Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([Br:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[Br:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(Br)c23)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H](Oc2cccc3cncc(Br)c23)CC1

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 121 (49.4 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (44.3 mg).
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:19]1[CH:28]=[CH:27][C:22](C(OC)=O)=[CH:21][CH:20]=1)=[O:7])(C)(C)C.F[C:30](F)(F)[C:31]([OH:33])=[O:32]>ClCCl>[C:31]([CH2:30][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]3[C:9]=2[CH2:8][C:6]([OH:5])=[O:7])=[CH:28][CH:27]=1)([OH:33])=[O:32]
Reactant: COC(=O)c1ccc(-c2nc3ccc(C)cn3c2CC(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(CC(=O)O)cc3)c(CC(=O)O)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 10 (3.1 g, 8.15 mmol) in dichloromethane (50 ml) was added to trifluoroacetic acid (25 ml). Following stirring at room temperature for 2 h the solution was concentrated to dryness. Potassium carbonate (10%) solution (100 ml) was added and the solution washed with diethyl ether (2×50 ml) and acidified to pH 6 with HCl (6M). The precipitate was filtered, washed with diethyl ether and recrystallized to give [2-(4-carboxymethylphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]acetic acid 11 as a white solid (1.65 g, 62%).
Reaction SMILES: [CH2:1]([C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH:2]=[CH2:3].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CC(C)=O>[CH2:1]([C:4]1[C:11]([O:12][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cccc1C=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1c(C=O)cccc1OCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 879.3 %

Procedure:
In a 1 L three necked round bottom flask equipped with a mechanical stirrer, thermometer and reflux condenser was added 300 mL acetone, 23.19 g of 2-allyl-3-hydroxybenzaldehyde (0.143 mole, 1 eq.), 2.13 g of sodium iodide (14 mmol., 0.1 eq), 39.52 g of potassium carbonate (28.6 mmol., 2 eq.) and 22.39 g of p-methoxybenzyl chloride (14.3 mmol., 1 eq.). The reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a bed of Hyflosupercel and the solvent removed by rotary evaporation. The residual dark oil was taken up in 200 mL of toluene and washed sequentially with 10% aqueous sodium hydroxide, water and brine. The organic phase was dried over sodium sulfate and decolourized with 5 g Darco G60. After filtration through a Celite pad, the solvent was removed by rotary evaporation to give 35.5 g of oil which was then recrystallized from 175 mL of hot IPA. After cooling to room temperature and further cooling to 0-5° C., the solids were filtered and washed with IPA to afford after drying at 40° C., 24.74 g (61%) of 2-allyl-3-(4-methoxy-benzyloxy)-benzaldehyde as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]([Mg]Cl)([CH3:25])[CH3:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[CH:23]([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[C@H](O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To 51C (6.50 g, 19.8 mmol) in THF (100 mL) at −78° C. was added a 2M THF solution of isopropylmagnesium chloride (30.0 mL, 60.0 mmol) over 20 min. The cold bath was removed and the reaction was stirred for 1 h. The reaction was then cooled to −60° C. and was quenched with saturated aqueous ammonium chloride. After warming to rt, the whole was diluted with EtOAc. The layers were separated and the organic layer washed with water and brine, then dried (MgSO4), filtered and concentrated. The resulting residue was purified via flash chromatography eluting with 20% EtOAc/hexane to provide the title compound (5.90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1
Reactant: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a solution of methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate (50 mg, 0.089 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.13 mL, 0.13 mmol). The solution was heated in a microwave reactor at 80° C. for 10 minutes and then 1 N hydrochloric acid (0.13 mL, 0.13 mmol) was added. The solution was concentrated and the residue was taken up with ethyl acetate and water. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylic acid (45 mg, 92%). 1H-NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.99 (d, J=9 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.31-3.22 (m, 1H), 1.73-1.66 (m, 2H), 3.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H). HRMS (ESI) C30H24Cl2N2O4 calculated: 547.1186 (M+H)+, found: 547.1186 (M+H)+.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:15]=3[C:16]([NH:36][CH2:35][CH:34]([C:29]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)[CH3:37])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: CC(CNC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=12.51 min. MS (ESI−): mass calcd. for C22H16Cl4N4O3S2, 587.94; m/z found, 587/589/591 [M−H]. 1H NMR (500 MHz, CDCl3): 11.22 (s, 1H), 8.35 (d, J=7.0, 1H), 8.24 (d, J=8.8, 1H), 7.89 (s, 1H), 7.74-7.71 (m, 1H), 7.41 (d, J=8.2, 1H), 7.29 (d, J=2.0, 1H), 7.14 (s, 1H), 7.05 (dd, J=8.2, 2.0, 1H), 5.79 (s, 1H), 3.69-3.63 (m, 1H), 3.34-3.29 (m, 1H), 3.03-2.99 (m, 1H), 1.31 (d, J=7.0, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:17]=1)(=[O:14])=[O:13].CN(CCO[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1Cl)N)C.BrC1C(OC)=C(OC)C=CC=1S(Cl)(=O)=O>ClC(Cl)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][S:12]([C:3]2[C:2]([C:35]3[CH:36]=[CH:37][CH:39]=[CH:40][CH:41]=3)=[CH:7][C:6]([O:8][CH3:9])=[C:5]([O:10][CH3:11])[CH:4]=2)(=[O:14])=[O:13])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27]
Reactant: COc1cc(Br)c(S(=O)(=O)Nc2ccc(Cl)c(OCCN(C)C)c2)cc1OC
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Agent: COc1ccc(S(=O)(=O)Cl)c(Br)c1OC
Solvent: CC(Cl)Cl
Product: COc1cc(-c2ccccc2)c(S(=O)(=O)Nc2ccc(Cl)c(OCCN(C)C)c2)cc1OC
Yield: 72 %

