Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=O)[C:31]=3[C:40]([O:42]CC)=[O:41])=[CH:24][C:23]=2[O:22]1>CCOCC.C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]([C:25]3[CH:26]=[CH:27][C:28]4[O:29][CH2:21][O:22][C:23]=4[CH:24]=3)[CH:31]2[C:40]([OH:42])=[O:41])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0° C. The resulting mtixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1F)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:17][C:16]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:12]=2[C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCOc1c(F)ccc([N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(F)c2c1NCCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.1 %

Procedure:
To an ice-cold solution of [2-(2,6-difluoro-3-nitrophenoxy)ethyl]carbamic acid tert-butyl ester (450 mg, 1.416 mmol) in DCM (20 mL) was added TFA (4 mL). The reaction mixture was stirred at RT for 2.5 h, then toluene was added and volatiles were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (10 mL), 2M Na2CO3 (10 mL) was added and the mixture stirred at RT for 1 h. The reaction mixture was partitioned between EtOAc and brine, the organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, eluant 10-30% EtOAc in cyclohexane) affording the title compound as an orange solid (250 mg, 89%). 1H NMR (CDCl3, 300 MHz): 7.94 (1H, bs), 7.78 (1H, dd, J=9.7, 5.4 Hz), 6.45 (1H, t, J=9.5 Hz), 4.31 (2H, t, J=4.6 Hz), 3.70-3.66 (2H, m)
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[C:17](Cl)(=[O:19])[CH3:18]>CN(C)C(=O)C>[C:17]([NH:1][C:2]1[C:10]([I:11])=[C:6]([C:7]([Cl:9])=[O:8])[C:5]([I:12])=[C:4]([C:3]=1[I:16])[C:13]([Cl:15])=[O:14])(=[O:19])[CH3:18]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Yield: 90 %

Procedure:
5-Amino-2,4,6-triiodoisophthaloyl chloride (190 g,0.32 g-mole) prepared as in Example 1 is dissolved in 475 ml of N,N-dimethylacetamide (DMAc) (dried over molecular sieves), and the solution is stirred and cooled to 0°-3° C. Acetyl chloride (75.1 g, 68 ml, 0.96 g-mole) is added dropwise over a period of 100 minutes, keeping the temperature between 0° C. and 3° C. The ice bath is removed and the solution is stirred overnight at room temperature (20°-25° C.). An additional charge of acetyl chloride (8.5 g, 0.11 g-mole) is added, and the mixture is stirred overnight (23 hours). The product (a creamy white sold) precipitates during this time. The mixture is cooled to 0°-5° C. and filtered while cold. After rinsing with three 100-ml portions of hexane on the funnel, the solution is stirred with three 200-ml portions of cold hexane for 10 minutes each time, collected by suction filtration, and dried in a vacuum desiccator (183 g, 90% yield). The product shows one major spot by TLC analysis.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:22])[CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)C(O)=O)=[CH:2]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:42]([CH2:45]C)CC)C.[OH2:47]>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:22][C:45](=[O:47])[NH:42][CH:7]2[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)=[CH:2]1
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Reactant: O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccoc2)O1
Yield: 83 %

Procedure:
To a solution of (2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (10.0 g, 31.8 mmol) in tetrahydrofuran (250 ml) were added diphenylphosphoryl azide (7.5 ml, 35.0 mmol) and triethylamine (6.7 ml, 47.7 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was allowed to stand at room temperature, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous-sodium hydrogen carbonate and saturated brine, dried, over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (4RS,5SR)-5-(3-furanyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (8.25 g, 83%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:47])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[C:30]([Br:47])=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)cn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 59.6 %

Procedure:
To a solution of compound 5-2 (110 mg, 0.2 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.22 mmol.) and the mixture was heated to reflux for 1 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 71 mg of 5-4.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@H:15]([CH2:29][OH:30])[CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[C:33]1([CH3:65])[CH:38]=[CH:37][C:36]([S:39]([N:42]2[CH2:47][CH2:46][C@H:45]([C:48](=[O:61])[NH:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([F:60])([F:59])[F:58])=[CH:52][CH:51]=3)[CH2:44][C@H:43]2[C:62]([OH:64])=[O:63])(=[O:41])=[O:40])=[CH:35][CH:34]=1.B.C1COCC1>>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C@@H:15]([CH2:29][OH:30])[CH2:14]2)=[O:12])=[CH:8][CH:9]=1.[C:33]1([CH3:65])[CH:34]=[CH:35][C:36]([S:39]([N:42]2[CH2:47][CH2:46][C@@H:45]([C:48](=[O:61])[NH:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([F:60])([F:59])[F:58])=[CH:52][CH:51]=3)[CH2:44][C@@H:43]2[C:62]([OH:64])=[O:63])(=[O:41])=[O:40])=[CH:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@H](C(=O)Nc3ccc(OC(F)(F)F)cc3)C[C@H]2C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@H](C(=O)Nc3ccc(OC(F)(F)F)cc3)C[C@H]2CO)cc1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)Nc3ccc(OC(F)(F)F)cc3)C[C@@H]2C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)Nc3ccc(OC(F)(F)F)cc3)C[C@@H]2CO)cc1

