Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([P:36](Cl)(Cl)=[O:37])[CH:33]=[CH:34][CH:35]=1>CCCCCC.C1CCCCC1>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([P:36]2(=[O:37])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: O=P1(c2cccc(C(F)(F)F)c2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.06 g, 0.126 mol) in hexane was added to a solution of tetramethylethylenediamine (3.71 g, 0.032 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (11 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to 0° C. in an ice bath. A solution of 3-trifluoromethylphenylphosphonic dichloride (16.8 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was added dropwise to the suspension. The ice bath was removed and the resulting mixture was stirred for 3 hours at 26° C. The reaction was quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed under vacuum and the resulting residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then water, dried over sodium sulfate and concentrated in vacuo to yield a brown oil. The brown oil was separated on a silica gel column using a 3:1 mixture of methylene chloride:ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and rechromatographed using methylene chloride as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo and the residue was triturated in cyclohexane to yield a white solid. The white solid was evacuated under high vacuum to remove any cyclohexane and the resulting residue was recrystallized from diethyl ether and petroleum ether to yield 1-[3-(trifluoromethyl)phenyl]-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (6.6 g, 30% yield) as a beige solid having a melting point of 48°-51° C. and the following analysis:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH2:16][O:17]C(=O)C)[O:12][C:11](=[O:21])[C:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C(O)C.C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH2:16][OH:17])[O:12][C:11](=[O:21])[C:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc(COC(C)=O)c(COC(C)=O)cc2oc1=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)Cc1c(-c2ccccc2)c2cc(CO)c(CO)cc2oc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A solution of ethyl 2-[6,7-bis(acetoxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate (240 mg) in ethanol (4 ml) was combined with DBU (0.4 ml), and stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (30 ml), and then washed with a 1 N solution of hydrochloric acid followed by a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was recrystallized from ether to obtain the title compound (167 mg, yield: 86%). Melting point: 130-131° C.
Reaction SMILES: C(N(CC)CC)C.O.[NH:9]1[CH2:17][CH2:16][CH:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1.[C:18](=O)([O:24]C(C)(C)C)[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:19][C:18]([N:9]1[CH2:17][CH2:16][CH:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
8.6 g of triethylamine and 20 ml of water are added to a solution of 10 g of isonipecotic acid in 100 ml of dioxane and the mixture is heated to 60° C. 20.25 g of di-tert-butyl carbonate are then added dropwise and the mixture is stirred for 1 hour at 60° C. and refluxed for 30 minutes. It is concentrated under vacuum, the residue is taken up with water and acidified to pH 3 by the addition of 2 N HCl solution and the precipitate formed is filtered off to give 17 g of the expected product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][OH:17].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:18][CH:15]([CH2:14][CH2:13][NH:12][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:16][OH:17]
Reactant: CC(CO)CCN
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CO)CCNCc1ccccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 96.2 %

Procedure:
2-Nitrobenzaldehyde (7.33 g, 48.5 mmol) and 4-amino-2-methylbutanol (5.00 g, 48.5 mmol) were dissolved in toluene (50 ml) and heated to reflux for two hours with Dean Stark dehydration apparatus. After allowed to cool, the solvent was evaporated under reduced pressure. The obtained concentrate was dissolved in methanol (100 ml), added with sodium borohydride (2.75 g, 72.8 mmol) under ice cooled condition and stirred at the same temperature for two hours. The reaction mixture was further stirred at room temperature for two hours, adjusted to pH 4 by adding 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. Water (30 ml) was added to dissolve the concentrate and after extracted with ethyl acetate, pH was adjusted to 8 by added a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 2-methyl-4-(2-nitrobenzylamino)butanol (11.12 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.CN([CH:18]=[O:19])C.[NH4+].[Cl-]>CCOCC>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH:18]=[O:19])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C=O)cn1
Temperature: -64 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-bromo-2-methoxy-pyridine (8.50 g, 45.2 mmol) in 100 mL dry ether under argon at −64° C. was added 1.6 M n-BuLi in hexanes. The resulting mixture was stirred at −64° C. for 40 minutes and allowed to warm to −35° C. To the resulting suspension was added 7.0 mL of dry DMF over 10 minutes. After 15 minutes, the mixture was allowed to warm to 0° C. and 75 mL of 5% NH4Cl was added. The resulting mixture was separated and the aqueous layer extracted with EtOAc (3×75 mL). The organics were combined, dried (MgSO4), filtered and evaporated under vacuum to give 2-methoxy-pyridine-5-carboxaldehyde as a tannish solid (recrystallized from hexane), 3.76 g (60.6%); m.p. 48.5-50° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:9]1([C:14]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:25]([O:27][C:28]([C:30]1=[CH:31][C:32]2[CH:47]=[CH:46][C:45](Br)=[CH:44][C:33]=2[N:34]=[C:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36]1)=[O:29])[CH3:26]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[CH2:25]([O:27][C:28]([C:30]1=[CH:31][C:32]2[CH:47]=[CH:46][C:45]([C:19]3[CH:20]=[CH:21][C:16]([C:14]([N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[O:15])=[CH:17][CH:18]=3)=[CH:44][C:33]=2[N:34]=[C:35]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:36]1)=[O:29])[CH3:26]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 47.6 %

Procedure:
Preparation of (1E,4E)-ethyl-2-(tert-butoxycarbonyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate(23): To an ethanol solution (15 mL) containing K3PO4 (938 mg, 4.42 mmol), 4-(pyrrolidine-1-carbonyl)phenylboronic acid (785 mg, 3.58 mmol), and (1E,4E)-ethyl-8-bromo-2-(tert-butoxycarbonyl)-3H-benzo[b]azepine-4-carboxylate (489 mg, 1.19 mmol), was added palladium acetate (80.5 mg, 0.358 mmol). The reaction was heated to 60° C. for 2 hours, then cooled to room temperature and concentrated to dryness. The brown oil was purified by preparative LC plate (100% EtOAc) to provide (1E,4E)-ethyl-2-(tert-butoxycarbonyl)-8(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate (277 mg, 46% yield) as a tan oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.O1CCCC1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
4.5 g (20 mmol) of 2-aminophenol, 3.0 mL (22 mmol) of triethylamine, and 50 mL of tetrahydrofuran (THF) were put in a 200 mL three-neck flask, and cooled to 0° C. After the cooling, 50 mL of THF solution containing 4.5 g (20 mmol) of 4-bromobenzoyl chloride was dropped under a nitrogen atmosphere. This solution was stirred at 0° C. for four hours under a nitrogen atmosphere. Then, water was added to the solution, and an organic layer and an aqueous layer were separated. An organic substance was extracted with ethyl acetate from the aqueous layer. The resulting extracted solution was combined with the organic layer, and the organic layer was washed with 0.2 M hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, and then dried with magnesium sulfate. This mixture was subjected to suction filtration through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was concentrated to give a solid. The obtained solid was recrystallized with ethyl acetate/hexane, whereby 5.3 g of the target white powder was obtained in a yield of 88%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:25](=[O:26])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])[CH2:24][CH2:23][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(=O)c2ccc(Br)cc2)CCC1
Reaction time: 18 h

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl (5.8 g, 23 mmol) in DMF (75 mL) was treated with 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (5.0 g, 23 mmol), HATU (9.7 g, 25 mmol), and DIPEA (12.9 mL, 34 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (3 10 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 to afford crude {1-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclobutyl}-carbamic acid tert-butyl ester, which was used without further purification. This material (6.54 g, 16 mmol) in xylenes (40 mL) was treated with ammonium acetate (6.1 g, 80 mmol). The reaction was stirred at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO3 (50 mL). The solution was dried over MgSO4 to afford crude {1-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 393 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OCCO3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (351 mg, 1.95 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol), HATU (1.11 g, 2.93 mmol) in anhydrous DMF (8 mL) is added DIPEA (484 μL, 2.93 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (59) as white solid (650 mg, 91%).
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC1=CC(=O)CC1
Product: O=C1C=C(Cc2ccccc2)CC1

Procedure:
The general procedure for the preparation of substrates using 3-ethoxycyclopentenone (0.88 g, 7.0 mmol) and benzylmagnesium chloride (10 mmol, 1 M in diethyl ether) gave, after flash chromatography (2:1 hexanes:ethyl acetate) and Kugelrohr distillation (0.4 torr, 200° C.), the title compound as a white solid (0.58 g, 50%). m.p. 32-33° C. Spectroscopic data were consistent with previously reported data for this compound.3
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]([C:22]2[CH:23]=[N:24][C:25]([NH:28][NH2:29])=[CH:26][CH:27]=2)[C:18]([F:21])([F:20])[F:19])[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])N.[CH:34]([O:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([CH:48]=O)[CH:44]=[CH:43]2)([CH3:36])[CH3:35]>>[F:1][CH2:2][CH2:3][N:4]([C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]([C:22]2[CH:27]=[CH:26][C:25]3[N:24]([C:48]([C:45]4[CH:44]=[CH:43][C:42]5[C:47](=[C:38]([O:37][CH:34]([CH3:36])[CH3:35])[CH:39]=[CH:40][CH:41]=5)[N:46]=4)=[N:29][N:28]=3)[CH:23]=2)[C:18]([F:21])([F:19])[F:20])[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: NC(=O)[O-]
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N(CCF)C(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl 2-fluoroethyl((S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate (0.10 g, 0.237 mmol) in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate and using 8-isopropoxyquinoline-2-carbaldehyde (0.051 g, 0.237 mmol) in place of 8-methoxyquinoline-2-carbaldehyde. LCMS APCI (+) m/z 617 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[NH:3]1.NN.O>C(O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[NH:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Batch size: 11.5 g (27.4 mmol) 2-{4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-isoindolin-1,3-dione and 2.7 ml (55 mmol) hydrazine.hydrate in 60 ml ethanol. The accumulated crude product is further processed without further purification: Yield 5.1 g (64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].CN1CCCC1=[O:21]>O>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:21])=[CH:4][C:3]=1[F:12]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c(F)cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
1.93 g (0.01 mole) of 5-chloro-2,4-difluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. After the completion of the reaction, part of 1-methyl-2-pyrrolidone was recovered. The resulting reaction mixture was diluted with 500 ml of water and then subjected to precipitation with a 10% aqueous hydrochloric acid solution. The resulting crystals were collected by filtration, washed with water, and dried to obtain 1.76 g of 5-chloro-4-fluorosalicylic acid. The isolated yield was 92.1% relative to the 5-chloro-2,4-difluorobenzoic acid used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:12]([CH3:18])[C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCCl>[Cl:23][CH2:24][C:25]([C:14]1[C:15]([CH3:16])=[C:11]([C:9](=[O:10])[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]([CH3:18])[C:13]=1[CH3:17])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1c(C(=O)CCl)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A solution of 48.65 g (0.17 mole) of (2,4-dichlorophenyl)(1,3,5-trimethyl-1H-pyrrol-2-yl)-methanone (5) in 480 mL 1,2-dichloroethane was cooled in an ice bath and 53.5 g (0.425 mole) of AlCl3 was added in four portions. A 33.5 mL portion of (0.425 mole) chloroacetyl chloride was added dropwise. The ice bath was removed and the reaction allowed to stir for 3 h under argon. A 10 g sample of AlCl3 was added and the reaction was stirred overnight. The mixture was poured into 1N HCl/ice and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The organics were combined and washed with water, NaHCO3, water, brine, and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from methylcyclohexane to give 53.50 g of product: mp 100°-102° C.; mass spectrum (Cl--CH4) m/z=358 (M+1); NMR 300 MHz (CDCl3 ) d 7.55 (s, 1H); 7.4 (s, 2H); 4.4 (s, 2H); 3.7 (s, 3H); 2.5 (s, 3H); 1.9 (s, 3H). Anal Calcd for C16H14NO2 : C, 53.58; H, 3.93; N, 3.91. Found: C, 53.48; H, 3.81; N, 3.93.
Reaction SMILES: I[CH2:2][CH:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH2:19]([O:26][C:27]1[CH:32]=[C:31](I)[CH:30]=[CH:29][C:28]=1[N:34]1[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:36](=[O:47])[CH2:35]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[N:34]1[CH2:35][C:36](=[O:47])[N:37]([CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[S:38]1(=[O:39])=[O:40])[CH2:2][CH:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C1NC(CI)c2ccccc2-c2ccccc21
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CC3NC(=O)c4ccccc4-c4ccccc43)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 7-iodomethyl-6,7-dihydro-dibenzo[c,e]azepin-5-one and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:31]4[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=4[F:33])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cc(F)ccc2F)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2,5-difluorophenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′,5′-difluoro-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a colorless solid. MS: 457.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(#N)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(COC2OCCNC2c2ccccc2)cc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCOC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 150 mg (0.37 mmol) of the trans-isomer of (±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl morpholine (Example 4) and 0.18 mL (1.00 mmol) of N,N-diisopropyl-ethyl-amine in 2 mL of acetonitrile was treated with 0.095 mL (1.00 mmol) of methyl bromoacetate and the resulting solution was stirred at rt for 20 h. The solution was concentrated in vacuo and the residue was partitioned between 20 mL of ethyl acetate and 5 mL of 0.5N aqueous potassium hydrogen sulfate solution. The layers were separated; the organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 164 mg (93%) of the trans-isomer of the title compound as an oil: 1H NMR 2.79 (dt, 1H, J=3.2, 11.2), 2.93 (dt, 1H, J=11.2, 1.6), 3.52 (d, 1H, J=7.2), 3.63 (s, 3H), 3.92 (dt, 1H, J=2.8, 11.6), 4.04 (ddd, 1H, J=11.6, 3.2, 1.6), 4.45 and 4.84 (AB q, 2H, J=13.2), 4.46 (d, 1H, J=7.2), 7.31-7.38 (m, 6H), 7.68 (s, 1H); IR (neat) 2861, 1744, 1455, 1375, 1346, 1278, 1170, 887, 759, 704, 682; FAB-MS 478(M+1)+.