Procedure:
2-Bromo-4,5-dimethoxybenzenesulfonyl chloride To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100 mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid (26 mL, 400 mmol). The reaction was allowed to slowly warm to ambient temperature and maintained for 3 hours, at which time it was concentrated and diluted with ether (300 mL). The resultant solution was then washed with ice cold water (2×250 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated to furnish a grayish powder (25 g, 78%). b) 2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide To a solution of 3-[2-(N,N-dimethylamino)ethoxy]-4-chloroaniline (1.9 g, 8.8 mmol) in dichloroethane (50 mL) was added 2-bromo-3,4-dimethoxybenzenesulfonyl chloride (2.8 g, 8.8 mmol). The resultant solution was maintained at ambient temperature for 3 days, then concentrated. Crystallization from ethanol gave the title compound (3.4 g, 72%). MS (ES+) m/e 493 [M+H]+ c) 4,5-Dimethoxy-biphenyl-2-sulfonic acid [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide To a solution of 2-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide (50 mg, 0.1 mmol) in dimethoxyethane/water (25:3, 2 mL) was added phenylboronic acid (120 mg, 1.0 mmol), cesium carbonate (820 mg, 2.5 mmol), and tetrakispalladium triphenylphosphine (6 mg, 0.005 mmol). The resultant mixture was heated at 90° C. for 16 hours, at which time it was diluted with ethyl acetate (10 mL) and washed with 5% sodium hydroxide (2×10 mL) and brine (10 mL). The solution was then dried over magnesium sulfate and concentrated to give a yellow oil. Purification by HPLC (gradient; 10% acetonitrile/water to 90% acetonitrile/water) furnished the title compound (15 mg, 31%) as a white solid. MS (ES+) m/e 491 [M+H]+ Example 20 was prepared as outlined in Example 19, substituting the appropriate starting materials.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[C:24]([O:39][CH3:40])=[CH:23][N:22]=3)[C:5]=2[CH3:41])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:29]([C:34]([OH:36])=[O:35])=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:39][CH3:40])=[CH:23][N:22]=3)[C:5]=2[CH3:41])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2nn(Cc3c(F)cc(OCC)cc3F)c(C3CC3)c2C)ncc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(=O)O)n3)c(C)c2C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.7 %

Procedure:
To a solution of 722 mg of ethyl 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)-pyridine-3-carboxylate 2-6-5 (1.28 mmol, 1.0 eq) in 13 mL THF and 1.6 mL methanol were added 256 mg sodium hydroxide (6.39 mmol, 5.0 eq). The mixture was stirred for 45 minutes at rt. Using 10% aqueous citric acid the pH of the mixture was adjusted to 3.5. The resulting suspension was filtered. The precipitate was washed with water and ethanol and subsequently dried to provide 660 mg of the desired product (1.11 mmol, 87%) as 90% pure target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][CH2:32][C:33](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:33]([CH2:32][CH2:31][O:30][CH3:29])[N:20]([CH3:21])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: COCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 6-benzyloxy-N4-methylquinoline-3,4-diamine (7.88 g, 28.2 mmol), prepared as described in Parts A-F of Example 57, in dichloromethane (300 mL) was cooled to 0° C.; triethylamine (4.2 mL, 30.3 mmol) was added. Methoxypropionyl chloride (3.3 mL, 30.6 mmol) was added dropwise over a period of five minutes, and the reaction was stirred at ambient temperature for 90 minutes. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (300 mL) and triethylamine (13 mL) and heated at 75° C. over two nights. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed with deionized water (3×200 mL) and concentrated under reduced pressure. Small volumes of hexanes and dichloromethane were added, and a white precipitate formed, which was isolated by filtration and washed with hexanes to provide 3.76 g of 8-benzyloxy-2-(2-methoxyethyl)-1-methyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=1[CH3:24])C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:16]1[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Cc1c(O)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(O)ccc(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)carbamate (500 mg, 1.46 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred at room temperature overnight, then the solvent was removed in vacuo, to give the title compound as yellow oil (200 mg, 97%).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][CH2:13][C:14]([CH3:28])([CH3:27])[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][CH2:13][C:14]([CH3:28])([CH3:27])[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCCC(C)(C)C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCCC(C)(C)C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyrate (1.24 g, 3.0 mmol) obtained from Example 10-(1) was reacted with anisole (1.8 g, 16.6 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutanoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above was reacted with oxalyl chloride (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 μl), and the reaction mixture was worked up to afford 4-[bis(allyloxy)phosphoryl]oxy-2,2-dimethylbutyl chloride as a crude product.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=O)C.[CH2:17](O)[CH3:18]>Cl>[CH2:17]([O:11][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([NH2:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])[CH3:18]
Reactant: CCO
Reactant: CC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)c1ccc(N)cc1[N+](=O)[O-]