Procedure:
In analogy to example 36 step C) the desired racemic mixture of (2S,4S)-2-hydroxymethyl-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide and (2R,4R)-2-hydroxymethyl-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.09 g) was obtained from the reaction of a racemic mixture of (2S,4S)-1-(toluene-4-sulfonyl)-4-(4-trifluoromethoxy-phenylcarbamoyl)-piperidine-2-carboxylic acid and (2R,4R)-1-(toluene-4-sulfonyl)-4-(4-trifluoromethoxy-phenylcarbamoyl)-piperidine-2-carboxylic acid (0.22 g) and borane-THF complex (1 molar in THF, 0.68 ml) as a white solid. MS (ESI): 473.2 (MH+).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.C(NC(C)[CH2:19][C:20]1[C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[C:26]=12)(C)C.O>CCCCCC.O1CCCC1>[CH3:19][C:20]1[C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[C:26]=12
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(C)=C21

Procedure:
The starting material is prepared as follows: 19.2 ml of tetramethyl-ethylenediamine are added under nitrogen to 53.3 ml of 2.4 M n-butyl lithium in hexane at room temperature and the mixture is allowed to react for 15 minutes. Thereupon the solution of 10.9 g of 1-(2-isopropylaminopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one in 160 ml of anhydrous tetrahydrofuran is added dropwise. The mixture is refluxed for 30 minutes and subsequently cooled in an ice bath. 120 ml of water are added dropwise and the mixture is stirred with cooling for 30 minutes. The precipitate is collected, washed with water and diethyl ether and dried, to yield the 1-methyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 215°-218°.
Reaction SMILES: [O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:16]=2[C:17]([O-:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)[C:3]([F:6])([F:5])[F:4].O.C(=O)([O-])[O-].[K+].[K+].SCC(CO)O>CN(C=O)C>[O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: OCC(O)CS
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
4-[2-(1-Oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (2.5 g) from Example 13 was dissolved in DMF (45 mL). Water (0.4 mL) followed by potassium carbonate (3.1 g) were added and the reaction mixture stirred at room temperature for 48 hours. Tlc of the reaction mixture showed the reaction to be incomplete. Additional potassium carbonate (0.6 g) and water (0.2 mL) were added and the reaction mixture stirred at room temperature for an another 18 hours. The insoluble materials were removed from the reaction mixture by filtration and washed with DMF. A 10% citric acid solution (100 mL) was added slowly to the filtrate and the resulting mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent removed under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to afford 2.06 g (85% yield) of the title compound, mp 185°-188° C., MS (FAB, thioglycerol) 550.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:38][CH2:37][C:11]2[N:12]=[C:13]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]3)[N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[Cl:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:38][CH2:37][C:11]2[N:12]=[C:13]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)[N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[Cl:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(c2nc3c(c(NCc4ccc(F)cc4Cl)n2)CN(C(=O)OC(C)(C)C)CC3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc(N3CCC(C(=O)O)CC3)nc(NCc3ccc(F)cc3Cl)c2C1
Temperature: 65 °C
Yield: 62 %

Procedure:
Ethyl 1-[6-tert-butoxycarbonyl-4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]piperidine-4-carboxylate (9.16 g, 16.1 mmol) prepared according to Process Step 3 was dissolved in ethanol (300 mL), and the solution was mixed with an aqueous sodium hydroxide solution (1 mol/L, 32 mL), followed by stirring at 65° C. for sixteen hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with water and washed with diethyl ether. The aqueous layer was neutralized with diluted hydrochloric acid (1 mol/L, 35 mL), the precipitated crystals were collected by filtration and thereby yielded 1-[6-tert-butoxycarbonyl-4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]piperidine-4-carboxylic acid (3.94 g). The filtrate was extracted with dichloromethane, the organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was mixed with diethyl ether for crystallization. The precipitated crystals were collected by filtration and thereby yielded crystals of the target compound (1.07 g, 5.01 g in total with the above-mentioned crystals, in a yield of 62%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].O>O1CCCC1.C(O)(C)(C)C>[F:22][C:20]1[CH:21]=[CH:14][C:15]([C:16]#[N:17])=[C:18]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:19]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1ccc(F)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 359 mg of trifluoroethanol in 3 mL of anhydrous tetrahydrofuran at 5° C. was slowly added 3.6 mL of a molar solution of potassium tert-butoxide in tert-butanol. The resulting solution was stirred for 30 minutes at 5° C. and slowly added to a solution of 500 mg of 2,4-difluoro-benzonitrile in 3 mL of anhydrous tetrahydrofuran at 5° C. The resulting mixture was stirred for 1 h at 5° C., then poured into water and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 90/ethyl acetate 10) to give 640 mg of 4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzonitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]1([CH:13]=[CH:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccccc1
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: Clc1ccc(C=CC=Cc2ccccc2)cc1

