Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CO[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[C:47]=1[CH2:54][C:55]([OH:57])=O.CN([C:61]([O:65]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH3:53][O:52][C:48]1[CH:49]=[CH:50][C:51]([O:65][CH3:61])=[CH:46][C:47]=1[CH2:54][C:55]([NH:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)=[O:57]
Reactant: COc1cccc(OC)c1CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)n3)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
Prepared using General Procedure 6. To a suspension of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 (90 mg, 0.157 mmol) and 2-(2,6-dimethoxyphenyl)acetic acid (30.7 mg, 0.157 mmol) stirring in DMF (2 mL) were added HATU (65.5 mg, 0.172 mmol), DMAP (15 mg, 0.123 mmol) and TEA (54.6 μL, 0.392 mmol). After stirring at room temperature for 18 h 2-(2,6-dimethoxyphenyl)acetic acid (30.7 mg, 0.157 mmol), HATU (65.5 mg, 0.172 mmol) and TEA (21.83 μl, 0.157 mmol) were added. The reaction mixture was stirred at room temperature for 72 h then at 50° C. for 2 h and 60° C. for 2 h. The reaction mixture was cooled to room temperature and more HATU (65.5 mg, 0.172 mmol) was added. After 18 h the reaction mixture was diluted with EA (25 mL) and washed with NaHCO3 (2×25 mL), 1 M HCl (2×25 mL) and brine (25 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EA/hexanes) to afford 47 mg (40%) of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-66. LCMS-ESI (m/z) calculated for C45H44N4O7: 752; found 753 [M+H]+, tR=2.79 min (Method 10).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N:5][C:4](=[O:7])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[C:12]([C:6]1[NH:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1=NC(=O)N=C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 3.0 g of 4-methylimidazol-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene is added dropwise 4.6 g of benzoyl chloride. The solution is warmed at 60° C. for 4 hours, poured over ice water, slurried with ether and the resulting solids filtered and dried to yield the title compound. M.P. 250°-54° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[OH:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(OC1C=CC(S(N2CCC(O)CC2C)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(C(CC)CC)N2N=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][OH:30])[CH2:33][CH2:34]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Agent: CCOc1ccc(S(=O)(=O)N2CCC(O)CC2C)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1

Procedure:
Analogously, using 400 mg (0.911 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 310 mg (2.734 mmol) of 4-hydroxymethylpiperidine, 270 mg (57.3% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23]>CN(C)C(=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:24]=[CH:22][N:23]=1
Reactant: N=CN
Reactant: N#Cc1c(F)cccc1Oc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2cccc(Oc3ccc(F)cc3)c12
Temperature: 162 °C
Yield: 10.7 %

Procedure:
A mixture of 2-fluoro-6-(4-fluorophenoxy) benzonitrile (2.5 g, 11 mmol, Maybridge) and formamidine acetate (2.3 g, 22 mmol, Aldrich) in 50 mL of N,N-dimethylacetamide was heated to 162° C. under nitrogen for 9 hours. After cooling to room temperature the reaction mixture was evaporated under reduced pressure. The product was suspended in 80 mL of cold water and the pH adjusted to 8.5 with concentrated ammonium hydroxide. After cooling the suspension overnight, the precipitate was collected by vacuum filtration, washed with water (25 mL), dried and recrystallized from 30 mL of ethanol at 4° C. The precipitate was collected by vacuum filtration, washed with ethanol, and dried at 50° C. to give 0.3 g (10.7% yield) of 4-amino-5-(4-fluorophenoxy)quinazoline, M.P. 188-190° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:21]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate (3 g, 10.47 mmol) in THF (20 mL) was added to a freshly prepared solution of LDA (prepared from n-butyllithium (26.2 mmol) in hexane and diisopropylamine (3.73 mL, 26.2 mmol) in 7 mL of THF) at −78° C. the reaction was stirred for 1 h, warmed to 0° C. for 5 min, cooled again to −78° C. followed by addition of methyl iodide (2.292 mL, 36.7 mmol). The reaction mixture was allowed to warm to room temperature overnight, quenched with aqueous ammonium chloride, and concentrated under vacuum to remove volatile solvents. The residual aqueous mixture was extracted with ether, and the ether solution was dried and concentrated under vacuum to give the crude product as an oil which was further purified via normal phase chromatography on silica gel (Biotage SP1, 40+S column) to give product (2.7 g; MS: (M+H)+=301.3) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].[CH2:22]([O:29][C:30]([NH:32][CH:33]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH3:45])[CH:38]=1)[C:34](O)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH:20][C:34](=[O:35])[CH:33]([NH:32][C:30]([O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH3:45])[CH:38]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COc1ccc(C(NC(=O)OCc2ccccc2)C(=O)O)cc1C