Procedure:
A solution of 4-acetylamino-2-nitrobenzoic acid (1.80 g, 8.0 mmol) in 12N hydrochloric acid (14 mL) and absolute ethyl alcohol (10 mL) was heated to 90°-100° C. for 5 h. Concentrated down in vacuo to remove ethyl alcohol only, adjusted pH to 4 with 1N sodium hydroxide and filtered off precipitate to give 140 mg (Y: 8%) of the title compound; 1H-NMR (CDCl3): δ 7.61 (d, J=8.5 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.74 (dd, J=8.5, 2.1 Hz, 1H), 6.52 (bs, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); MS (DCI) m/e: 211 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:14]([O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:25][CH2:26]2)[C:3]=1[CH3:16])[CH3:15]
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: CCOc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 43 %

Procedure:
By using 5-bromo-7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (570 mg, 2.0 mmol) synthesized in Reference example 84 and 1-(4-methylphenyl)piperazine (704 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 327 mg (yield 43%).
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18](O)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24]C)C>>[C:1]([NH:9][CH:10]([CH2:18][N:23]([CH3:24])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: CCN(CC)CC
Product: CN(C)CC(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 26.5 g of N-benzoyl phenyalanine (XIII) in 200 ml of T.H.F. are added 11 g of triethylamine, it is cooled to 0° C. and 11 g of ethyl chloroformiate are added. After 30 mn at 0° C., a solution of 4.5 g of diethyllamine in 50 ml of T.H.F. is added, then it is left for 2 hours at ambient temperature. Then the solvent is evaporated, the residue taken up in water, extracted with chlorofrom, dried on sodium sulfate, filtered and the filtrate evaporated. Thus, the expected product was obtained with a yield of 81% Melting point: 150° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[NH2:13])([O-:9])=[O:8].N1C=CC=CC=1.O>CN(C)C=O>[N+:7]([C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[NH:13][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])([O-:9])=[O:8]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
iso-Butyryl chloride (6.3 ml.) was added dropwise during 15 minutes to a stirred solution of 3,5-dinitroaniline (5.5 g.) in a mixture of dimethylformamide (18 ml.) and dry pyridine (18 ml.) maintained at a temperature of 0°-5°C. The reaction mixture was allowed to warm to room temperature during 30 minutes and then added to a mixture of ice and water (200 ml.). The precipitate was filtered off, dissolved in dimethylformamide (50 ml.) and added to a mixture of ice and water (300 ml.) containing concentrated hydrochloric acid (10 ml.). The precipitate was filtered off, washed with saturated aqueous sodium bicarbonate solution and then with water and dried. Crystallisation from aqueous ethanol gave 3',5'-dinitro-iso-butyranilide (5.6 g.), m.p. 165°-168°C.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>C1(C)C=CC=CC=1.CO.ClCCl>[C:13]1([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1cccs1
Reactant: OB(O)c1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: c1ccc(-c2cccs2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
To a solution of 2-iodothiophene (2.8 ml, 25 mmol) and palladium tetrakistriphenylphosphine (866 mg, 0.75 mmol) in toluene (50 ml) under a nitrogen atmosphere was added aqueous sodium carbonate (2M, 25 ml) followed by a solution of phenylboronic acid (3.7 mg, 30 mmol) in methanol (12.5 ml). The vigorously stirred mixture was heated at 80° C. for 6 hours and then cooled to room temperature. Aqueous sodium carbonate (2M, 125 ml), dichloromethane (250 ml) and 0.88 ammonia solution (12 ml) were added to the reaction. The two phases were separated, and the aqueous phase extracted with dichloromethane (50 ml). The combined organic phases were washed with brine (80 ml), dried (MgSO4) and evaporated in vacuo to an oil. Purification by chromatography on silica gel eluting with hexane gave the title compound as a colourless oil (1.35 g, 36%) which solidified on standing. δH (CDCl3) 7.06-7.09 (1H, m, ArH), 7.25-7.31 (3H, m, ArH), 7.35-7.39 (2H, m, ArH, 7.60-7.62 (2H, m, ArH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccncc1Br
Product: Cc1ccncc1C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from tert-butyl(4-cyano-2-ethynylphenoxy)acetate (Intermediate 46) and 3-bromo-4-methylpyridine (53), the title compound was obtained as a dark orange sticky solid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.