Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[H-].[Na+].[CH3:14]I>CN(C=O)C>[CH3:14][O:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4]
Reactant: CI
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1N
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
To a stirred solution of 20 g (129.9 mmol) 2-hydroxy-6-nitroaniline in 150 ml DMF, NaH (3.42 g, 143 mmol, 95%) is added at 0° C. and stirring is continued for 1.5 h. MeI (9.3 ml, 150 mmol) is added and the reaction mixture is stirred at room temperature for 1 h. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. To the residue 50 ml of hexane:diethyl ether=4:1 is added and the resulting suspension is stirred for 5 minutes. 20 g of the title compound are obtained after filtration of the mixture as a brown crystalline solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
A mixture of methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1, 177 mg, 0.50 mmol), 3-fluorophenol (224 mg, 2.0 mmol) and sodium bicarbonate (105 mg, 1.25 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 100° C. for 24 h. After cooling, the reaction mixture was partitioned between water (50 mL) and dichloromethane (50 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated. The residue was purified by flash column chromatography on silica gel (10 g) eluting with hexane/ethyl acetate (4/1) to afford 180 mg (84%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.07–7.98 (3H, m), 7.47–7.37 (3H, m), 7.07–6.99 (1H, m), 6.98–6.88 (2H, m), 5.42–5.31 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 429 (M+H)+, 427 (M−H)−.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][N:18]1[CH2:17][CH2:16][N:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: [H][H]
Reactant: CN1CCN([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN([C@H]2CC[C@H](N)CC2)CC1

Procedure:
(trans)-N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexanamine 17a (3.35 g, 8.90 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (335 mg, 10%), filled with hydrogen three times. The reaction solution was reacted at 3 atmosphere for 12 hours and filtered. The filtrate was concentrated under reduced pressure followed by the addition of 10 mL of 1 M hydrochloric acid and extracted with dichloromethane (30 mL×3). The aqueous phase was added dropwise with saturated aqueous sodium carbonate solution to adjust pH to 11, extracted with dichloromethane (50 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and was concentrated under reduced pressure to obtain the crude title compound (trans)-4-(4-methylpiperazin-1-yl)cyclohexanamine 17b (0.82 g, yield: 46.7%) as a yellow oil liquid, which was used in the next step without further furification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:23]1([CH2:26][O:27][C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:37]2[CH2:36][CH2:35][N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:26][CH:23]4[CH2:24][CH2:25]4)[CH:29]=3)[CH2:39][CH2:38]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: c1cc(OCC2CC2)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(OCC3CC3)c2)CC1
Yield: 90 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-cyclopropylmethoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:33])[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=4)[N:25]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:33][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=2)[CH2:15][CH2:16][N:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=3)[N:25]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Methyl 2-bromoacetate (0.121 mL, 1.28 mmol) was added to 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (323 mg, 0.85 mmol) and potassium carbonate (235 mg, 1.70 mmol) in DMF (5 mL). The resulting suspension was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness, then water (50 mL) was added and the mixture was stirred for 20 minutes. The resulting precipitate was collected by filtration, washed with water then ether and dried to afford methyl 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (384 mg, 100%) as a beige solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:11]\[N:12]1[CH2:17][CH2:16][CH2:15]CC1)/[C:3]([NH:5][C:6](=[O:10])OCC)=[S:4].Cl.[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32](CCCN)[CH2:31][CH2:30]2)[CH:26]=[C:25]([C:39]([F:42])([F:41])[F:40])[N:24]=1)([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1>CO>[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:15][CH2:16][CH2:17][N:12]3[CH:11]=[C:2]([CH3:1])[C:3]([SH:4])=[N:5][C:6]3=[O:10])[CH2:33][CH2:34]2)[CH:26]=[C:25]([C:39]([F:40])([F:41])[F:42])[N:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1nc(N2CCN(CCCN)CC2)cc(C(F)(F)F)n1
Reactant: CCOC(=O)NC(=S)/C(C)=C/N1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1cn(CCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1S
Yield: 40.9 %

Procedure:
0.7 g (2.7 mmol) of ethyl (2E)-2-methyl-3-piperidin-1-ylprop-2-enethioylcarbamate (WO 00/61579), 0.9 g (2.6 mmol) of 3-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-amine hydrochloride from Example 1.2 and 0.6 g (5.5 mmol) of N-methylmorpholine in 20 ml of methanol were stirred at room temperature under a nitrogen atmosphere for 12 hours. Insolubles were removed by filtration, washed three times with methanol and water and then recrystallized from ethyl acetate. Drying in vacuo at 50° C. resulted in 0.5 g of the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]([C:12]1[NH:13][C:14]([CH2:19][OH:20])=[C:15](CO)[N:16]=1)([CH3:11])[CH3:10]>C(O)C>[CH:9]([C:12]1[NH:13][C:14]([CH2:19][OH:20])=[C:15]([Cl:1])[N:16]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1nc(CO)c(CO)[nH]1
Solvent: CCO
Product: CC(C)c1nc(Cl)c(CO)[nH]1
Reaction time: 0.42 h

Procedure:
2.81 Grams (21 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 3.47 g (20.4 mmol) of a 2-isopropyl-4,5-bis(hydroxymethyl) imidazole and 220 ml of ethanol at a temperature of 40° to 45° C. with stirring over a period of about 25 minutes. The mixture was stirred at the same temperature for two hours to effect the reaction, and then ethanol was distilled off under reduced pressure. The resulting reaction product was washed with water to obtain a pale yellowish powdery crystalline 2-isopropyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 1.69 g (yield, 47.4%). By using acetonitrile, the recrystallization was effected twice to obtain a colorless crystalline product in pure form. The TLC and spectra of this compound were the same as the properties exhibited by the above-mentioned 2-isopropyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(OCC)(=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>[Cl-].[Na+].O>[O:21]1[CH2:22][CH2:23][N:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(N2CCOCC2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Methyl 2-chloroisonicotinate (320 mg, 1.89 mmol) was dissolved in morpholine (5 mL) and stirred at 90° C. for 4 hours. The reaction mixture was added with saturated brine and ethyl acetate, and the organic layer was separated, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain methyl 2-morpholinoisonicotinate (50 mg, 98%).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C)C(=N)N(C)C>ClCCl>[C:1]1([CH:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCC(O)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-phenyl-2-aminoethanol (5.323 g, 38.80 mmole) in 50 mL dichloromethane was added tert-butyldimethylsilyl chloride (7.030 g, 46.63 mmole) followed, after 15 minutes by tetramethylguanidine (2.430 g, 21.09 mmole). The reaction mixture was stirred at room temperature for 15 minutes and quenched by addition of water (40 mL). Layers were separated. The aqueous phase was extracted with dichloromethane (40 mL). Combined organic phases were washed with brine (2×50 mL), dried over magnesium sulfate and concentrated in vacuo to give crude 2-phenyl-2-tert-butyl dimethylsiloxy-1-ethylamine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ncccn1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ncccn4)c23)C1
Temperature: 160 °C
Reaction time: 48 h
Yield: 39.9 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide (110 mg, 0.328 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (197 mg, 0.982 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue was diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(pyrimidine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (67.6 mg, 40% yield) as a solid. LCMS (APCI+) m/z 416, 418 (M+H)+, Retention time=3.40 minutes (Method 2).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)=[C:11]([O:39][CH2:40][CH3:41])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:47])=[O:46]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@:18]2([CH3:20])[C@:17]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[N:16]([C:36]([N:54]3[CH2:53][CH2:52][N:51]([CH2:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:56][CH2:55]3)=[O:37])[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])=[CH:10][C:11]=3[O:39][CH2:40][CH3:41])=[N:19]2)=[CH:26][CH:25]=1
Reactant: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N5O6S2Cl2 [(M+H)+] 806.2574, observed 806.2579.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[CH2:7][C:8]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:11]=[C:10]([CH2:23][CH3:24])[C:9]=1[O:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1.[H-].[Na+]>CN(C)C=O>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([Cl:32])[CH:29]=1)[O:25][C:9]1[C:10]([CH2:23][CH3:24])=[N:11][N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:8]=1[CH2:7][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(Cn2cccn2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 86.7 %

Procedure:
Pyrazole (23 mg, 0.330 mmol) was added in one portion to a stirred solution of the bromide of Example 137 (148 mg, 0.300 mmol) and sodium hydride (60% dispersion in oil, 13.2 mg, 0.330 mmol) in N,N-dimethylformamide (2 ml) at room temperature under nitrogen. The reaction was stirred for 5 hours, quenched with water (1.00 ml) and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and the resulting solution was washed with 1M aqueous potassium carbonate solution (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (125 mg) as a colourless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:23]([F:41])[CH:22]=1.[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52]O)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][O:38][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([NH:25][C:24]3[CH:39]=[CH:40][C:21]([Cl:20])=[CH:22][C:23]=3[F:41])=[N:27][CH:28]=[N:29]2)=[CH:34][C:33]=1[O:36][CH3:37])=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Triphenylphosphine (2.46 g, 9.3 mmol) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.0 g, 3.1 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (25 ml) and the suspension stirred at 0° C. for 30 minutes. A solution of 3-(N-tert-butoxycarbonylamino)-1-propanol (0.65 g, 3.7 mmol) in methylene chloride (3 ml) was added and then diethyl azodicarboxylate (1.47 ml, 7.6 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with methylene chloride and washed with aqueous sodium hydrogen carbonate solution, water and then brine. The resultant solution was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine (100/0/0 and then 95/4/1) to give 7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4chloro-2-fluoroanilino)-6-methoxyquinazoline (620 mg, 42%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12]CC)=O)=[C:6]([CH3:15])[N:5]=[C:4]([CH2:16][O:17][CH3:18])[N:3]=1.Cl.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(O)CCC>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:26]2[C:2]3[N:3]=[C:4]([CH2:16][O:17][CH3:18])[N:5]=[C:6]([CH3:15])[C:7]=3[CH2:8][CH2:9][C:10]2=[O:12])=[CH:23][CH:22]=1
Reactant: CCOC(=O)CCc1c(C)nc(COC)nc1Cl
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: COCc1nc(C)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Yield: 73.6 %

