Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CN(C=[O:38])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:38])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C=O
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(O)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (100 mg) in DMF (2 mL) was added sodium hydride (60%, 9.4 mg) at room temperature, and the mixture was stirred for 30 min in the air. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (40.3 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2c(F)cccc2F)cc1

Procedure:
Compound (100) was prepared from compound (20) and (2,6-difluorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.83 mins, m/z (ES−) 343 (M−H for C19H14F2O4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][C:21](=[O:23])[CH3:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1c[nH]c2cc(F)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reaction time: 1 h

Procedure:
To a solution of 2-(6-fluoro-1H-indol-3-yl)-ethylamine (0.88 g) and NEt3 (2.27 ml) in CH2Cl2 (8 ml) was added acetic acid anhydride (0.43 ml) and stirring was continued at 22° C. for 1 h. The mixture was washed with 1 N aqueous HCl, the organic layer was dried and evaporated. The residue was chromatographed on silica using CH2Cl2/MeOH (25:1) to give the title compound as a pale yellow oil. MS: 219.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH:18]=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH2:18][OH:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCn1nc(C)c(C=O)c1Sc1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1nc(C)c(CO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
A mixture of 1.1 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde and 0.53 g of sodium borohydride in 25 ml of anhydrous methanol was stirred under nitrogen at room temperature for 15 minutes. Water (25 ml) was added and the mixture was extracted three times with 20 ml of diethyl ether. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40-60° C.) (1:3) for the elution to give 902 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl]-methanol as a yellow oil. Mass spectrum (ES) m/z 317 [M+H]+.
Reaction SMILES: N#N.[SH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[SiH4].[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCCCCC.C(N(CC)CC)C>[C:18]([S:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: CCCCCCCC(=O)Cl
Agent: N#N
Agent: [SiH4]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Yield: 86.8 %

Procedure:
Into a 12-liter, three-necked round bottom flask equipped with mechanical stirrer, addition funnel, thermocouple, heating mantle, N2 inlet, and temperature controller were charged 1,021 grams of 3-mercaptopropyltriethoxysilane (SILQUEST® A-1891 silane from OSi Specialties, Inc., a subsidiary of Crompton Corp. of Greenwich, Conn.), 433 grams of triethylamine, and 3,000 ml hexane. The solution was cooled in an ice bath, and 693 grams of octanoyl chloride were added over a two hour period via the addition funnel. After addition of the acid chloride was complete, the mixture was filtered two times, first through a 0.1 μm filter and then through a 0.01 μm filter, using a pressure filter, to remove the salt. The solvent was removed under vacuum. The remaining yellow liquid was vacuum distilled to yield 1,349 grams of octanoylthiopropyltriethoxysilane as a clear, very light yellow liquid. The yield was 87 percent.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:19])[CH2:14][C:15](OC)=[O:16])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:21].[NH2:22][NH2:23]>C(O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:16])[NH:22][N:23]=3)=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:21]
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)SCC(=O)N2C
Reactant: NN
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)SCC(=O)N2C

Procedure:
Methyl 4-(3,4-dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-7-yl)-4-oxo-3-methylbutyrate (1.7 g) was heated at reflux overnight with 0.3 ml of hydrazine in 50 ml of ethanol. Filtration gave a white powder which was chromatographed on silica gel eluted with 5% methanol in methylene chloride, yielding 110 mg of the named compound, mp 193°-194.5° C.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH2:21][CH3:22])([CH2:19]O)[CH2:17][OH:18]>>[OH:18][CH2:17][C:16]1([CH2:21][CH3:22])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCC(N)(CO)CO
Product: CCCCCCCCCCCC1=NC(CC)(CO)CO1
Yield: 90.1 %

Procedure:
26 g (130 mmoles) of dodecanoic acid and 31 g (260 mmoles) of 2-amino-2-ethyl-1,3-propanediol were condensed together by heating at 185°-190° C. for 30 hours. Work up and distillation of the residue at 160°-162° C./1 mm Hg gave 33.19 g (90%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([Mg]Cl)cc1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(C#N)c2)cc1
Yield: 89 %

Procedure:
4-methylphenylmagnesium chloride (49 g, 20% solution in tetrahydrofuran) is added dropwise over eight hours to a refluxing solution of 3-bromobenzonitrile (10 g), palladium (II) acetate (2.4 g) and triphenylphosphine (5.8 g) in tetrahydrofuran (200 ml). [HPLC: yield 89-91%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (3:1) (200 ml ) and the aqueous phase separated off. The solvent is removed by distillation and the crude product purified by column chromatrography (Kieselgel 60; n-hezane/acetone 3:1) to give 4'-methylbiphenyl-3-carbonitrile as a solid, m.pt. 59-61° C. 1H NMR (CDCl3): 2.41(s,3H), 7.29(d,2H), 7.46(d,2H), 7.49-7.63(m,2H) 7.77-7.85(m,2H).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18].O>C(O)(C)(C)C>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH:16]([C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:12])[C:17]#[N:18]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(OC)nc1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)C(C#N)c2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C
Yield: 29.3 %

