Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:35])[CH:10]=1.N1C=CC=CC=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Yield: 42 %

Procedure:
To a solution of 2′,4′-difluoro-5-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-amine (65 mg, 0.136 mmol) in DCM was added pyridine (21 mg, 2.72 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (21 mg, 0.164 mmol, 1.2 eq.). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 9.04 (s, 1H), 8.99-8.98 (d, 1H), 8.90 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.76-7.70 (m, 2H), 7.49 (m, 2H), 7.35 (d, 1H), 4.82 (m, 1H), 3.95 (d, 2H), 3.58-3.55 (t, 2H), 3.36-3.28 (m, 2H), 2.12 (m, 2H), 1.29-1.24 (t, 3H), 1.08-1.06 (t, 2H); LC-MS (ESI): Calculated mass: 565.5; Observed mass: 565.9 [M+H]+ (rt: 1.44 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N1C=CN=C1)([N:17]1C=CN=C1)=O.O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH2:17])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc(Br)cc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Br)cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 3-bromonaphthalene-1-carboxylic acid (0.30 g) in tetrahydrofuran (3 mL) was added 1,1′-carbonyldiimidazole (0.29 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added ammonia water (1.0 mL, 28% aqueous solution), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was stirred at room temperature for 15 minutes. The precipitated solid was collected by filtration. The obtained solid was washed with water and 1 mol/L hydrochloric acid, and dried to give 3-bromonaphthalene-1-carboxylic amide (0.28 g).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2]C.[C:6]([C:10]1[O:11][C:12]([CH2:36]C)=[C:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:27]3[CH:26]=[CH:25]S[C:23]=3[C:22]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[C:30]([OH:32])=[O:31])=[CH:21][CH:20]=2)[N:14]=1)(C)([CH3:8])C>O=[Os](=O)(=O)=O.[BH4-].[Na+]>[CH2:34]([O:33][CH:29]([CH2:28][C:22]1[C:23]2[C:27](=[CH:26][CH:25]=[CH:1][CH:2]=2)[C:19]([O:18][CH2:17][CH2:16][CH2:15][C:13]2[N:14]=[C:10]([CH2:6][CH3:8])[O:11][C:12]=2[CH3:36])=[CH:20][CH:21]=1)[C:30]([OH:32])=[O:31])[CH3:35]
Reactant: CCC(=O)Cl
Reactant: CCOC(Cc1ccc(OCCCc2nc(C(C)(C)C)oc2CC)c2ccsc12)C(=O)O
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(Cc1ccc(OCCCc2nc(CC)oc2C)c2ccccc12)C(=O)O

Procedure:
was prepared in analogy to example 59, but starting the reaction sequence with propionyl chloride instead of isobutyryl chloride, and elaborating the terminal double bond via hydroboration with 9-BBN (as described in example 53) into a primary hydroxy group instead of oxidative cleavage with OsO4/NaBH4, as off-white solid of mp. 113–17°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O-])=O)=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([CH:15]([CH3:17])[CH3:16])[NH:5]1
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Reactant: Nc1ccc(CC(=O)[O-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Cl)c1-n1[nH]c(C(C)C)c2c(=O)nc(Cc3ccc(N)cc3)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
Part D: To a stirred solution of 1.4 g (4.8 mmol) 5-amino-3-isopropyl-1-(2-chloro-6-methyl-phenyl)pyrazole-4-carboxamide in 100 mL absolute ethanol was added 5.14 g (28.8 mmol) of 4-amino-phenylacetate followed by 10.7 mL (28.8 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux and the heating mantle was then removed. The reaction was treated with water and 10% aq. HOAc, cooled to ambient temperature, and filtered. The solid purified by column chromatography on silica gel using 1:1 hexanes-EtOAc as eluant to afford 743 mg (38%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)-pyrazolo[3,4-d]pyrimidin-4-one, mp 206-207° C. Mass Spec. (CI+): 408 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([F:28])[CH:21]=2)[CH:17]=[C:16]([N:29]2[C@H:34]([CH3:35])[CH2:33][O:32][C@H:31]([CH2:36][NH2:37])[CH2:30]2)[N:15]=1>C1COCC1>[NH2:13][C:14]1[N:15]=[C:16]([N:29]2[C@H:34]([CH3:35])[CH2:33][O:32][C@H:31]([CH2:36][NH:37][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([F:28])[CH:21]=2)[N:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNS(C)(=O)=O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
Triethylamine (41 μL, 0.30 mmol) and methanesulfonyl chloride (21 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (85 mg, 0.25 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (108 mg, about 90% pure) as a yellow solid. LC-MS (ES) m/z=421 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([N:13]([CH2:15][P:16](=[O:19])([OH:18])[OH:17])[CH3:14])(=[O:12])=[O:11].[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1.ClC(Cl)(Cl)C#N>N1C=CC=CC=1>[NH4+:13].[N+:26]([C:25]1[CH:20]=[CH:21][C:22]([O:19][P:16]([CH2:15][N:13]([S:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])[CH3:14])(=[O:18])[O-:17])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CN(CP(=O)(O)O)S(=O)(=O)c1cc2ccccc2s1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: N#CC(Cl)(Cl)Cl
Product: CN(CP(=O)([O-])Oc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1cc2ccccc2s1
Product: [NH4+]
Reaction time: 5 h
Yield: 173 %

