Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CC(C)COc1ccc(B2OCC(C)(C)CO2)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (1.00 g, 2.96 mmol) was mixed with 5,5-dimethyl-2-(2-isobutyloxypyridin-5-yl)-1,3,2-dioxaborinane (1.4 g, purity 80%, 4.3 mmol), Pd(PPh3)4 (0.17 g, 0.15 mmol) and sodium carbonate (0.62 g, 5.9 mmol) in tolune/ethanol/water 8:2:1 (15 ml) and refluxed for 8 hours under nitrogen. After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-isobutyloxypyridin-5-yl)phenyl]oxazoline was obtained, 1.14 g, colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(Br)cc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of phosphorous oxychloride (26.1 g) and dry dimethylformamide (50.9 ml), cooled to -10° C., was added 5-bromoindole (30 g) in portions. The reaction mixture was stirred at 10° C. for 1 hr. and at 35° C. for 1 hr. Ice (100 g) was added to the reaction mixture, followed by sodium hydroxide solution (50 ml). The mixture was heated on a steam bath for one-half hour. The precipitate was collected and recrystallized from ethanol to give 35.5 g (97.7%) of product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:18](Cl)=[O:19])[CH:12]=[C:13]([CH:17]=1)[C:14](Cl)=[O:15])(=[O:7])[CH3:6].Cl.C(Cl)Cl.F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:18](=[O:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:13]([C:14](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:17]=2)[CH:17]=1)(=[O:7])[CH3:6]
Reactant: Fc1ccccc1
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)c2ccccc2)cc(C(=O)c2ccccc2)c1
Temperature: 17.5 °C
Reaction time: 12 h

Procedure:
Into a 250 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, a nitrogen inlet, and a dropping funnel, aluminum chloride (10.85 g, 81.4 mmol) and fluorobenzene (80 mL) were introduced. The flask was then placed in an ice-water bath with its temperature maintained between 15-20° C. The solution of 5-acetyloxyisophthaloyl dichloride (8.5 g, 32.5 mmol) in fluorobenzene (20 mL) was then added dropwise for 20 min. The reaction mixture was then allowed to warm up to room temperature and stand with stirring at room temperature for 12 h. The resulting light brown solution was poured into ice-water (500 mL) containing hydrochloric acid (50 mL). Methylene chloride (50 mL) was then added to the mixture and the organic layer was separated with the aid of a separatory funnel. The solvent of the organic extract was then removed on a rotary evaporator. The resulting yellow jelly-like residue was further dried under the reduced pressure to give 11.8 g of 1-acetoxy-3,5-bis(benzoyl)benzene (95.5% crude yield). The 1-acetoxy-3,5-bis(benzoyl)benzene was then dissolved in ethanol (130 mL), followed by the addition of a solution of potassium hydroxide (10.0 g, 178 mmol) in water (20 mL). The resulting mixture was subsequently heated under the reflux for 1.5 h. After it was allowed to cool to near room temperature, the solution was poured into ice-water (500 mL) containing hydrochloric acid (50 mL). The precipitates were collected by suction filtration, air-dried overnight and finally recrystallized from toluene to afford 9.9 g (90% overall yield) of 3,5-Bis(4-fluorobenzoyl)phenol as white crystals, m.p. 133.5-134° C. Anal. Calcd. for C20H12F2O3: C, 71.01%; H, 3.58%; O, 14.19%. Found: C, 70.79%; H, 3.98%; O, 14.51%. FT-IR (KBr, cm−1): 1596, 1657, 3298. Mass spectrum (m/e): 338 (M+, 100% relative abundance). 1H-NMR (CDCl3, δ in ppm): 7.13-7.19 (d, 4H, Ar), 7.48-7.49 (d, 2H, Ar), 7.53-7.54 (d, 1H, Ar), 7.84-7.89 (dd, 4H, Ar). 13C-NMR (CDCl3, δ in ppm): 115.71, 120.52, 121.96, 132.73, 133.36, 138.83, 157.69, 167.34, 194.32.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:14])=O.BrN1C(=O)CCC1=O.[BrH:24]>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:7]([C:8]([Cl:14])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Br
Reactant: COC(=O)CCCCC(=O)O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCC(Br)C(=O)Cl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of adipic acid monomethyl ester (8.0 g) in carbon tetrachloride (5 ml) was added thionyl chloride (14.4 ml). The mixture was stirred at 65° C. for 30 minutes. N-Bromosuccinimide (10.7 g), carbon tetrachloride (25 ml) and 48; hydrobromic acid aqueous solution (0.5 ml) was added to the mixture. The mixture was refluxed for 1.5 hours, cooled at room temperature and filtered off. The filtrate was evaporated and distillated at reduced pressure to give methyl 5-bromo-5-chloroformylpentanoate as an oil (9.02 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:40]=3[F:41])[N:7]=2)[CH2:17][CH2:18]1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3cccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluorophenyl)boronic acid gave 223. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.27 (dd, J=8.7, 3.9 Hz, 1H), 8.12 (t, J=9.1 Hz, 1H), 7.90 (s, 1H), 7.69-7.52 (m, 2H), 7.47-7.37 (m, 1H), 4.84 (dd, J=10.3, 3.7 Hz, 1H), 4.39-4.16 (m, 1H), 4.12-3.86 (m, 2H), 3.76 (s, 3H), 3.15-3.02 (m, 1H), 2.12-2.01 (m, 1H), 1.84-1.70 (m, 1H), 1.70-1.56 (m, 4H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]3[CH2:53][CH2:52][CH2:51][N:50]3C(OC(C)(C)C)=O)=[O:48])=[CH:42][CH:41]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24](=[O:38])[C@@H:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24](=[O:38])[C@@H:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[O:18])=[CH:12][CH:11]=2)[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]3[CH2:53][CH2:52][CH2:51][NH:50]3)=[O:48])=[CH:42][CH:41]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Yield: 93 %

