Cc1nc2ccccc2nc1Cl
Agent: C
Solvent: CC(C)=O
Product: C=CCNC(=N)Sc1nc2ccccc2nc1C
Product: Cl
Yield: 75.6 %

Procedure:
2-Chloro-3-methylquinoxaline (5.359 g., 0.03 mole) was dissolved in 75 ml. of acetone, treated with Norit and filtered. The filtrate was added to a solution of 3.485 g. (0.03 mole) of allylthiourea in 50 ml. of acetone while the solution was stirred at room temperature under N2. A precipitate had formed at the end of 2 hours. Stirring was continued for 31/2 hours. The solid that was filtered off was washed with acetone, then ether and dried, to give 6.68 g. (75.6% yield) of product as a pink solid, m.p. 113°-114° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([OH:17])=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([CH:13]=1)[CH:11]=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A mixture of 5-butoxy-4-hydroxy-2-nitrobenzaldehyde (31 g; 0.13 mole), benzyl chloride (20.2 g; 0.16 mole) and potassium carbonate (22.11 g; 0.16 mole) in 80 ml of dimethylformamide is heated for 2 hours under reflux with stirring. The reaction mixture is poured into 200 ml of ice-cold water and the precipitate filtered off. After recrystallization in a hexane/toluene mixture, 4-benzyloxy-5-butoxy-2-nitrobenzaldehyde (30.2 g; yield: 71%; yellow powder) is obtained; melting point 94° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C([N:8]([CH2:11][CH3:12])CC)C.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(#N)C>[C:11]([CH:12]1[CH:17]([C:5]2[N:1]=[N:2][N:3]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:4]=2)[CH2:16][CH2:15][CH2:14]1)#[N:8]
Reactant: CCCCCCCCCCCCBr
Reactant: CCN(CC)CC
Reactant: c1nnn[nH]1
Solvent: CC#N
Product: CCCCCCCCCCCCn1nnc(C2CCCC2C#N)n1

Procedure:
The tetrazole (b) obtained above (11.0 g; 0.067 moles) was dissolved in acetonitrile (150 mL) containing one equivalent of triethylamine (6.8 g; 0.067 moles). The solution was heated to reflux followed by the addition of 1-bromo dodecane (16.8 g; 0.067 moles). Isolation of the 2-isomer was achieved employing the same conditions described for Example 11. Yield: 7.5 g; colorless liquid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([CH:26]=[CH2:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([CH2:26][CH2:27][NH:32][CH2:31][CH2:30][O:29][CH3:28])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Reactant: COCCN
Product: COCCNCCc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Yield: 96 %

Procedure:
N*2*,N*4*-Dibenzyl-3-nitro-6-vinyl-pyridine-2,4-diamine (50 mg, 0.14 mmol) was suspended in 2-methoxy-ethylamine (1 ml) and the mixture refluxed for 1 h. Excess reagents was removed in vacuo, the residue dissolved in DCM (10 ml), washed with 2×H2O, dried and concentrated. The crude material was purified by column chromatography on silica, eluting with DCM:MeOH, 92:8 to give the title compound as a yellow oil, (58 mg, 96%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][CH:21]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:21]1[CH:20]=[N:19][N:12]2[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)=[N:10][C:11]=12
Reactant: ClI
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.0 g, 15.1 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.40 g, 17.1 mmol) and drop wise a solution of iodine monochloride (2.77 g, 17.1 mmol) in acetic acid (10 mLl). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 94%) as a yellow solid. MS (EI) 457.0[(M)+]; mp 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[C:16]([C:23]([OH:25])=O)=[CH:15][C:13]=2[N:14]=1.F[B-](F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.C1COCC1.C1(N)CCCCC1>CN(C=O)C>[CH:35]1([NH:31][C:23]([C:16]2[C:17]3[O:21][C:20]([CH3:22])=[CH:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:14][C:13]=3[CH:15]=2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:34]1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c(o1)c(C(=O)NC1CCCCC1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 13.3 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2,6-dichlorophenyl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-9, 0.050 g, 0.132 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.085 g, 0.265 mmol), TEA (1 mL), THF (5.0 mL), DMF (1.0 mL) and cyclohexyl amine (0.026 g, 0.265 mmol) to afford 0.008 g of the desired product. 1HNMR (DMSO-d6): δ 1.23-1.30 (m, 2H), 1.31-1.36 (m, 4H), 1.89 (m, 4H), 3.85 (m, 1H), 4.19 (s, 3H), 6.74 (s, 1H), 7.41-7.94 (m, 4H), 9.07 (s, 1H), 11.00-12.00 (s, 2H).