Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[C:7](=[NH:10])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[C:1]([C:5]1[N:6]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:10]/[C:23](=[O:24])[C:22]2[CH:26]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])/[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(=N)n1C[C@H]1CCCO1
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\scc(C(C)(C)C)n1C[C@H]1CCCO1

Procedure:
The product from Example 318A and 5-chloro-2-methoxy-benzoic acid were processed using the method described in Example 300 to afford the title compound. 1H NMR (300 MHz, CDCl3) −2.23 (m, 1H), 3.67-3.76 (m, 1H), 3.83-3.89 (m, 1H), 3.90 (s, 3H), 4.40 (dd, J=15.0, 7.5 Hz, 1H), 4.57-4.68 (m, 2H), 6.35 (s, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.7, 2.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H). MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+]([O-])=O.[CH3:25][OH:26].C[O-].[Na+]>C(O)(=O)C>[CH3:25][O:26][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)[C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)OCO3
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
A solution of 500 mg (1.45 mmol) of 6-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]-benzimidazole in 20 ml of abs. methanol is treated with 300 mg of sodium methylate, whereupon the mixture is boiled at reflux under argon for 18 hours. The reaction mixture is buffered by means of glacial acetic acid and concentrated in vacuo. The residue is treated with methylene chloride/sodium bicarbonate solution, whereupon the organic solution is dried and concentrated. By recrystallization from ethyl acetate there is obtained 6-[[(4-methoxy-3-methyl-2-pyridyl)methyl)thio)-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 215°-220°.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[C:3]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=2)[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(N[C@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 90 °C
Yield: 67.8 %

Procedure:
5-Bromo-N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (42.0 g, 106 mmol) was dissolved in toluene (1900 mL) and DMF (100 mL). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) CH2Cl2 (0.9 g, 1.06 mmol), 3,4-dichlorophenylboronic acid (20.2 g, 106 mmol) and sodium carbonate solution (2M, 106 mL). This mixture was heated to 90° C. for 2 h, cooled to room temperature and partitioned between ethyl acetate (1000 mL) and water (2000 mL), the water phase was separated, extracted twice more with ethyl acetate (2×1000 mL) and the organic phases were washed once with water and once with brine (1000 mL each). Organic phases were pooled, dried with MgSO4 and the volatiles removed in vacuo. The residue was dissolved in diethyl ether (500 mL) and filtered through diatomaceous earth. The title compound precipitated when n-heptane (500 mL) was added drop wise to the diethyl ether solution, was filtered off and dried in vacuo to give 33.3 g the title compound as an off-white solid; MS 463.079 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[N:12]=[C:11]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:10]([CH2:28][CH3:29])=[N:9][C:8]=2[C:30](=[O:32])[NH2:31])=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:30]([C:8]1[N:9]=[C:10]([CH2:28][CH3:29])[C:11]([O:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)=[N:12][C:7]=1[O:6][C:5]1[CH:33]=[CH:34][C:2]([C:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH:38]=2)=[CH:3][CH:4]=1)(=[O:32])[NH2:31]
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCc1nc(C(N)=O)c(Oc2ccc(Br)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Oc2ccc(C3=CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a mixture of tert-butyl (3-{[6-(4-bromophenoxy)-5-carbamoyl-3-ethylpyrazin-2-yl]oxy}phenyl)carbamate (540 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (273 mg), and N,N-dimethylformamide (10 mL) were added a 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride-dichloromethane complex (83 mg) and cesium carbonate (665 mg), followed by reacting at 80° C. for 1 hour. The reaction mixture was left to be cooled, and then ethyl acetate was added thereto. The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) and silica gel column chromatography (NH2 type, eluent; chloroform:methanol=100:0-98:2) to obtain tert-butyl [3-({5-carbamoyl-3-ethyl-6-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazin-2-yl}oxy)phenyl]carbamate (153 mg) as a pale yellow oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:18]>CCO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[C:6]([C:4]([NH2:18])=[O:3])[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: N
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Crude 3-(4-hydroxy-phenyl)-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 1; 1.9 g, 8.15 mmol) was taken up in a solution of EtOH saturated with NH3. The mixture was stirred overnight at room temperature under nitrogen. The solvent was evaporated to give 3-(4-hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (1.17 g, 70%) as a flaky white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[CH:19]([N:22]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([O:32][CH3:33])[CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:35]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:31])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[C:26]([O:32][CH3:33])[CH:25]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C(O)c1cc(OC)c(OC)c(OC)c1
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15°) solution of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) is added n-BuLi (3 ml of 1.6 M solution in hexane). The reaction mixture is stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction is cooled to -30° C. and a solution of 4-formyl-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.18 g, 3.9 mmol) in THF (5 ml) is added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction is poured onto 0.5 N KHSO4 and extracted with ethyl acetate. The organic layer is washed with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH:12]=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[C:11]([C:12]([OH:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: COc1c(C=O)ccc2c1CCC2
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: COc1c(C(=O)O)ccc2c1CCC2
Temperature: 26.5 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a clear solution of 4-Methoxy-indan-5-carbaldehyde (11.5 gm, 0.065 mole) in Dichloromethane (100 ml), Sulphamic acid (19.0 gm, 0.196 mole) was added at 25-28°. A solution of Sodium chlorite (15.28 gm, 0.169 mole) in water (50 ml) was added at 5-10° C. The reaction mixture was stirred for 5 hours at 25-28° C. Finally the reaction mixture was poured into water (200 ml) and extracted with Dichloromethane (2×200 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give 12.0 gm of desired product as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: OCCN1CCOCC1
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCOCC1)C(=O)C2c1ccccc1

Procedure:
The title compound, MS: m/e=598.1 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dione and N-(2-hydroxyethyl)-morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1I
Temperature: 20 °C
Yield: 90 %

Procedure:
Add 5-bromo-2-iodobenzoic acid (1998 g, 6.11 mol) portion wise to a 20° C. solution of sulfuric acid (100 mL) in methanol (13 L). Heat the suspension to reflux for 24 hours, then cool to 20° C. and remove the solvent under reduced pressure. Pour the residue into a 1:1 mixture of methyl-tert-butyl ether and ice water (20 L) and separate the phases. Extract the aqueous phase with methyl-tert-butyl ether (1.5 L), combine the organic phases and wash with aqueous 0.2 M NaOH (5 L), wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve the crude product in 40-45° C. petroleum ether (10 L), filter through a pad of diatomaceous earth and evaporate under reduced pressure. Dissolve the residue in petroleum ether (5 L) and cool to −50° C., filter the first crop solids, wash the solid with ice cold petroleum ether. Evaporate the mother liquor, redissolve the solid in petroleum ether (1 L), cool to −50° C., and filter a second crop. Combine first and second crops and dry in open air to provide the title compound as a yellow solid (1880 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:42])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34]CC6C=CC=CC=6)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)(=O)C.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:42])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(CCOCc5ccccc5)CC4)cc2)CO3)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(CCO)CC4)cc2)CO3)CC1
Yield: 28.6 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl]-4-[4-(2-benzyloxyethyl)-piperazin-1-yl]benzamide (150 mg, 0.27 mmol) was dissolved in acetic acid (10 mL) and palladium (10%) on carbon (12 mg) was added. Hydrogenation at room temperature and at atmospheric pressure for 14 h followed by filtration and evaporation of the solvent in vacuo gave 180 mg of a crude product. The residue was partitioned between methylene chloride (60 mL) and 2 M NH3 (5 mL) and washed with brine (5 mL). Drying (MgSO4) the solution and evaporation of the solvent in vacuo gave 120 mg of crude material. Purification by preparative TLC on silica using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent afforded 37 mg (29% yield) of the title compound as a white solid: mp 211–212° C.; EIMS (70 eV) m/z (relative intensity) 479 (8, M+); [α]22D−26° (c 0.26, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][CH2:11][Cl:12])[C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: ClCCCNc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Oc1ccccc1)N(CCCCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Thionyl chloride (4.4 mL) was added to a solution of 3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added, followed by extraction with ethyl acetate (200 mL). Heptane (100 mL) was added to the resulting extract to prepare a mixed solution. The solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=2:1) to obtain (4-chlorophenyl)-(3-chloropropyl)amine. (4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45 mL). Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL) were added at 0° C., and the reaction solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g). Phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g) was dissolved in ethanol (60 mL). Hydrazine monohydrate (5.65 mL) was added at room temperature, and the reaction solution was heated under reflux for 17 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 2.19 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=[CH:22][C:9]=1[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33]Br)[CH3:30]>O>[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33][N:11]([CH2:10][C:9]1[CH:22]=[CH:23][C:24]2[O:28][CH2:27][O:26][C:25]=2[C:8]=1[O:7][CH3:6])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:30]
Reactant: CCOC(CBr)OCC
Reactant: COc1c(CNS(=O)(=O)c2ccc(C)cc2)ccc2c1OCO2
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 100 °C
Reaction time: 10 h
Yield: 79.3 %