Procedure:
To a suspension of potassium-tert-butylate (2.052 g) in tert-butanol (25 ml) was added methyl-6-methoxynicotinate (2.5 g). 2,4-Dichlorobenzyl cyanide (2.782 g) was added portion wise. The mixture was heated to 100° C. for 1.5 h. After cooling to room temperature, water (100 ml) was added and the mixture was washed with diethyl ether. The aqueous phase was neutralized with concentrated aqueous HCl and extracted with EtOAc. The organic phase was washed with water and with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound (1.407 g) as a yellow foam that was used in the next step without further purification. MS (m/e)=321.0 [M+H+].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:16])C.C(O)(=O)C>[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:16])=[CH:3][CH:4]=1
Reactant: CCCCC(CC)COC(=O)CCN(CC)CC
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 2.34 g (10 mmol) of p-iodoanisole, 2.57 g (10 mmol) of 2-ethylhexyl β-diethylamino-propionate, 0.9 g (15 mmol) of acetic acid and 15 mg of palladium on charcoal (5%) is stirred at 150° C. for 2 hours. Therafter, the mixture is worked up as in Example 1. 2-Ethylhexyl p-methoxycinnamate is obtained in 93% yield.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:21].O>C1COCC1>[ClH:21].[ClH:21].[N:15]1([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CC[C@H](CN2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl(trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)carbamate (1.3 g, 4.5 mmol) in THF (15 mL) was added aqueous 6 N HCl (6 mL) and water (6 mL) and the reaction mixture was stirred with heat at 65° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to afford the desired product (1.2 g, >99%) as an off-white solid. ESI MS m/z 183 [C11H22FN2+H]+
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]2[CH2:8][N:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl-].[Li+]>CS(C)=O.O>[CH2:26]([O:25][C:23]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:9]=2[CH2:8]1)=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c3c(nc(C)c2C(=O)O)CCN(C(=O)OCc2ccccc2)C3)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
A mixture of 6-benzyl 3-methyl 2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-3,6(5H)-dicarboxylate (intermediate 10) (0.482 g, 1.12 mmol) and lithium chloride (0.475 g, 11.19 mmol) in 2,6-lutadine (10 mL) and DMSO (10.00 mL) was stirred at 130° C. for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc to remove unreacted starting material and impurities. The aqueous phase was made acidic with 1N HCl and extracted with EtOAc (2×'s) then CH2Cl2. The organic extracts were combined, dried (Na2SO4), filtered and concentrated to provide 6-((benzyloxy)carbonyl)-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (74.2 mg, 15% yield) as an amber oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (br. s., 4H), 7.24 (d, J=7.83 Hz, 3H), 7.13 (d, J=7.58 Hz, 2H), 5.11 (s, 2H), 4.36 (s, 2H), 3.78 (t, J=5.62 Hz, 2H), 3.30 (br. s., 2H), 2.80 (br. s., 3H), 2.38 (s, 3H). LCMS (M+H) calcd for C25H25N2O4: 417.18. found: 417.4.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(CC)CC)C.[Cl-].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.Cl>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:22]([O:33][CH3:34])=[O:32])=[CH:24][CH:25]=1)=[O:28])#[N:10]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: Br
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reaction time: 3 h

Procedure:
1.50 g (6.2 mmol) of 3-(2-aminoethoxy)benzonitrile hydrobromide and 3 ml of triethylamine were stirred in 15 ml of dimethylformamide under cooling with ice. 1.23 g (6.2 mmol) of monomethyl terephthalate chloride was slowly added thereto, and they were stirred for 3 hours. The temperature was elevated to the room temperature, and the reaction liquid was diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:18]=2)[C:13]1=[O:30].C(N(CC)CC)C.[N:38]1([CH2:44][C:45]#[CH:46])[CH2:43]COC[CH2:39]1>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:39][N:38]([CH3:43])[CH2:44][CH2:45][CH2:46][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:13]2=[O:30])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(CCCN(C)C)cc3c2=O)c1
Temperature: 80 °C
Yield: 86.9 %