Procedure:
A reaction mixture consisting of 500 mg (1.56 mmol) of (xv), 265 mg (1.90 mmol) of p-nitrophenol, 1.1 mL (111 mmol) of trichloroacetonitrile, and 5 mL of anhydrous pyridine was stirred in a sealed tube for 5 hours at 105–110° C. After the reaction was complete, pyridine was evaporated in vacuum, the oily residue was chromatographed on a silica gel column, eluent chloroform/MeOH/ammonium hydroxide (9:2:0.1) to yield 620 mg (87%) of the title compound as a pale crystalline substance: 1H NMR: (300 MHz, DMSO-d6) δH 2.89 (s, CH3), 3.07 (d, J=11.5 Hz, 2 H), 7.15 (br s, 4 H, NH4), 7.37 (d, J=9.3 Hz, 2 H, Ar—H), 7.47–7.57 (m, 2 H, Ar—H), 8.01–8.14 (m, 5 H, Ar—H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:11])[NH:9][OH:10])([CH3:6])([CH3:5])[CH3:4].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15].O>CN(C)C=O.O1CCCC1>[C:3]([O:7][C:8](=[O:11])[NH:9][O:10][C:14]([N:13]([CH3:17])[CH3:12])=[O:15])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)ONC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a suspension of sodium hydride (865 mg) in dimethylformamide (12 mL) and tetrahydrofuran (15 mL) was added t-butyl-N-hydroxycarbamate (2.5 g) on an ice bath. After stirring for 30 minutes, dimethylcarbamoyl chloride (2.32 g) was added and was stirred for 1 hour. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The solid that was obtained by drying the organic layer and removing the solvent by evaporation was washed with hexane, and a colorless solid (3.18 g) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:22]([Cl:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>>[ClH:30].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc2cccc(N3CCN(CCN)CC3)c2c1
Product: COc1ccc2cccc(N3CCN(CCNC(=O)c4cccnc4)CC3)c2c1
Product: Cl

Procedure:
This compound was prepared according to the process described in Example 1, Stage E, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine and nicotinoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.[ClH:15]>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: Cl
Reactant: COc1ccc(CO)c(OC)c1OC
Solvent: O
Product: COc1ccc(CCl)c(OC)c1OC
Temperature: 0 °C

Procedure:
5.0 g (4.34 mmols) of 2,3,4-trimethoxybenzyl alcohol was dropwise added to 10 ml of conc. hydrochloric acid under stirring at 0° C. The mixture was stirred at 0° C. for further 5 minutes. After the reaction, water was added to the mixture followed by extraction of the solution with diethyl ether. The diethyl ether layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford 4.80 g of 2,3,4-trimethoxybenzyl chloride as a crude product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:12][C:5]1([CH2:16][N+:13]([O-:15])=[O:14])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: O
Product: O=C1Nc2ccc(I)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 48 h

Procedure:
5-iodoisatin (0.136 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 48 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [C:1]1([C:7]([CH2:9]C=O)=N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.[C:18](O)(=O)C>>[C:1]1([C:7]2[CH:9]=[N:12][C:13]3[N:14]([N:15]=[CH:16][N:17]=3)[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc[nH]n1
Reactant: N=C(CC=O)c1ccccc1
Reactant: CC(=O)O
Product: c1ccc(-c2cnc3ncnn3c2)cc1
Temperature: 25 °C

Procedure:
An equimolar mixture of (phenyl)formimidoylacetaldehyde and 3-amino-1,2,4-triazole in glacial acetic acid (5 ml. acetic acid to 0.01 mole of reagents) is refluxed for 2 hours and allowed to cool to room temperature. The solid which separates is collected, washed with glacial acetic acid and dried. The solid is recrystallized from glacial acetic acid to give the product, m.p. 164°-167° C.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:24][CH2:23]3)[N:12]=[C:13]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[C:6]=12.C1(C)C=CC(S([CH2:44][N+:45]#[C-:46])(=O)=O)=CC=1.O>CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C@@H:25]2[CH2:26][CH2:27][C@H:22]([N:11]3[C:7]4=[N:8][CH:9]=[N:10][C:5]([NH2:4])=[C:6]4[C:13]([C:14]4[CH:21]=[CH:20][C:17]([C:18]5[O:19][CH:46]=[N:45][CH:44]=5)=[CH:16][CH:15]=4)=[N:12]3)[CH2:23][CH2:24]2)[CH2:33][CH2:32]1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(-c5cnco5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
Sodium methoxide (130 mg, 2.41 mmol) was added in portions to a mixture of 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (300 mg, 0.715 mmol) in methanol (20 mL). After 5 minutes, (p-tolylsulfonyl)methyl isocyanide (tosmic) (167 mg, 0.858 mmol) was added in portions. The solution was heated at reflux for 5 hours. Water (10 mL) was added while it was still hot. After cooling on ice for 5 minutes, the solid was filtered and washed with a mixture of methanol/water (50/50, 2 mL) then dried. The filtrate was evaporated to remove organic solvent and the solid was collected and washed with water. The combined solid was first purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase then re-crystallized twice from DMF to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(1,3-oxazol-5-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 27%). 1H NMR (DMSO-d6) δ 1.61 (m, 2H), 1.71 (m, 2H), 2.10 (m, 2H), 2.15 (s, 3H), 2.44 (m, 1H), 4.82 (m, 1H), 7.78 (m, 3H), 7.79 (m, 2H), 8.24 (s, 1H), 8.51 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=459.2, Rt=0.72 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1.[OH-].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>C(O)C>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Br)s3)CC2)cc1
Reactant: Sc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2(C(=O)Nc3ncc(Sc4ccccc4Cl)s3)CC2)cc1
Yield: 26 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid (5-bromo-thiazol-2-yl)-amide (35 mg, 0.10 mmol) was dissolved in ethanol (0.50 mL) containing potassium hydroxide (11 mg, 0.20 mmol). 2-Chloro-benzenethiol (11 L, 0.10 mmol) is added and the mixture is subjected to microwave irradiation for 15 minutes at 115° C. The crude reaction mixture is then separated by reverse-phase preparative liquid chromatography to yield the pure product (11 mg, 0.026 mmol, 26%). ESI-MS m/z calc. 416.0. found; 417.1 (M+1)+ Retention time 4.03 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[ClH:16].[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:23][CH2:22]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Product: COc1cc(-c2ccccc2CN2CCCN(Cc3ccccc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Product: Cl

Procedure:
2-(3,4,5-Trimethoxyphenyl)benzyl chloride (307 mg) and homopiperazine (53 mg) were reacted in the same manner as in Example 1 to obtain a free base of the title compound. This compound was converted into a dihydrochloride in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8][CH2:7][N:6]1[CH3:21])=[O:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@]1(COCc2ccccc2)CCCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@]1(COCc2ccccc2)CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of Intermediate 85c (3.37 g, 13.5 mmol) and formaldehyde (37% aqueous, 4.38 mL, 54.1 mmol) in DCM (140 mL) was stirred at RT for 30 min, then sodium triacetoxyborohydride (5.74 g, 27.1 mmol) was added. This mixture was stirred at RT for 18 h then washed with sat. aq. NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a clear oil (2.59 g, 72%). LCMS (Method 4): Rt 1.85 min, m/z 263 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH2:14][O:15]C(=O)C)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=1)=O.CC1C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>C1(C)C(CCO)=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:1]([CH2:2][C:3]2[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=2)[C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1
Reactant: CC(=O)OCCOc1ccc(CN)nc1[N+](=O)[O-]
Reactant: CCCOc1ccc(C(=O)CCC(=O)c2ccccc2Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1CCO
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc(-c2ccc(-c3ccccc3Cl)n2Cc2ccc(OCCO)c([N+](=O)[O-])n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
To a solution of 0.2 gm of acetic acid 2-(6-aminomethyl-2-nitropyridin-3-yloxy)-ethyl ester (0.8 mmol) in 3 mL of 5:1 toluene-ethanol was added 0.20 gm of 1-(2-chlorophenyl)-4-(4-propoxyphenyl)-butane-1,4-dione and 10 mg of p-TsOH. The reaction mixture stirred at 100° C. for 72 h. The reaction mixture was poured into 200 mL of CHCl3 and washed twice with water (100 mL), saturated brine, dried (Na2SO4), and the solvents removed under reduced pressure. The residue was purified by column chromatography using 4% methanol-chloroform as an eluent to give 100 mg (25% yield) of an oil. This was used without further purification or characterization.
Reaction SMILES: [C:1](O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.[C:11]1([CH:19]=[C:17]([OH:18])[CH:16]=[C:14]([OH:15])[CH:13]=1)[OH:12]>>[OH:12][C:11]1[C:19]2[C:1](=[O:9])[C:2]3[C:8](=[CH:7][CH:6]=[CH:5][CH:3]=3)[O:18][C:17]=2[CH:16]=[C:14]([OH:15])[CH:13]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: O=C(O)c1ccccc1O
Product: O=c1c2ccccc2oc2cc(O)cc(O)c12
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Salicylic acid (1.25 g, 9.1 mmol), phloroglucinol (1.26 g, 10 mmol), ZnCl□(3.1 g, 22.8 mmol) and POCl□ (8 mL) were charged to a dry round-bottom flask, and the reaction mixture was stirred at 80° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was very slowly added to ice water. When the reaction liquid was poured in ice water, ice was added portionwise to prevent overheating. The resulting precipitate was allowed to stand at 4° C. overnight, combined, washed with water and ether, and then dried under reduced pressure to give a reddish brown solid compound (1.94 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:15][C:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:25][C:26]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29].[C:43]1(C)C=CC=CC=1>>[CH:28]([C:27]1[C:26]([O:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH3:19])=[C:33]([C:2]2[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:6][CH:5]=[C:4]([CH2:15][C:16]([O:18][CH3:43])=[O:17])[CH:3]=2)[CH:32]=[CH:31][CH:30]=1)=[O:29]
Reactant: COCCOCOc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COCCOCOc1ccc(CC(=O)[O-])cc1Br
Reactant: Cc1ccccc1
Product: COCCOCOc1ccc(CC(=O)OC)cc1-c1cccc(C=O)c1OCOCCOC

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-4-(2-methoxyethoxymethoxy)phenylacetate (2.43 g, 7.28 mmol) and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzaldehyde in toluene (7.28 mmol, 0.1 M, 73 mL), gave methyl [3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (2.42 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][Br:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Br-:12].[C:1]([O:9][CH2:10][CH2:11][N+:24]([CH2:23][CH2:22][O:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:25])[CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CN(C)CCOC(=O)c1ccccc1
Solvent: CC#N
Product: C[N+](C)(CCOC(=O)c1ccccc1)CCOC(=O)c1ccccc1
Product: [Br-]
Yield: 74.2 %

Procedure:
Equimolar amounts of 2-bromoethyl benzoate (45.8 g) and 2-(N,N-dimethylamino)ethyl benzoate (38.5 g) were dissolved in 170 ml of acetonitrile and heated at reflux for 16 hours. The reaction mixture was then cooled and the resultant solid was collected, washed with ether, and dried to yield 62.4 g of the title compound, mp=169°-70° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:24][C:25]1[S:26][C:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][C:29]=1[CH3:30].[Sn](Cl)(Cl)(Cl)Cl>CN(C)C=O.C(Cl)Cl>[CH2:31]([C:27]1[S:26][C:25]([CH3:24])=[C:29]([CH3:30])[C:28]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C(C)C

Procedure:
Using 3,5-diisopropyl-p-anisic acid (5.0 g, 21.2 mmol, RN-117439-59-5), oxalyl chloride (2.2 mL, 25.4 mmol), N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.3 g, 21.2 mmol), tin(IV) chloride (5.0 mL, 42.7 mmol), and anhydrous methylene chloride (82 mL) the title compound was prepared according to the procedure in Example 2, step 1 to give 4.1 g (45%) NMR (DMSO-d6) δ 7.47 (s, 2 H), 7.23-7.12 (m, 3 H), 7.02-6.99 (m, 2 H), 3.86 (s, 2 H), 3.73 (s, 3 H), 3.31-3.20 (m, 2 H), 2.27 (s, 3 H), 1.82 (s, 3 H), 1.15 (d, 12 H). MS(EI), [M+] 420.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:4][C:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl-:1].[CH3:14][C:5]1[S:4][C:3]([CH2:2][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1sc(CCl)nc1-c1ccccc1
Product: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Product: [Cl-]

Procedure:
2-Chloromethyl-5-methyl-4-phenylthiazole and triphenylphosphine were reacted in the same manner as in Reference Example 7 to yield (5- methyl-4-phenyl-2-thiazolylmethyl)triphenylphosphonium chloride. Melting point 256°-257° C.