Procedure:
44 mg (1.1 mmol) of 60% oil dispersion of sodium hydride was washed twice with 2 ml of dry hexane to eliminate oil. 2 ml of dry N,N-dimethylformamide, 335 mg (1 mmol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-p-toluenesulfonamide (1) and 0.18 ml (1.1 mmol) of bromoacetaldehyde diethylacetal (purity 95%) were added in order. The resulting mixture was stirred at 100° C. for 10 hours. On cooling, to this 5 ml of water was added and the reaction mixture was extracted with 8 ml and then 2 ml of methylene chloride successively. The liquid extract was washed with 5 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluate: ethylacetate/n-hexane=1/4) to obtain 358 mg of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluenesulfonyl)aminoacetaldehyde diethylacetal (2) as an oil. Yield 79%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](I)[N:3]=1.[CH3:9][O-:10].[Na+].CO>O>[I:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:10][CH3:9])[N:3]=1
Reactant: Ic1cncc(I)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cncc(I)n1
Yield: 100 %

Procedure:
2,6-Diiodopyrazine (5.0 g, 15 mmol) was added to a solution of sodium methoxide in methanol (prepared from sodium (0.35 g, 15 mmol) and methanol (40 ml)) and the mixture was heated at reflux temperature for 1 hour. After cooling, the solution was diluted with water (200 ml) and extracted with diethylether (3×100 ml). The combined extracts were washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give the product as a white solid (3.5 g, 100%) m. pt. 35.7-37.2
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 1443) in 2 mL of CDCl3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 1444.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CCCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (77 mg, 75%), MS (ISP) m/z=413.4 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and pentanoic acid.
Reaction SMILES: [PH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].[N:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[N+]=[N-]>>[CH2:2]([P:1]([CH2:4][CH3:5])([NH:6][Si:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCPCC
Product: CCP(CC)(=N[Si](C)(C)C)N[Si](C)(C)C
Yield: 72 %

Procedure:
This compound was synthesized as above by using Et2PH instead of Ph2PH. Et2PH (2.00 mL, 17.4 mmol, d=0.7862) and N3SiMe3 (5.00 mL, 35.8 mmol, d=0.868, 95%) were refluxed overnight in a round bottom flask with a reflux condenser under a positive pressure of nitrogen. After 12 hours the product was distilled through a short path distillation apparatus (0.01 mm, 56-60° C.) to yield a clear liquid (3.30 g, 72%). 1H NMR (C6D6): δ 1.12 (overlapping dq, CH2, 4H), 0.84 (overlapping dt, CH3, JHP=17.3 Hz, JHH=7.4 Hz, 6H), 0.73 (br s, NH, 1H), 0.29 (s, SiCH3, 18H). 13C{1H} NMR (C6D6): δ 26.6 (d, PCH2CH3, JCP=78.2 Hz), 6.5 (d, PCH2CH3, JCP=3.7 Hz), 3.3 (exchange broadened s, SiMe3); 31P{1H} NMR (C6D6): δ 20.1. Analysis calculated for C10H29N2PSi2: C, 45.41; H, 6.06; N, 4.81. Found: C, 68.73; H, 6.13; N, 4.73.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29]O)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.S(Cl)([Cl:33])=O>C(Cl)Cl.C1COCC1>[Cl:33][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=1)=[N:18][CH:19]=[N:20]2
Reactant: OCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: ClCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
To a stirred solution of the 2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethanol (20 g) in DCM (200 ml) and THF (200 ml) was added thionyl chloride (20 ml) at ambient temperature. The solution was then heated under reflux for 2 hours. The solution was cooled and product filtered off to give 5-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine as its hydrochloride salt (25 g, 98%); NMR spectrum (DMSO-d6) 4.20-4.40 (t, 2H), 4.60-4.80 (t, 2H), 5.40 (s, 2H), 7.20-7.60 (m, 3H), 7.60-7.80 (m, 3H), 7.90-8.10 (m, 3H), 8.60-8.70 (d, 1H), 8.9 (s, 1H), 10.65-10.83 (bs, 1H); Mass spectrum MH+ 441.