Procedure:
A mixture of the methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate (400 mg), PdCl2(PPh3)2 (16 mg), CuI (9 mg) and triethylamine (632 μl) were stirred in acetonitrile (10 ml) for 10 minutes. 3-(4-morpholinyl)-1-propyne (114 mg) in acetonitrile (4 ml) was then added dropwise and the reaction was heated at 80° C. for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown oil. The oil was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield methyl 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a brown oil (298 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.55 (m, 4H), 3.57 (s, 2H), 3.63 (m, 4H), 3.87 (s, 3H), 6.78 (d, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.79 (m, 2H), 7.86 (s, 1H), 7.99 (d, 1H), 8.24 (s, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH2:18][CH2:19]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCCN1CCN(c2ccccn2)CC1
Yield: 71.2 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), 1-(pyridin-2-yl)piperazine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 1-(pent-4-ynyl)-4-(pyridin-2-yl)piperazine (1.02 g).
Reaction SMILES: Cl.[C:2]1([C@H:12]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[C:24]([C:23]1[CH:27]=[CH:28][C:20]([N:17]2[CH2:18][CH2:19][C@H:15]([NH:14][C@@H:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[CH3:13])[CH2:16]2)=[CH:21][CH:22]=1)(=[O:26])[CH3:29]
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg of 4-[(S)-3-[(R)-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) in 5 ml of methylene chloride (MeOH free) was added dropwise 43 μl of oxalyl chloride, and then, several drops of dimethylformamide were added to the mixture, and the resulting mixture was stirred under room temperature for 16 hours. The solvent was removed from the reaction mixture to obtain the residue. (2) To the compound obtained as mentioned above were added dimethylamine (82 μl of 2M THF solution) and 10 ml of methylene chloride to dissolve them, 70.2 μl of triethylamine was added to the mixture, and the mixture was stirred under room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate 7:1→0:1) to obtain 22.4 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (3) To a solution of 22.4 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was concentrated, t-butanol was added to the residue to dissolve the same, and freeze-dried to obtain 22.9 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (Example 3.012 in the following Table A3).
Reaction SMILES: [CH2:1]([C@H:3]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[CH2:4][OH:5])[CH3:2].C([OH:14])(C)C.N[C@H](C(OC)=O)CC1C=CC=CC=1.N[C@@H](C(OC)=O)CC1C=CC=CC=1>CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([C@H:3]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[C:4]([OH:14])=[O:5])[CH3:2]
Reactant: CC[C@@H](CO)CC[N+](=O)[O-]
Reactant: CC(C)O
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: COC(=O)[C@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC[C@H](CC[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To 1.0 mmol alcohol 2b dissolved in 10 mL acetone at 0° C. was added 1.5 mmol H2Cr2O7 (3 mL Jones reagent). The mixture was stirred for 5 h, during which time the mixture warmed to room temperature. Excess isopropanol was added, and the mixture was stirred for 10 min. The mixture was filtered, and the solution was diluted with 2 mL 2 N HCl and extracted with Et2O. Complete extraction of the product into the Et2O phase was monitored by TLC. The organic layers was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give a viscous oil, of which the desired product 3 was purified via column chromatography eluting with EtOAc/hexane (1:10 to 1:3; v/v) to give pure product as a yellow oil in 92% yield. TLC Rf=0.45 (EtOAc/hexanes, v/v, 1:1) 1H NMR (300 MHz, CDCl3) 4.56-4.41 (m, 2H), 2.53-2.44 (m, 1H), 2.38-2.19 (m, 2H), 1.84-1.60 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.66, 73.55, 43.57, 28.41, 25.24, 11.41. HRMS m/z (ESI): calc. for C6H11NO4Na [M+Na]+ 184.0586, found 184.0578. Optical rotation: [α]rtD +17.51 (c=3.82, CHCl3). The ee of this compound (>95%) was determined by coupling one portion to L-Phe-OMe and another portion to D-Phe-OMe and then analyzing the products by 1H NMR spectroscopy.
Reaction SMILES: N[C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[ClH:14].N([O-])=O.[Na+]>O>[Cl:14][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Yield: 83 %

Procedure:
3-Amino-2,4,5-trifluorobenzoic acid (Example 2), 0.52 g, and 3 g of cupric chloride are added to 10 ml of a 3% aqueous solution of hydrochloric acid and the mixture is stirred with ice bath cooling. A solution of 0.32 g of sodium nitrite in 4 ml of water is added to the reaction mixture in portions over a one-hour period while maintaining the reaction at 0°-5° C. The ice bath is then removed and the mixture is stirred for two hours at room temperature. Toluene, 20 ml, and 15 ml of water are added with stirring. The layers are separated and the aqueous layer extracted with 20 ml of toluene. The combined toluene extracts are extracted with 4 ml of a 36% aqueous solution of hydrochloric acid and then concentrated to a solid under reduced pressure to give 0.48 g (83%) of 3-chloro-2,4,5-trifluorobenzoic acid as a tan solid; GC (98.4%); HPLC (89.2%); recrystallization from heptanes gives 0.40 g (70%) of 3-chloro-2,4,5-trifluorobenzoic acid; mp 109°-111° C.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14]Br>C(O)(=O)C.O>[Br:14][C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Yield: 70 %

Procedure:
One mole of theophylline is dissolved in 2.5 liters of acetic acid containing one liter of water, and kept at 50° C., until the theophylline is dissolved and the medium becomes homogeneous. 1.1 mole of bromine is then added, drop by drop, and the bromine derivative, 8-bromotheophylline precipitates in the medium. The solution is then ccoled to room temperature , and the product filtered and washed with water, and then dried to give 70-85% yield of 8-bromo-theophylline.