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(NC(=O)OCc2ccccc2)c2ccc(OC)c(C)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (0.93 g, 3.04 mmol), benzyloxycarbonylamino-(4-methoxy-3-methyl-phenyl)-acetic acid (1.0 g, 3.04 mmol), diisopropylethylamine (2.1 mL, 12 mmol) and 1-hydroxybenzotriazole (0.46 g, 3.04 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexaflurorophosphate (1.15 g, 3.04 mmol). The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give 2-{(S)-2-[2-benzyloxycarbonylamino-2-(4-methoxy-3-methyl-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as a white solid (1.3 g, 69%).
Reaction SMILES: Cl.[NH2:2][OH:3].CO.[OH-].[Na+].[C:8](#[N:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8](=[N:2][OH:3])([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=NO)c1ccccc1
Temperature: 57.5 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (8.85 g, 0.126 moles) and methanol (45 mL) were charged to a 100 mL flask, followed by 51% sodium hydroxide (9.82 g, 0.125 moles). To this mixture was added benzonitrile (10.32 g, 0.100 moles), and the reaction was heated to 55-60° C. and held for 2 hours. HPLC showed that the reaction was complete by the disappearance of benzonitrile. A portion of the methanol (30 mL) was removed by distillation, deionized (DI) water was added (22 mL), and the remaining methanol was distilled at 300 torr to give two liquid phases (benzamide oxime melt and salt water). 2-Methyltetrahydrofuran (20.0 g) was added, and the aqueous salt phase was drained off to give 33.34 g of a solution of benzamide oxime in 2-methyltetrahydrofuran, 39.45% by loss on drying and HPLC. The yield of benzamide oxime was 96.5%.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2:36].[Ca+2:37]>C(OCC(C)C)(=O)C.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:36].[OH2:5].[Ca+2:37]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: [O-2]
Agent: [Ca+2]
Solvent: O
Solvent: CC(=O)OCC(C)C
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Temperature: 5 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Pseudomonic acid was dissolved in isobutyl acetate (130 ml). Calcium oxide (0.29 g) was suspended in water (32 ml) and added to the solution of pseudomonic acid. The mixture was stirred for 2 hours, and the phases were separated. The volume of the aqueous phase was reduced to 15 ml by vacuum distillation. The mixture was cooled to 5° C. After stirring for 2 hours, the crystalline product was filtered and washed with cooled water (5 ml). The product was dried in an air circulated oven at RT. Mupirocin calcium dihydrate (3.3 g, 62%) was obtained.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24]O)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O=S(Cl)Cl>[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Yield: 100.9 %

Procedure:
A heterogeneous mixture of 3-chlorosulfonyl-benzoic acid (11.0 g, 50.0 mmol) in 18 mL of SOCl2 was refluxed for 3 h. Thereafter the excess of SOCl2 was removed, the residual brown oil was dissolved in 60 mL of CH3CN, and then 2-(p-tolylsulfonyl)ethanol (9.4 g, 47.0 mmol, 0.95 eq.) was added. The mixture was heated to reflux temperature for 20 h. Thereafter the most of CH3CN was removed, the resulting oil was purified by short column chromatography (silica gel, CH2Cl2) to give light brown oil, which was dried further under vacuum to yield 19.1 g (95%) of a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CO.ClCCl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol) and dichloromethane (25 mL). Cool in an ice bath. Add N,N-diisopropylethylamine (3.17 mL, 18.2 mmol) and methanesulfonyl chloride (0.71 mL, 9.1 mmol). After 30 minutes, warm to ambient temperature. After 4 hours, dilute the reaction mixture with dichloromethane and extract three times with a 1 aqueous hydrochloric acid solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give methyl 2-methoxy-5-methylsulfonamidobenzoate: mp; 82-83° C. Elemental Analysis calculated for C10H13NO5S: C, 46.32; H, 5.05; N, 5.40. Found C, 46.44; H, 4.96; N, 5.19.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][C:12]3([CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[O:11][CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.ClCCl.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][C:12]3([CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[O:11][CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCC3(CC2)CN(c2cccc(F)c2)C(=O)CO3)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1COC2(CCN(c3ccc(O)cc3)CC2)CN1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The methoxy compound (205 mg, 0.553 mmol) obtained in (a) was dissolved in chloroform, and at 0° C., 1.0 M boron tribromide/dichloromethane solution (2.2 ml, 2.2 mmol) was dropwise added thereto, and this was stirred overnight at room temperature. At 0° C., the reaction solution was neutralized by adding aqueous 2 N sodium hydroxide solution thereto, and extracted with chloroform, and the organic layer was washed with saturated saline. The organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure to obtain the phenol compound as a crude product (165 mg, 84%).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH2:2].[CH3:14][CH:15]([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>C(O)C>[NH2:19][C:18]1[N:1]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:2]=[C:16]([CH:15]([CH3:21])[CH3:14])[CH:17]=1
Reactant: CC(C)C(=O)CC#N
Reactant: CCOC(=O)c1cccc(NN)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc(-n2nc(C(C)C)cc2N)c1
Yield: 88.2 %

Procedure:
To a mixture of ethyl 3-hydrazinobenzoate (from Example A81, 3 g, 16.6 mmol) and 4-methyl-3-oxopentanenitrile (2.7 g, 24.9 mmol) in ethanol (50 mL) was added conc. HCl (5 mL). The resulting mixture was heated to reflux for 3 h. After removal of the solvent, the residue was washed with Et2O to afford ethyl 3-(5-amino-3-isopropyl-1H-pyrazol-1-yl)benzoate (4 g), which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[C:18]([C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C#Cc1ccc(CO)cc1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(CO)cc3)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Ethynyl-4-(hydroxymethyl)benzene (169 mg, 1.28 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (364 mg, 0.638 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature overnight, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as brown oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][P:8]([CH:13](O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6].C(Cl)[Cl:27].N1C=CC=CC=1>O>[CH2:5]([O:7][P:8]([CH:13]([Cl:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: ClCCl
Reactant: CCOP(=O)(OCC)C(O)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOP(=O)(OCC)C(Cl)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
8.7 g (0.073 mol) of thionyl chloride were added to a mixture of 22.96 g (0.07 mol) of 4-trifluoromethoxy-α-hydroxy-benzylphosphonic acid diethyl ester, 70 ml of methylene chloride and 5.6 g (0.07 mol) of pyridine at 20°-40° C. in the course of about 1 hour, while cooling slightly with water. The reaction mixture was then heated to 50° C. for 3 hours and was subsequently stirred for 12 hours without further action of heat. The mixture was poured onto about 100 g of ice-water and the organic phase was separated off and dried. After distilling off the solvent, the residue was concentrated under 2 mm Hg and at 45° C. 18.7 g (77.1% of theory) of 4-trifluoromethoxy-α-chloro-benzyl-phosphonic acid diethyl ester were obtained as a yellow viscous oil with a refractive index of nD22 : 1.4968.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]1.O>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCN1CCCC(CBr)C1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A stirring mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 hour. 3-(Bromomethyl)-1-ethylpiperidine (141 mg) was added and the stirring mixture heated at 50° C. for 3 hours. After 16 hours at ambient temperature, heating at 50° C. was continued for a further 3 hours to complete the reaction. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a white solid (99 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:40][CH2:39][C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: NCc1cccs1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCc2cccs2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-thienylmethylamine the title compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z=434.4.