Procedure:
A mixture of ethyl 3-(4-chloro-6-methyl-2-methoxymethylpyrimidin-5-yl)propionate (3.6 g, 0.013 mol), 4-bromobenzylamine hydrochloride (3.0 g, 0.013 mol), NaHCO3 (2.4 g, 0.028 mol), and nBuOH (25 mL) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, and extracted with CH2Cl2. The combined extracts were dried (MgSO4) and concentrated to give a brown oil. Purification by flash chromatography (5% MeOH/CH2Cl2) gave 3.6 g (72%) of product as an off-white solid, mp 64°-66° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:40]=[CH:39][CH:38]=[CH:37][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]3)[N:10]=1.O.[OH-].[Li+:44]>C1COCC1.O>[C:33]([O:32][C:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:37]=[CH:38][CH:39]=[CH:40][C:5]=4[CH2:4][C:3]([O-:41])=[O:2])[C:14]([C:15]([F:17])([F:16])[F:18])=[CH:13][N:12]=3)[CH:21]=2)[CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35].[Li+:44]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)ccc2C1
Yield: 80.9 %

Procedure:
tert-Butyl 6-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I80) (520 mg, 0.91 mmol) was dissolved in THF (20 mL) and a solution of lithium hydroxide hydrate (76 mg. 1.8 mmol) in water (5 mL) was added. After 18 hours the THF was removed under reduced pressure, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulfate) and evaporated to give the title compound (I81) (414 mg, 81% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.36 (s, 1H), 8.65 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.20-7.02 (m, 5H), 4.45 (5, 2H), 3.54 (t, J=5.8 Hz, 2H), 3.17 (s, 2H), 3.14-2.98 (m, 4H), 2.76 (t, J=5.7 Hz, 2H), 1.43 (s, 9H). LCMS Method C: rt 6.51 min; m/z 557.1 [M−Li+2H] 501.1 [M−tBu−Li+3H]+, 457.1 [M−Li−Boc+3H]+; m/z 555.1 [M−Li]−.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=[O:32])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12](=[O:32])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
To a solution of vanillin (330 mg, 2.2 mmol), cis-eicosapentaenoic acid (800 mg, 2.65 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (DCM, 15 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (720 mg, 3.53 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as an eluent to give the product as an oil (710 mg, 75%). IR (neat) νmax 3012, 2961, 2931, 2855, 1767, 1701, 1600, 1271, 1149, 1119, 1032 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.94 (1H, s, —CHO), 7.49 (1H, d, J=1.6 Hz, H-2), 7.47 (1H, dd, J=8.0, 1.6 Hz, H-6), 7.20 (1H, d, J=8.0 Hz, H-5), 5.30-5.48 (10H, m, H-5′, 6′, 8′, 9′, 11′, 12′, 14′, 15′, 17′, 18′), 3.89 (3H, s, —OCH3), 2.80-2.88 (8H, m, H-7′, 10′, 13′, 16′), 2.58-2.67 (2H, m, H-2′), 2.22-2.25 (2H, m, H-19′), 2.05-2.11 (2H, m, H-4′), 1.81-189 (2H, m, H-3′), 0.97 (3H, t, J=7.4 Hz, H-20′).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:7]=1)=[O:5])C.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[O:22]1>>[O:22]1[C:23]2[CH:24]=[CH:25][C:26]([C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]4[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[CH:10][CH:9]=4)=[CH:19][CH:18]=3)=[CH:27][C:28]=2[O:29][CH2:21]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cccc(COc2ccc(I)cc2)n1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)n1

Procedure:
6-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure 3 from 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid ethyl ester (of Intermediate 3) and 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=350.