Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][C:25](=O)[CH:24]([F:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]([F:28])[CH:25]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:30]=2[Cl:29])[CH2:26]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(F)C1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(F)C(NCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Add sodium triacetoxyborohydride (156 mg, 0.73 mmol) to a mixture of 3-fluoro-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol) and 2,4-dichlorobenzylamine (65 μL, 0.5 mmol) in 1,2-dichloroethane (1.5 mL), followed by 2 drops of glacial acetic acid and stir overnight at room temperature. Pour the crude mixture into 2 N sodium hydroxide and extract with ethyl acetate, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel to give 3-(2,4-dichlorobenzylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.44 (2H, m), 7.20-7.28 (1H, m), 5.03 (1H, d, J=54.07 Hz), 3.21-3.95 (6H, m), 2.99-3.15 (1H, m), 1.45 (9H, s), MS (ES): m/z=363 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16]C)=[O:15].[CH3:18][O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([O:28][CH3:29])[C:20]=1[O:19][CH3:18])[C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COC(=O)CC1=C(C)Cc2ccc(OC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-methoxy-2-methyl-3-indenylacetate 8.7 g (0.037 mol) and 2,3,4-trimethoxybenzaldehyde, 7.99 g (1.1 equivalent) is added 16+ ml (2.0+ equivalents) of 25% methanolic sodium methoxide. The mixture is stirred at reflux under nitrogen for 2 hours. An equal volume of water is added dropwise and refluxing continues for 30 min. The solution is cooled, diluted with water and extracted with ether (3×). Residual ether is blown off with nitrogen, and then the aqueous solution is acidified with 50% glacial acetic acid. The precipitated product is collected and washed thoroughly with water. The crude product is crystallized to give 5-methoxy-2-methyl-1-(2,3,4-trimethoxybenzylidene)-3-indenyl acetic acid. (R and R1 =H, R2 =OCH3, R3 and R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, R9 =H, R10 and R11 =double bond, m=0, n=0, M=OH)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]([NH2:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:22][C@@H:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH3:21])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccc(Cl)c([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde 1 (1.71 g, 9.2 mmol) and (R)-1-(3-chlorophenyl)ethanamine (1.115 g, 7.2 mmol) in DCE (15 mL) at room temperature was added acetic acid (2.0 mL, 35 mmol) and NaBH(OAc)3 (2.23 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 d, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave (R)—N-(4-chloro-3-nitrobenzyl)-1-(3-chlorophenyl)ethanamine 30 (2.03 g, 87% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.7 Hz, 3H), 3.66 (s, 2H), 3.77 (q, J=6.7 Hz, 1H), 7.18-7.32 (m, 5H), 7.44-7.48 (m, 2H), 7.83 (s, 1H). Mass spectrum: calculated for C15H14Cl2N2O2 324.0. found 325.1 (M++1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCOC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(tetrahydro-3-furanyloxy)-1H-isoindole-1,3(2H)-dione (1.5 mmol, 357 mg) was combined with hydrazine (1.7 mmol, 0.053 mL) in anhydrous THF (3 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 1 hour. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (1.5 mmol, 316 mg) and diisopropylethylamine (1.8 mmol, 0.320 mL) was added. After stirring at room temperature for 18 hours, the reaction was concentrated to a solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate). The purified product was then combined with ether and filtered to remove the residual phthalimide-hydrazine biproduct. The filtrate was then crystallized by adding hexanes providing 203 mg (48%) white crystals. Rf=0.2 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl3): 67 7.82 (2H,d), 6.99 (2H,d), 6.85 (1H,s), 4.82-4.79 (1H,m), 3.97-3.87 (2H, m), 3.87 (3H,s), 3.83-3.70 (2H,m), 2.12-1.99 (2H,m).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Yield: 64.