Procedure:
0.112 g (0.5 millimol) of palladium acetate, 10.05 g (50 millimols) of 4-chlorocinnamyl chloride, 6.5 g (62.5 millimols) of styrene and 9.27 g (50 millimols) of tri-n-butylamine in 50 ml of p-xylene are stirred for 23/4 hours at 120° C. The crude product is chromatographed on silica gel in methylene chloride and is recrystallised from n-hexane. 0.5 g (4% of theory) of the above compound are obtained in the form of white crystals of melting point 161.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34](Cl)=[O:35]>O1CCCC1>[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:21][CH3:22])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:35]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: O=C(Cl)/C=C/CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of N4-(3-chloro-4-fluorophenyl)-7-methoxy-4,6-quinazolinediamine (8) (4.0 g, 12.5 mmol) in dry tetrahydrofuran (150 mL) under nitrogen was added triethylamine (19 mmol), followed by freshly prepared (2E)-4-bromo-2-butenoyl chloride (15 mmol) in dry tetrahydrofuran (50 mL). The resulting solution was then stirred at room temperature for 2 hours and concentrated under reduced pressure. Trituration from dichloromethane gave crude (2E)-4-bromo-N-[4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl]-2-butenamide (4.6 g) that was used directly.
Reaction SMILES: C(O[C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:14])[CH:9]2[NH2:13])[C:6]=1[C:15]([OH:17])=[O:16])(=O)C.[NH2:18][CH:19]([CH2:25][F:26])[CH2:20][CH2:21][C:22](Cl)=[O:23].[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>>[NH2:18][CH:19]([CH2:25][F:26])[CH2:20][CH2:21][C:22]([NH:13][CH:9]1[C:8](=[O:14])[N:7]2[CH:10]1[S:11][CH2:12][C:5]([CH2:31][O:30][C:27](=[O:29])[CH3:28])=[C:6]2[C:15]([OH:17])=[O:16])=[O:23]
Reactant: NC(CF)CCC(=O)Cl
Reactant: CCOC(C)=O
Reactant: CC(=O)OC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCC(N)CF)C2SC1

Procedure:
A mixture of 1 g of 3-acetyloxy-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 4-amino-4-fluoromethylbutyric acid chloride wherein the free amino group is protected with tert-butoxycarbonyl in 50 ml of ethyl acetate is refluxed for two hours after which the solvent is removed leaving a residue which is treated with mild acid and chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[4-amino-4-fluoromethylbutyryl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH2:9].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH2:9])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=C(c1ccccc1O)n1ccnc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(c1ccccc1OC(c1ccccc1)(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a suspension of 1-[1-(2-hydroxyphenyl)vinyl]imidazole (500 mg) and triethylamine (407 mg) in dry methylene chloride (5 ml) is added trityl chloride (1.12 g) under stirring at room temperature, and the mixture is stirred at room temperature for 1 hour. To the mixture ice water is added and extracted with methylene chloride. The methylene chloride extract is dried on anhydrous sodium sulfate, and then concentrated. The residue is chromatographed on a column of silica gel, and eluted with methylene chloride-methanol (3-5%). The eluate is concentrated and the residue is crystallized from isopropyl ether and a small amount of petroleum ether to give 1-[1-(2-trityloxyphenyl)vinyl]imidazole (525 mg). mp. 149°-144° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[OH-].[NH4+:32]>>[NH2:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:22]([Cl:28])=[CH:23][N:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: [NH4+]
Agent: [OH-]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 28% ammonium hydroxide following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h, then second aliquot of NH4OH added, then 60° C., 24 h).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O1CCOCC1.O.[Cl-].[Na+].O>[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Method J10) To the solution of 6-aminocaproic acid (2h) (0.982 g, 7.5 mmol) in water/dioxane (1:1) mixture (30 ml) NaOH (0.8 g, 20 mmol) in H2O (2 ml) and benzoyl chloride (1/67) (1.16 ml, 10 mmol) were added. The mixture was stirred for 6 h at room temperature and diluted with brine (150 ml). The mixture was washed with diethyl ether (2×25 ml), acidified with conc. HCl to pH 4, and extracted with ethyl acetate (4×25 ml). The organic solution was washed with brine (3×25 ml), dried (Na2SO4) and evaporated. The crude title compound (1.589 g, 90%) was purified by column chromatography on silica gel with chloroform -ethyl acetate (1:2) as eluent. 1H NMR (CDCl3, HMDS) δ: 1.18-1.85(m, 6H); 2.34(t, J=7.0 Hz, 2H); 3.45(q, J=6.0 Hz, 2H); 6.27(bs, 1H); 7.29-7.52(m, 3H); 7.61-7.85(m, 2H); 10.41(bs, 1H).