Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: CCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 75.6 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and n-butylamine (0.0134 g, 0.184 mmol) gives the title compound (0.0458 g, 75.7%): TOF MS ES+ 330.2 (M+H)+, HRMS calcd for C18H24N3O3 330.1818 (M+H)+, found 330.1802, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.9 min, 100% purity.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].Br[CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH2:21][CH3:22]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
50% Sodium hydride 4 g (160 mmol) in mineral oil was suspended, under nitrogen atmosphere, in 250 ml of anhydrous dimethylformamide. A solution of 15 g (69 mmol) of 2-(3-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of anhydrous dimethylformamide was added thereto, at room temperature, in a dropwise fashion and under stirring. The resulting mixture was stirred for 12 additional hours and then a solution of 18 ml (197 mmol) of 1-bromopropane in 50 ml of dry dimethylformamide was added. The reaction mixture was stirred for 18 hours further and thereafter poured into 1000 ml of ethyl acetate, washed with water (5×500 ml), dried and evaporated in vacuo. Purification of the residue by column chromatography on 500 g of silica gel, using hexane-ethyl acetate (90:10) as eluant provided 17.61 g (98%) of 1-propyl-2-(3'-nitrobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1.CN(C=O)C.F[C:19]1[N:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[C:26]2[CH3:31])=[CH:21][CH:20]=1>>[CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([O:11][C:19]3[N:24]=[CH:23][C:22]([N:25]4[C:26]([CH3:31])=[N:27][NH:28][C:29]4=[O:30])=[CH:21][CH:20]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2cccc(O)c21
Reactant: Cc1n[nH]c(=O)n1-c1ccc(F)nc1
Solvent: CN(C)C=O
Product: Cc1n[nH]c(=O)n1-c1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of 3,3-dimethyl-2H-benzofuran-4-ol (WO2012/076877 Intermediate 50, 30 mg, 0.18 mmol) in dry DMF (0.5 mL) dipotassium carbonate (50.5 mg, 0.36 mmol) and then 4-(6-fluoro-3-pyridyl)-3-methyl-1H-1,2,4-triazol-5-one (Intermediate 8, 24.8 mg, 0.128 mmol) were added and the reaction mixture was stirred for 8 hours at 110° C. The reaction was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and dichloromethane/methanol from 99.5:0.5 to 95:5 as eluent affording the title compound (12 mg) as yellow pale solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[Cl:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]2[NH:1][C:24](=[O:25])[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:3]=2[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-methylphenyl)amino]-1-piperidinecarboxylate (D7) (0.292 mmol, 100 mg) was dissolved in 10 ml of dichloromethane and a 20% solution in toluene of phosgene (1.05 eq., 150 microliters) followed by triethylamine (2.1 eq., 85 microliters) were added at 0° C.; the reaction mixture was then stirred at 0° C. for 30 minutes and subsequently quenched with citric acid (10% aqueous solution). The reaction mixture was diluted with dichloromethane, the two phases were separated and the aqueous phase was extracted with dichloromethane (1×); the organic phases were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate-hexane) to yield the title compound, 50 mg, 50%, M+−H=364.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:26]([CH3:28])[CH3:27])=[C:11]([CH2:13][CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[N:12]=1.[I-:29].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:26]([CH3:28])[CH3:27])=[C:11]([CH2:13][CH2:14][I:29])[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CCI
Yield: 95.4 %

Procedure:
In acetone (2 mL) was dissolved 2-(2-chlorophenyl)-5-isopropyl-4-[2-(p-toluenesulfonyloxy)ethyl]oxazole (123 mg, 0.293 mmol). To the solution was added sodium iodide (176 mg, 1.17 mmol). The mixture was heated overnight under reflux. The reaction mixture was allowed to reach room temperature, poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated, to obtain the desired compound (105 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH2:9][CH3:10])[N:3]=1.[N:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:29]=1[S:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:23]2[CH:22]=[CH:21][C:20]([S:17]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)(=[O:19])=[O:18])=[CH:25][CH:24]=2)=[C:4]([CH2:9][CH3:10])[N:3]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCc1nc(N)ccc1Br
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Product: CCc1nc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-ethylpyridine and 4-(N-morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2-chloro-4-trifluoromethylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.41 (1H, d, J 10 Hz, A-ring CH ortho to SO2NH), 7.81-7.63 (5H, m, Ar CH's), 7.20 (2H, d, 2×C-ring CH's), 6.94 (1H, d, J 10 Hz, pyridyl CH's), 3.83-3.77 (4H, m, CH2OCH2), 3.09-2.98 (4H, m, CH2NCH2), 2.93 (3H, q, J 9 Hz, CH2CH3), 1.31 (3H, t, J 9 Hz, CH2CH3). Hplc (Luna 2, Gradient 5): rt=6.26 minutes. LC/MS rt=6.92 minutes, 622 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.[Li]CCCC.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=1.CCOCC>C1COCC1>[Cl:16][C:17]1[N:18]=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:21]([O:10][CH:8]2[CH2:9][CH:3]3[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]3)[CH2:7]2)[N:22]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN1C2CCC1CC(O)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C2CCC1CC(Oc1nc(Cl)nc(N3CCOCC3)n1)C2
Temperature: -78 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
In a three neck flask equipped with stirring bar under N2 atmosphere tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to −78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes. To the reaction mixture 2,4,-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4,24, mmole) was added and allowed to stir overnight. For work up, ether (100 mL) was added. The organic layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. filtered and the solvents were removed to obtain a colorless oil. Further purification by flash-chromatography using CH2Cl2/MeOH/NH3 (15:1:0.1) gave the product as white solid (600 mg, 42% yield); MS (ESI) m/z 340
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:32]([O:31][C:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])[C:6]([OH:39])=[O:5])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)s1)NC1=NCCCN1