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 106 mg 5-bromo-2-oxindole, and 75 μL piperidine in 2 mL ethanol were heated to 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 120 mg (64%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[C:22]12([CH2:32][C:33](O)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:21])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: CC(C)c1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 168A and 2-(adamantan-1-yl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H), 8.39-8.42 (m, 1H), 7.89-8.02 (m, 2H), 7.75-7.78 (m, 1H), 7.50-7.53 (m, 2H), 7.43-7.46 (m, 2H), 2.96-3.06 (m, 1H), 2.05 (s, 2H), 1.94-1.97 (m, 3H), 1.65-1.72 (m, 9H), 1.58-1.64 (m, 3H), 1.28 (d, J=6.9 Hz, 6H); MS (APCI+) M/Z 457 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1cccc(Cl)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 12 and 3-chlorobenzen sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([OH:37])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:41]1([O:47][C:48](Cl)=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CO>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([O:37][C:48]([O:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[S:49])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1OC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
In an atmosphere of argon gas, 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (151 mg, 0.3 mmole) was dissolved into acetonitrile (5 ml), to which were then added 4-dimethylaminopyridine (75.1 mg, 0.62 mmole) and phenyloxythiocarbonyl chloride (57 μl, 0.33 mmole). After stirring the resulting mixture at room temperature for 24 hours. 0.1M aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water and then with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-(phenoxythiocarbonyloxy)cyclohexyl]-adenine (109 mg, Yield 56.8%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(NC1C2C(=CC=CC=2)CCC1)(=[O:18])C>>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCCc2ccccc21
Reactant: CC(=O)Nc1cccc2c1CCCCC2
Product: CC(=O)Nc1cccc2c1C(=O)CCCC2

Procedure:
The reaction was carried out in the same manner as in -Example 1-(1), except that 200 mg of the compound prepared in (1) above was used instead of 1-acetylaminotetraline of Example 1-(1). The reaction product was post-treated to produce 55 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CC(C)=O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2,5-dihydroxybenzoate (1.5 g, 8.92 mmol), potassium carbonate (7.50 g, 54.2 mmol), and dry acetone (100 ml) was stirred at room temperature for 30 min. To the mixture was added TsCl (1.72 g, 9.00 mmol) portionwise and the mixture was refluxed for 7 h. The reaction mixture was used in the next step directly.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([CH3:54])=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([N:50]([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:51][N:50]([CH3:52])[C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:53])[N:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH3:54])[CH:49]=[CH:48]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: Cc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 78 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (69 mg, 0.16 mmol), 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (36 mg, 0.10 mmol), potassium phosphate (43 mg, 0.20 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (2.9 mg, 0.0061 mmol), and bis(dibenzylidineacetone)palladium(0) (1.7 mg, 0.0030 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 10% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (46 mg, 0.078 mmol). MS (ESI) 591.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:16][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:19]=[O:20])=[CH:3][CH:4]=1)[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccccc2C=O)cc1
Yield: 21.1 %

Procedure:
The title compound (68 mg, 21%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.892 mmol, prepared in example 1), 2-formylbenzeneboronic acid (180 mg, 1.085 mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg, 0.036 mmol), 2 M sodium carbonate (320 mg in 1.5 mL water), and 1,2-dimethoxyethane (6 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 280 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (0.300 g, 0.763 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.316 g, 0.839 mmol) according to the general procedure VI. Obtained as an off-white solid (0.040 g, 10%). MS (ISP) 532.1 [(M+H)+]; mp 227° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@@H:15]([C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].Cl.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[NH:1]1[C:21](=[O:23])[CH2:20][NH:19][C:17](=[O:18])[C@@H:15]([CH3:16])[NH:14][C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[CH2:2]1