Procedure:
The product from Example 114B (0.20 g, 0.24 mmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (2 mL) at ambient temperature for 2 hours. The solution was concentrated, taken up in 25% isopropanol in chloroform, washed with sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give 0.16 g (91%) of the title compound.
Reaction SMILES: [CH3:1][C:2](Br)([CH3:17])[C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:2]([CH3:17])([CH3:1])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)(C)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 816 h

Procedure:
Methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (1.58 g) was added to a stirred solution of 1-(4-pyridyl)piperazine (1.63 g) in acetonitrile (40 ml). After 34 days, the solid formed was removed by filtration and the filtrate evaporated to give an oil. Purification by flash chromatography on silica, eluting with 0.5 to 4.0% v/v methanol/dichloromethane gave the title compound, 240 mg, as a white foam: NMR (d6DMSO) δ 8.49 (2H, d), 8.12 (2H, d), 6.96 (2H, d), 6.77 (2H, d), 4.87 (2H, s), 3.69 (3H, s),.3.28 (4H, t), 2.58 (4H, t), 1.25 (6H, s); m/e 398 (M+H)+ ; calculated for C22H27N3O4.0.25H2O: C, 65.7; H, 6.8; N, 10.4. found: C, 65.3; H, 6.9; N, 10.4%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:23][CH:24]1[O:40][C@H:39]([CH2:41][OH:42])[C@@H:29]([O:30][CH2:31][C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)[C@H:27]([OH:28])[C@@H:25]1[OH:26]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:23][CH:24]1[O:40][C@H:39]([CH2:41][OH:42])[C@@H:29]([O:30][CH2:31][C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)[C@H:27]([OH:28])[C@@H:25]1[OH:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC(=O)OC1CCCCC1)C(=O)O

Procedure:
Boc-Asp(O-cHex)-Man(4-MBzl) (52 g) was treated with 50% TFA/methylene chloride (400 mL) for 45 min at room temperature. The solvent was evaporated and chased several times with methylene chloride to eliminate traces of TFA. The product precipitated as its TFA salt upon addition of ether. The solid was collected and air dried to yield a white solid (46.7 g, 88%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:25])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:12]=[CH:13]2)=[C:8]([CH:26]2[CH2:28][CH2:27]2)[CH:7]=1)=[O:5])C.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:26]1([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:25])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:12]=[CH:13]3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(OC)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)cc1
Temperature: 60 °C

Procedure:
A solution of 1-cyclopropyl-8-(4-methoxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (68 mg, 0.180 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (33 mg, 0.78 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 47 as yellow solid (22 mg, 35%). ESI-MS m/z: 350 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.30 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 3.84 (s, 3H), 2.86 (s, 3H), 2.53-2.51 (m, 1H), 1.06-1.04 (m, 2H), 0.78-0.75 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([F:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Chloroacetyl chloride (0.60 ml, 7.54 mmol) was dissolved in toluene (6 ml), and the solution was added with 4-fluoroaniline (0.72 ml, 7.52 mmol) at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure to obtain the title compound as pale yellow solid (1.07 g, yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.[CH:15](OCC)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][CH:15]=[O:16])=[CH:4][N:3]=1
Reactant: CCOC=O
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Product: O=CN=C1SCCN1Cc1ccc(Cl)nc1