Procedure:
50 mg of the product obtained in step h) were dissolved in 5 ml of dichloromethane, and with stirring 0.5 ml of trifluoroacetic acid were added dropwise at room temperature. After 4 hours the ester was no more detectable. The mixture was evaporated under reduced pressure, and the remaining residue was dissolved in acetic acid and again evaporated under reduced pressure. This procedure was repeated twice. Then the residue was triturated vigorously with diethyl ether. The crystals formed were isolated by suction followed by washing with diethyl ether. After drying in vacuo 30 mg of the title compound were obtained as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: Cc1ccc(Br)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Br)cc1C1OCCO1
Temperature: 130 °C
Reaction time: 21 h

Procedure:
To a solution of INT 30 (17.3 g, 87 mmol) in toluene (505 mL) was added ethane-1,2-diol (24.3 mL, 436 mmol) followed by p-toluenesulfonic acid monohydrate (0.83 g, 4.36 mmol). The reaction mixture was stirred at 130° C. for 21 hours. The mixture was washed with saturated aqueous NaHCO3 (2×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by Kugelrohr distillation to give INT 31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25].[OH-].[Na+]>C(#N)C.O>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1)(=[O:26])=[O:25]
Reactant: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Yield: 29.2 %

Procedure:
A suspension of 1.15 g (5 mmol) of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 200 ml of water, and 0.42 g (5 mmol) of sodium bicarbonate is stirred at 0°-5° and a solution of 3.6 ml (30 mmol) of methanesulfonyl chloride and 30 ml of acetonitrile is added over a 2 hr. period. During the addition, the pH of the reaction is maintained at 6.9-7.3 with 1 N sodium hydroxide. After the addition, the reaction is stirred at 0°-5° for 2 hrs. The precipitated solid is filtered and dried to give 0.45 g of 6-[3-(methylsulfonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1c(I)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(I)c1C
Reaction time: 40 h

Procedure:
A mixture of 3-iodo-2-methyl-benzoic acid (90 mmol, 23.6 g), methanol (250 mL), and concentrated sulfuric acid (13 mL) was refluxed with stirring for 40 h before it was concentrated in vacuo. The residue was dissolved in ethyl acetate and the mixture was neutralized by adding small portions of a saturated aqueous NaHCO3 solution with stirring. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish oil (24.3 g); 1H NMR (CDCl3, 200 MHz): δ=7.96 (d, 1H), 7.71 (d, 1H), 6.91 (t, 1H), 3.89 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CN(C)C=O.O>[CH3:12][S:13]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol) in N,N-dimethylformamide (25 mL) was added sodium methanesulfinate (7.10 g, 69.6 mmol). The reaction mixture was stirred at 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was stirred for 10 minutes and filtered through a medium frit to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6](=[O:7])[C:5]2=[CH:28][CH:29]=1.[C:30]([O:47][CH:48]([CH2:56][O:57][C:58](=[O:74])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:49][S:50][CH2:51][CH2:52][C:53](O)=[O:54])(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:30]([O:47][CH:48]([CH2:56][O:57][C:58](=[O:74])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:49][S:50][CH2:51][CH2:52][C:53]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:6](=[O:7])[C:5]2=[CH:28][CH:29]=1)=[O:54])(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CCC(C(=O)OC(C)(C)C)N1C(=O)c2ccc(N)cc2C1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)C(=O)N(C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2=O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4-amino-N-(1,3-bis-(t-butyloxycarbonyl)propyl)phthalimide (178 mg) in pyridine (2.3 ml), phosphorus trichloride (0.020 ml) was added, followed by stirring at room temperature for 2 hours. To this mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 24 (150 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:acetone=3:1) to yield the title compound (190 mg, yield 80%) as a wax-like substance.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[C:10](O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:10]1[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nnc(-c2ccccc2)c2ccoc12
Solvent: c1ccncc1
Solvent: O
Product: Clc1nnc(-c2ccccc2)c2ccoc12

Procedure:
A slurry of 4-phenylfuro[3,2-d]pyridazin-7-ol (0.327 g, 1.5 mmol) and pyridine (0.38 ml, 4.6 mmol) in 5 mL POCl3 was heated with a water-cooled reflux condenser with drying tube to 130° C. for 3 h. The brown solution was cooled and the reaction judged complete by LCMS. The reaction was poured onto ice with stirring. The solution was neutralized with 6 N NaOH and ice to control temperature. The resulting mixture was extracted into DCM (3×). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The solid was adsorbed onto 2 g silica gel from DCM/MeOH and dried. The material was purified by silica gel chromatography, eluting with 0-20% EtOAc/DCM to give 7-chloro-4-phenylfuro[3,2-d]pyridazine as an off-white solid. MS m/z=231 [M+H]+. Calc'd for C12H7ClN2O: 230.7.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.CO.[OH-].[Na+].Cl>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
Methyl 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylate (156 mg, 0.39 mmol) was added into the mixture of methanol (5 mL) and sodium hydroxide (5 M, 2 mL). The reaction mixture was stirred at room temperature overnight. After that, the reaction was diluted with 20 mL of water, acidified with 2 M of hydrochloric acid to pH 6 and diluted with ethyl acetate (30 mL). The organic layer was separated and washed with water. The solvent was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel to give 135 mg of product. MS obsd. (ESI+) [(M+H)+] 387.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH2:24]([O:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-butoxyphenyl)-5-phenylbenzoxazole (174 mg, 0.49 mmol) and 1,2,4-benzenetricarboxylic anhydride (94 mg, 0.49 mmol) the title compound was obtained (146 mg, 56%). 1H NMR (DMSO) δ 8.44(dd, 1H), 8.32(s, 1H), 8.18(d, 1H), 8.12(d, 1H), 8.05(d, 1H), 7.82(d, 1H), 7.71(m, 4H), 7.48(m, 3H), 7.39(t, 1H), 4.25(t, 2H), 1.83(m, 2H), 1.58(m, 2H), 1.00(t, 3H). MS 533 m/z (M+H)+.
Reaction SMILES: [C:1]1([N:7]([CH2:30]CC(OC)=O)[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].[C:43]([O:46][CH2:47][CH3:48])(=[O:45])[CH3:44].C(O)C.N>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][CH2:44][C:43]([O:46][CH2:47][CH3:48])=[O:45])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:41])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: [NH4+]
Reactant: COC(=O)CCN(C(=O)c1cnc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 82 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 82% of theory, C27H29N7O3 (499.58) Rf value: 0.20 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU107##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CN(P(N(C)C)N(C)C)C.[H-].[Na+].[CH3:27][CH2:28][CH2:29]I>C1(C)C=CC=CC=1.CN(P(N(C)C)N(C)C)C.C1(C)C=CC=CC=1>[CH:11]([C:5]([CH2:27][CH2:28][CH3:29])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:14])([CH3:12])[CH3:13]
Reactant: CCCI
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: CN(C)P(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OCC)(C(=O)OCC)C(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of diethylisopropylmalonate (10.1g) in 15 ml of a 25% solution of HMPT (hexamethylphosphorus triamide) in toluene was added dropwise over 15 minutes to a suspension of sodium hydride (70 mM) in 25% HMPT/toluene (15 ml) at 50°-70° C. N-propyl iodide (17.0g) was then added over 30 minutes at 70°-100° C. and the mixture stirred at 120°-130° C. for 11/2 hours. After cooling, methylated spirits (10 ml) was added and the mixture poured onto a mixture of ice/hydrochloric acid. The product was extracted with ether, the ethereal extracts washed with sodium bicarbonate (X2), then water and dried over anhydrous magnesium sulphate. Removal of the solvent gave diethyl 2-isopropyl-2-propylmalonate as a yellow liquid b.p. 92°-94°/1 mm Hg. 87% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[NH:19][C:20](=O)/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].CC(O)C.Cl>O>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[CH:22]=[CH:21]/[C:20]1[NH:19][C:3]2=[CH:4][C:5]3[C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3N)c(N)cc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(/C=C/c4ccccc4N)nc3cc21
Yield: 93.2 %

Procedure:
(E)-N-(6-Amino-3,3-dimethyl-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-(2-amino-phenyl)-acrylamide (0.82 g) is dissolved in water, 2-propanol and concentrated hydrochloric acid and heated for 3 h under reflux. After re-cooling the mixture is concentrated in vacuo. The residue is taken-up in EtOAc and saturated K2CO3 solution. After an aqueous work-up the desired compound (0.73 g) is obtained as a yellow solid. A small amount was treated with hydrochloric acid (2 N) to give the hydrochloric salt which precipitated in a pure form.