Reactant: C[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1NC(=O)CNC(=O)CNC(=O)[C@@H](C)NC(=O)CNC1=O
Temperature: -40 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
This compound was synthesized by the method of Veber, D. F. et al, J. Org. Chem. 44, 3101-5 (1979). To a solution of Gly-Ala-Gly-DAla-Gly.HCl prepared as in Example 34D (9.70 g, 26.4 mmol) in anhydrous DMF (3200 ml) was added enough TEA to adjust the pH to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the resulting mixture was cooled to -40° C. To this mixture was added DPPA (8.86 g, 32.2 mmol) dropwise over 5 min. The temperature was maintained at ~-35° C. for a period of 5 h and then the reaction mixture was stored at -25° C. (internal temperature) for 48 h thereafter. During this time the pH was monitored periodically (as described above) and maintained at ~8 by the addition of TEA. After this time the reaction mixture was allowed to stand at 0° C. for 48 h. Again the pH was monitored periodically and maintained at ~8 by the addition of TEA. After this time the reaction was diluted with water (3200ml) and stirred with Bio-Rad AG 501-X8 (mixed-bed) resin (1500 g) for 6 h. The resin was separated by filtration and the solution was concentrated to dryness. Trituration of the residue with refluxing THF for 12 h, filtration of the hot THF and drying at high vacuum afforded 5.50 g (67% yield) of the product as a white powder: mp >300° C. (dec); 1H NMR (DMSO-d6) δ 1.16-1.25 (m, 6 H), 3.38-4.23 (m, 8 H), 7.55 (t, J=5.6 Hz, 1 H), 7.60 (t, J=5.4 Hz, 1 H), 8.20-8.25 (m, 1 H), 8.40 (d, J=7.6 Hz, 1 H); FAB mass spectrum (NBA+Li+) m/z 320 (M+Li)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:19][C:20]1[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:22][O:23][C:24]=1[CH3:25]>C1COCC1>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[CH2:19][CH2:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Cc1ncc(C(=O)O)s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (100 mg, 0.7 mmol) in THF (5 mL) at −72° C. and under argon was added LDA (0.7 mL of a 2M solution in THF, 1.40 mmol) dropwise. After 1.5 h a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (145 mg, 0.7 mmol) in THF (5 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (1N, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated then triturated with diisopropyl ether to give the title compound (135 mg, 61%) as a light brown solid which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])(=[O:10])=[O:9])=[O:4].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[Na+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])(=[O:9])=[O:10])[C:28](=[O:29])[N:27]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C1CN1S(=O)(=O)c1ccccc1C(F)(F)F
Agent: [I-]
Agent: [Na+]
Product: COC(=O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1

Procedure:
In analogy to example 1, (RS)-1-(2-trifluoromethyl-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester was reacted with phenylisocyanate and sodiumiodide to give (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[CH:32](NC(C)C)(C)[CH3:33].[Li].C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH2:30]([C:22]([O:21][CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])([CH2:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:31]
Reactant: CC(C)NC(C)C
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (480 mg, 1.11 mmol) was added dropwise over 30 minutes to a solution of lithium diisopropylamine (LDA) (2.0 M, 750 μL, 1.50 mmol) in dry tetrahydrofuran (10 mL) held at −70° C. under nitrogen. The reaction mixture was stirred for 30 minutes. Ethyl iodide (312 mg, 2.00 mmol) was added in one portion and the resulting mixture was warmed to ambient temperature during 1 hour. The reaction mixture was stirred at ambient temperature for 17 hours. The mixture was poured into saturated NH4Cl (aq.) (50 mL) and extracted with heptane (2×50 mL). The combined organic phases was washed successively with brine (50 mL), 0.25 M HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0→95:5) as eluent. Concentration of the appropriate fractions afforded 343 mg (67% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 0.84 (t, 6H), 0.99 (td, 3H), 1.35-1.55 (m, 11H), 1.54-1.69 (m, 2H), 1.68-1.87 (m, 4H), 1.99-2.24 (m, 4H), 2.74-2.99 (m, 8H), 3.31 (t, 2H), 5.23-5.52 (m, 10H); MS (electro spray): 401.3 [M−1]−.