Procedure:
A mixture of 3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and 10 ml of ethyl formate was heated at the boiling point of ethyl formate for 5 hours with stirring. After distilling the excessive ethyl formate off followed by purification by a silica gel column chromatography, the resultant intended solid was washed with diethyl ether. Yield: 32 mg (13%). Melting point: 99-100° C.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:36])[CH3:35]>>[C:34]([N:17]1[CH2:18][CH2:19][C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[C@H:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:16]1)(=[O:36])[CH3:35]
Reactant: CC(=O)O
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Product: CC(=O)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and acetic acid (6.9 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]OS(CC1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[I:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17]
Reactant: Cc1ccc(CS(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(C#N)ccc1I
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2.0 g (8.16 mmol) of 3-hydroxy-4-iodobenzonitrile was dissolved in 20 ml of DMF. 5.8 g (16.3 mmol) of 1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine and 3.37 g (24.4 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 50° C. for 16 hours. 1.5 g (4.2 mmol) of 1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine was added to the obtained mixture, and they were stirred at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: O=C1COc2ccc(F)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(F)cc2N1CCCCl
Yield: 77.5 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.090 g, 0.54 mmol), Cs2CO3 (0.263 g, 0.81 mmol) and 3-chloro-1-iodopropane (0.121 g, 0.59 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (8173MF55b) (0.102 g, 78%). 1HNMR(CDCl3) δ 6.95-6.91 (m, 1H), 6.82-6.78 (m, 1H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.19-2.11 (m, 2H); 13CNMR(CDCl3) δ 164.6, 158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5 Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 31.1 %

Procedure:
L-alanyl-L-proline t-butylester (2.42 g, 10 mmole) was dissolved in methylene chloride (50 ml), and triethylamine (1.01 g, 10 mmole) was added thereto with cooling to -20° C and stirring. Methylene chloride (5 ml) solution of ethanesulfonylchloride (1.29 g, 10 mmole) was added dropwise to the solution while keeping the temperature thereof to -20° C. and then stirred overnight at room temperature. The solution was washed with 10% aqueous citric acid, water, 5% aqueous sodium bicarbonate and water in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give oily residue of N-ethanesulfonyl-L-alanyl-L-proline t-butylester(yield: 1.04 g, 31.1%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH2:20]([O:27][CH2:28][CH2:29]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([CH2:29][CH2:28][O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:19])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOCc1ccccc1)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
Sodium hydride (406 mg) was dissolved in dimethylformamide (20 mL) and the solution was cooled to 0° C. To this solution was added phenylmalonic acid diethyl ester (2.0 g), and the mixture was stirred at room temperature for 30 minutes. Bromoethyl benzyl ether (2.0 g) was further added thereto, stirred at 60° C. for 4 hours, and water was added thereto. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:9 to give the title compound (1.2 g).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:18]>C(Cl)Cl>[CH3:18][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N(c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 96 h
Yield: 47.8 %

Procedure:
2.08 g of DIEA and then 1.745 g of ethyl chloroformate are added to a solution of 1.6 g of benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 5.2 in 11 ml of DCM. The mixture is stirred at AT for 4 days. It is evaporated under reduced pressure. The residue is taken up in 10 ml of pyridine (10 ml) and 0.7 g of ethyl chloroformate is added. The mixture is stirred at AT for 4 h 00. It is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (10/90, v/v) as far as (30/70, v/v), to give 0.875 g of the expected product.
Reaction SMILES: [Cl-:1].[CH3:2][NH+:3]([CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.[O:28]1[CH2:47][CH:29]1[CH2:30][O:31][CH2:32][CH2:33][CH2:34][Si:35]([CH3:46])([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[O:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>C(O)(C)C>[Cl-:1].[CH3:2][N+:3]([CH3:20])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:47][CH:29]([OH:28])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][Si:35]([CH3:46])([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[O:36][Si:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCCCCCCCCCCCCCC[NH+](C)C
Reactant: C[Si](C)(C)O[Si](C)(CCCOCC1CO1)O[Si](C)(C)C
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CC(O)COCCC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 80 °C

Procedure:
A 500-ml, three-necked, round-bottomed flask was equipped with a stirrer, addition funnel, dry ice/acetone condenser, thermometer and electric heating mantle. The flask was flushed continuously with argon. The flask was charged with 167.2 g (0.55 equivalent) of dimethyl hexadecyl ammonium chloride (Sartomer Chemical Company, West Chester, Pa.), 0.028 g (0.27 milliequivalent) of triethylamine (Aldrich), and 250 g of isopropanol. To the stirred flask contents 65.2 g of the epoxy trisiloxane of Example 1 was added over a ten-minute period. The reaction mixture was stirred and heated at 80° C. for five hours to form a clear solution. The reaction mixture was cooled to ambient temperature and flushed overnight with dry argon. The solvent and other low-boiling materials were removed by rotary evaporation at 45° C. The yield of the quaternary ammonium salt (Compound II), a light yellow oil, was 118 g (87%). The elemental analysis was as follows: