Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[Cl:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([O:41]CC)=[O:40].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]=4[Cl:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([OH:41])=[O:40]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C(F)(F)F)cc5Cl)nn4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.034 g, 0.054 mmol) in 3:1 THF/EtOH (1 ml) was added 1M sodium hydroxide (0.22 ml, 0.22 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated to dryness, taken up in water, and acidified with 1M hydrochloric acid. The reaction was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.030 g, 0.050 mmol, 92% yield).
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[CH:6][NH+:5]=1.[F:15][C:16]1([F:29])[O:28][C:19]2=[CH:20][C:21]3[NH:25][C:24]([SH:26])=[N:23][C:22]=3[CH:27]=[C:18]2[O:17]1.O>C(O)C.[OH-].[Na+]>[F:29][C:16]1([F:15])[O:28][C:19]2=[CH:20][C:21]3[NH:25][C:24]([S:26][CH2:3][C:4]4[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[CH:6][N:5]=4)=[N:23][C:22]=3[CH:27]=[C:18]2[O:17]1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: COc1c[nH+]c(CCl)c(C)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.96 g of 2-chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride are added to a solution of 0.92 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol in 10 ml of ethanol and 10 ml of 1N sodium hydroxide solution. The yellow reaction mixture is stirred at 20° C. for 1 hour, a further 10 ml of water are added, whereupon a colorless solid precipitates out, the mixture is stirred for a further 5 hours and filtered and the residue is rinsed with 1N sodium hydroxide solution and water and dried to constant weight. The amorphous powder is recrystallized from methylene chloride/diisopropyl ether. 1.5 g (93% of theory) of the title compound are obtained in the form of colorless crystals of m.p. 160°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17])[C:5]([OH:7])=[O:6])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)O)ccc1N1CCCCC1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of 3-amino-4-(2-methylpiperidin-1-yl)benzoic acid obtained in step 2 (100 mg; 0.43 mmol) in pyridine (69.04 μL, 0.85 mmol) and DCM (4 mL), was added acetyl chloride (36.42 μL; 0.51 mmol). The reaction mixture was then stirred at 40° C. for 5 h after which solvents were evaporated under vacuum, solid residue was triturated with ethylacetate and re-evaporated. Finally, water was added to the reaction mixture which was sonicated, filtered, dried under vacuum to give the title compound as a white solid (95 mg, 81%). 1H NMR (DMSO-d6, 300 MHz) δ 12.76 (bs, 1H), 8.97 (s, 1H), 8.66 (s, 1H), 7.64 (dd, J=8.2, 2.1 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.07-3.01 (m, 1H), 2.86-2.82 (m, 1H), 2.57-2.51 (m, 1H), 2.15 (s, 3H), 1.82-1.77 (m, 4H), 1.47-1.42 (m, 2H), 0.78 (d, J=6 Hz, 3H). LC/MS (Method B): 277.2 (M+H)+. HPLC (Method A) Rt 1.77 min (purity: 91.3%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[S:11][C:12]2[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([C:2]3[N:3]([CH3:29])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[S:11][C:12]=2[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccccc4[nH]3)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccccc4n3C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
0.05 g of 2-(1H-Benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (0.14 mmol) were dissolved in dry DMF (2.0 ml) and treated with 0.005 g NaH (65% in oil, 0.14 mmol) at 0° C. After stirring at ambient temperature for 1 h, 25 μl MeI (0.4 mmol) was added and the reaction mixture was stirred for 16 h. The suspension was filtered and the residue on the filter dried in vacuo. One obtained 0.042 g of 4-methoxy-2-(1-methyl-1H-benzoimidazol-2-yl)-7-morpholin-4-yl-benzothiazole (81%) as a yellow solid; M.p.: 283–285° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Cl.[OH-].[Na+]>C(#N)C>[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15][O:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1nc2cccc(O)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc2cccc(OCc3c(C)cccc3C)c2[nH]1
Yield: 16.9 %

Procedure:
4-hydroxy-2-methylbenzimidazole (0.59 g, 4 mmol) was dissolved in acetonitrile (15 ml). To the solution were added 2,6-dimethylbenzylchloride (0.52 g, 4 mmol) and sodium hydroxide (0.16 g, 4 mmol) (dissolved in 1 ml water) and the reaction mixture was refluxed for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and was washed with 2 M NaOH. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel. The product was eluted with methylene chloride containing 5% methanol. Crystallization from acetonitrile gave 0.18 g (18%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:25]C=O)[CH:6]=[C:7]([CH2:14][P:15]([O:21]C(C)C)([O:17]C(C)C)=[O:16])[CH2:8][CH2:9][O:10]C(=O)C)[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH2:25])[CH:6]=[C:7]([CH2:14][P:15]([OH:17])([OH:21])=[O:16])[CH2:8][CH2:9][OH:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CCO)CP(=O)(O)O
Reaction time: 22 h

Procedure:
3.57 g (8.5 mmol) of 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 22 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 22 ml of ethanol, and a mixture of 22 ml of propylene oxide and 22 ml of ethanol is added dropwise. A suspension forms, which is stirred for a further 90 minutes and then filtered with suction. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 195° (decomp.) is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[CH2:9]=O.[In+3]>C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:9][C:3]=2[CH:4]=[CH:5]1
Reactant: C=O
Reactant: OCCc1cccs1
Agent: [In+3]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Yield: 43 %

Procedure:
10.0 g of 2-thiopheneethanol, 2.8 g of paraformaldehyde, and 2.2 g of indium(III) triplate were added to 780 mL of acetonitrile, and the resulting mixture was refluxed for 12 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to obtain 4.7 g (yield of 43%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1.C([O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[N:31][C:32](Cl)=[CH:33][CH:34]=2)[N:29]=1)C1C=CC=CC=1>C1COCC1>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:32]2[N:31]=[C:30]3[C:35]([CH:36]=[CH:37][C:28](=[O:27])[NH:29]3)=[CH:34][CH:33]=2)[CH2:14][CH2:15]1
Reactant: Clc1ccc2ccc(OCc3ccccc3)nc2n1
Reactant: OCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1ccc2ccc(OCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
An intermediate compound, 2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-[1,8]naphthyridine, was produced as follows: To a suspension of 3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propan-1-ol hydrochloride (400 mg, 1.23 mmol) in THF (5 mL) cooled to −40° C. was added KOtBU (1 M in THF, 2.3 mL, 2.3 mmol, 1.9 equiv). The mixture became a cloudy solution. After stirring for 20 min at −40° C., 2-benzyloxy-7-chloro-[1,8]naphthyridine (333 mg, 1.23 mmol) was added as a solution in THF (8 mL) via cannula. The reaction was allowed to warm to 0° C. slowly over 1 h. The reaction was quenched with saturated NH4Cl and H2O and extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (CH2Cl2 to 2% MeOH/CH2Cl2) gave the title compound as a clear oil/foam (367 mg, 0.701 mmol, 57%). MS: APCI: M+1: 523.0 (Exact Mass: 522.16).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]3)[C:5]=2[CH:4]=1
Reactant: OCCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Reactant: CC(=O)Cl
Product: CC(=O)OCCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 49.2 %

Procedure:
Using the procedure of Example XXXV, 18.7 g (0.04 mole) of 2-trifluoromethyl-10-[3-(4-{3-hydroxypropoxy}-piperidino)-propyl]-phenothiazine (prepared in Example XVIII) and 3.14 g (0.04 mole) of acetyl chloride were reacted to obtain 10 g (49% yield) of 2-trifluoromethyl-10-[3-(4-{3-acetoxypropoxy}-piperidino)-propyl]-phenothiazine as a clear amber oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=2)=[CH:13][CH:12]=1)([CH2:9][CH3:10])[CH3:8].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:40]([O:39][CH2:38][CH2:37][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:18]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:7]([CH2:9][CH3:10])[CH3:8])=[CH:16][CH:15]=3)[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:29][C:30]=1[CH3:35])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(O)c(C)c3)nc3ccccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
K2CO3 (0.135 g, 0.97 mmol) was added to a solution of 3-(4-sec-butylphenyl)-2-(4-hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.250 g, 0.65 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 30 min, then (2-bromoethoxy)(tert-butyl)dimethylsilane (0.16 mL, 0.78 mmol) was added and the reaction was heated at reflux temperature for 3 hours, before concentrating in vacuo and dissolving the residue in EtOAc. The organics were washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 40% EtOAc in heptane, afforded 2-(4-(2-(tert-butyldimethylsilyloxy)-ethoxy)-3-methylphenyl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.320 g, 90%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].CN(C=O)C.Cl[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]([CH3:39])[N:27]=[C:28]2[C:37]=1[C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:30]=[C:29]2[NH2:38]>O>[NH2:38][C:29]1[C:28]2=[N:27][N:26]([CH3:39])[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:37]2[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=1
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70.2 %

Procedure:
Potassium phthalimide (4.90 mg, 26.4 mmol), sodium iodide (495 mg, 3.30 mmol), and DMF (22 mL) were added to 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (4.00 g, 13.2 mmol, prepared as described in Parts A-F of Examples 454-489), and the reaction was heated at 90° C. for two hours under a nitrogen atmosphere and allowed to cool to ambient temperature. Water (100 mL) was added and a precipitate formed and was isolated by filtration to yield 3.7 g of 2-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione that was used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
The titled compound is made in a manner substantially similar to Preparation 28 starting from the 6-chloro-pyridin-3-ol and 4-trifluoromethylphenyl boronic acid.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:3]([OH:5])=[O:4].[C:24](Cl)(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O.C(N(C(C)C)C(C)C)C>[C:24]([NH:1][CH:2]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:3]([OH:5])=[O:4])(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a mixture of 335 mg (±)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]3-yl) propanoic acid in 30 ml dimethyl formamide and 0.76 ml N-ethyldiisopropylamine under nitrogen are added dropwise at room temperature within 10 minutes 0.4 ml palmitic acid chloride. The mixture is stirred at room temperature for 26 hours. The solvent is evaporated in vacuo. The oily residue is taken up in water, acidified with 2N HCl to pH 1 and extracted with diethyl ether. The extract is washed with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated. The residue is recrystallized from diethyl ether/petroleum ether to yield the title compound, m.p. 130°-140°. MS (FAB):574(MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(Nc2cc(NCCO)ncn2)cc1
Temperature: 200 °C

Procedure:
250 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 62 mg of ethanolamine and 296 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated. The evaporation residue was subjected to crystallization from an n-BuOH/EtOH solvent mixture.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:36]2[CH:37]=[CH:32][CH:33]=[C:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:35]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: OB(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cccc(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)c1
Temperature: 90 °C
Yield: 31.9 %

Procedure:
[4-(Dibenzylamino)phenyl]boronic acid (UK Patent Application No. GB 2276161 (1994)) (400 mL, 1.26 mmol) was stirred in 5 mL dry toluene and potassium carbonate was added followed by ethyl (3-bromophenyl)acetate (338 mg, 1.39 mmol) as a solution in toluene (1 mL). The reaction vessel was evacuated and refilled with nitrogen (5 times). Pd(PPh3)4 (73 mg, 0.06 mmol) was added as a solution in toluene (1 mL) and the vessel was deoxygenated as before. The reaction mixture was heated at 90° C. for 16 h then cooled and filtered through diatomaceous earth. Volatile material was removed by evaporation, the residue was adsorbed onto silica and purified by chromatography eluting with 10-50% EtOAc/isohexane to give the title compound (175 mg, 32%) as a gum; 1H NMR δ 1.18 (t, 3H), 3.67 (s, 2H), 4.07 (q, 2H), 4.76 (s, 4H), 6.76 (d, 2H), 7.11 (d, 2H), 7.44-7.20 (m, 14H); MS m/e MH+ 436.
Reaction SMILES: ClC(OCC(C)C)=O.C[N:10]1[CH2:15][CH2:14]O[CH2:12][CH2:11]1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=O)=[CH:29][CH:28]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(NCC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:16]([O:20][C:21](=[O:22])[NH:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33](=[O:35])[N:10]([CH2:15][CH3:14])[CH2:11][CH3:12])=[CH:36][CH:37]=1)=[O:26])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
Isobutyl chloroformate (0.84 ml; 6.5 mmol) was added to a stirred solution of 4-methylmorpholine (0.72 ml; 6.5 mmol) and the compound of example 1f (2.0 g; 6.5 mmol) in DMF (10 ml) at −25° C., followed by the addition of diethyl amine (0.88 ml; 8.45 mmol). The reaction mixture was stirred for 15 min., poured into a 10% aqueous NaHCO3 solution and extracted with EtOAc. The EtOAc layer was washed with brine, concentrated and crystallized using EtOAc-PE60-80° C. to obtain the title compound. Yield, 1.95 g (82%); mp, 100-01° C.; MS (EI): 364 (M+), 291, 234 (100%); analysis: C19H28N2O5 requires C, 62.62; H, 7.74; N, 7.69; found: C, 62.43; H, 7.60; N, 7.25%.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][C:19]1[C:24](=[O:25])[N:23]2[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]2=[N:21][C:20]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][C:19]3[C:24](=[O:25])[N:23]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]4=[N:21][C:20]=3[CH3:31])[CH2:6][CH:5]=2)=[CH:8]1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCCl
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
A solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)indole (25 g, 0.126 mol), 3-(2-chloroethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (33 g, 0.139 mol) and potassium carbonate (17.5 g, 0.127 mol) in acetonitrile (500 ml) and water (100 ml) was heated under reflux for 18 h. After cooling the precipitate was collected and washed with water, isopropyl alcohol and petroleum ether respectively. Yield 38 g (76%) of a pale yellow solid. M.p.: 210-212° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][N:12](C)C)=[CH:5][CH:4]=1.O.[NH2:17]N.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][N:17]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CN(C)CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc(C2=NNCC2)cc1
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 1-(4-chloro-phenyl)-3-dimethylamino-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50° C. The mixture was refluxed for 2 hours, and evaporated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic phase was washed twice with water, dried and evaporated under reduced pressure, to give 25.0 g of a yellow solid, m.p. 90-100° C.
Reaction SMILES: O=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(O)C>[OH:20][N:19]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: NO
Reactant: O=C1Cc2ccccc2C=Cc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1Cc2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 5-oxo-dibenzo[a,e]cyclooctene (1 g, Example 1, step E) in ethanol (40 ml) was added hydroxylamine hydrochloride (0.316 g) and pyridine (0.404 ml). This mixture was heated to reflux for 8hr, cooled to room temperature and evaporated to dryness. To the residue was added ethyl acetate (100 ml). water (100 ml),then sodium hydroxide (1M) until pH 10. The aqueous layer was extracted with ethyl acetate (200 ml), the combined organic layers were washed with water (100 ml), brine (100 ml) then dried and evaporated to yield the crude product. Recrystallisation from ethyl acetate-hexane gave pure 5-hydroxyimino-dibenzo[a,e]cyclooctene (0.72 g, m.p. 191°-192°C.