Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9])=C.Cl.[OH-].[Na+]>CCO.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc12
Yield: 96 %

Procedure:
A solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (2-vinyloxyethoxy) amide (11a) (55.4 mg, 0.114 mmol) and aqueous HCl (1 M, 0.23 mL) in EtOH (3 mL) was stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 6-7 with aqueous NaOH (2 N). The reaction was diluted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 50.2 mg (96% yield) of the desired product (12a). MS APCI (−) m/z 456, 458 (M+, Br, Cl pattern) detected: 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 4.01 (t, 2H), 3.74 (t, 2H), 2.60 (s, 3H): 19F NMR (376 MHz, CD3OD) −140.85 (s, 1F).
Reaction SMILES: [CH2:1](B1OC(C)(C)C(C)(C)O1)[CH:2]=[CH2:3].[CH:13]([C:15]1[C@H:20]([C:21]([O:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[N:19]2[C:37](=[O:49])[C@@H:38]([NH:39][C:40](=[O:48])[CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:18]2[S:17][CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[OH:14][CH:13]([C:15]1[C@H:20]([C:21]([O:23][CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:22])[N:19]2[C:37](=[O:49])[C@@H:38]([NH:39][C:40](=[O:48])[CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@H:18]2[S:17][CH:16]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Solvent: Cc1ccccc1
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.3 mmol), diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol), 0.4 nm molecular sieves (50 mg), and toluene (2 ml) was heated under reflux for 3 h and then cooled and purified by chromatography as in part a to give the title compound S-diastereomer, 20 mg (18%), and the R-diastereomer, 23 mg (20%).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[C:12]2=[O:20])[CH2:7][CH2:6]1)=[O:4].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][CH:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][C:14]4=[CH:16][N:17]=[C:18]([CH3:19])[N:13]4[C:12]3=[O:20])[CH2:7][CH2:6]2)=[O:4])=[O:36])=[CH:30][CH:29]=1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccc(Cl)cc3)c3ccccc3)CC1)C2
Yield: 62.7 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (0.10 g) obtained in Example 50b) was dissolved in DMF (3.0 ml), 4-chlorophenyl isocyanate (0.05 g) was added thereto, and mixed at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to methanol/ethyl acetate=1/10). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.09 g, 59%).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18]
Reactant: CI
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
To 2.53 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 100 ml of dry dimethylformamide was added 0.6 g of sodium hydride (50% in oil). This mixture was stirred under argon, for 1 hour, then 0.78 ml of methyl iodide was added. This mixture was stirred overnight, then poured into 300 ml of water and extracted with 50 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (98:2). The active fractions were combined, evaporated and the solid recrystallized from dichloromethane-hexane, giving 1.39 g of the desired product as light orange crystals mp 166°-169° C.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@H:27]([CH:28]=[CH:29][Sn](CCCC)(CCCC)CCCC)[CH2:26][CH2:25][C:24]1=[O:43].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[C:24](=[O:43])[CH2:25][CH2:26][C@H:27]1[CH:28]=[CH:29][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(=O)c1cccc2ccccc12
Temperature: 100 °C

Procedure:
A solution of tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol) in dry toluene (10 mL) was evacuated under vacuum and was purged with carbon monoxide (3×). Naphthalene-1-carbonyl chloride (320 mg, 1.68 mmol) was added followed by addition of trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl)-heptanoic acid methyl ester (the compound of Preparation 1, Step D, 1.0 g, 1.85 mmol) and 2,6-di-tert-butyl-4-methylphenol (few crystals). The mixture was heated at 100° C. under an atmosphere of carbon monoxide for 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and the insolubles were removed by filtration through a pad of Celite®. The filtrate was washed with 10% aqueous ammonium hydroxide, dried (magnesium sulfate), filtered, and concentrated. Purification by flash chromatography (hexanes to 20% ethyl acetate in hexanes) provided the title compound of Step A (162 mg). 1H NMR (CDCl3, 250 MHz) d 8.31 (m, 1H), 8.00 (d, 1H), 7.91 (m, 1H), 7.70 (dd, 1H), 7.55 (m, 3H), 6.91-6.71 (m, 2H), 3.68 (s, 3H), 2.75 (m, 1H), 2.42-2.11 (m, 5H), 2.00 (m, 1H), 1.81-1.20 (m, 9H), 1.94 (t, 2H); MS 407 (M+1), 424 (M+18).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)C(C)C)C.[C:20]([C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:36]=3[Cl:45])=[CH:31][CH:30]=2)[C:26]([CH3:46])=[N:25][C:24]=1[CH3:47])(=[O:22])[NH2:21].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:20]([C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:2][C@@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:43])=[CH:37][C:36]=3[Cl:45])=[CH:31][CH:30]=2)[C:26]([CH3:46])=[N:25][C:24]=1[CH3:47])(=[O:22])[NH2:21]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 123.5 %

Procedure:
A mixture of (S)-methyl 2-amino-3-methylbutanoate hydrochloride (95 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford (S)-methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-3-methylbutanoate (327 mg, 124%) which was used without further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (43.3 mL of a 0.3M stock solution, 12.99 mmol) cooled to −78° C. was treated with (3-nitro-phenyl)-acetic acid methyl ester (2.45 g, 12.56 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (32 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (2.78 g, 13.23 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.78 mL), and the mixture was stirred at −78° C. for 3 h. The reaction was warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (25 mL) and was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (2×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63 g, 46.8%) as pale yellow oil: EI-HRMS m/e calcd for C15H19NO4 (M+) 277.1314, found 277.1317.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][N:25]=1.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[N:25][CH:26]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)nc1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cccc3c2C(=O)OC(C)(C)O3)cn1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
8.7 g of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)benzodioxin-4-one, 23.2 g of 2-methoxy-5-tributylstannylpyridine, 3.4 g of lithium chloride, 0.6 g of tetrakistriphenylphosphinepalladium0 and 70 mg of 2,6-di-t-butyl-4-methylphenol are dissolved in 150 ml of dioxane and the mixture is stirred for 3 h at 140° C. in an autoclave. It is then concentrated under reduced pressure, the residue is stirred with 200 ml of n-pentane and filtered on a little silica gel 60, the latter is subsequently washed with n-pentane and the product is eluted using ethyl acetate. After concentration, 10.3 g of m.p. 160° C. remain.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12]/[C:13]/2=[N:16]/[OH:17])=[CH:9][CH:8]=1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>C(Cl)Cl>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:17]/[N:16]=[C:13]1/[CH2:12][CH2:11][C:10]2[C:14]/1=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=2)([CH3:20])[CH3:19]
Reactant: O/N=C1/CCc2ccc(Br)cc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](O/N=C1/CCc2ccc(Br)cc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of imidazole (11 g, 162 mmol) in 100 mL of dry DCM was added dropwise to a solution of (Z)-6-bromo-2,3-dihydro-1H-inden-1-one oxime (1C) (18.2 g, 81 mmol) and triisopropylsilyl chloride (23.3 g, 121.5 mmol) in solution in 40 mL of dry DCM. The reaction mixture was stirred for 16 hours at rt. It was then filtered to remove the precipitate and the filtrate was concentrated under vacuum. The crude material was purified by column chromatography on silica gel to provide (Z)-6-bromo-2,3-dihydro-1H-inden-1-one O-triisopropylsilyl oxime (10). The crude product was taken on to the next step immediately.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:27]([N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[C:28]#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[C:28][CH2:27][N:30]3[C:34](=[O:35])[C:33]4[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: Fc1ccccc1C1=NCc2nnc(C(F)(F)F)n2-c2ccc(I)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C(F)(F)F)n1-2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.94 g (2 mmol) of 6-(2-fluorophenyl) 8-iodo-1-(trifluoromethyl)-4H-[1,2,4]triazolo [4,3-a][1,4]-benzodiazepine, 0.55 g (3 mmol) of N-propargylphthalimide 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 0.6 ml of triethylamine and 50 ml of dimethylformamide was degassed with argon for 10 minutes. Palladium acetate, 25 mg. was then added and the mixture was stirred for 3 days at room temperature. The product was precipitated by dilution with sodium bicarbonate solution and was collected by filtration. It was dissolved in methylene chloride and the solution was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-ProPynyl}-1H-isoindole-1,3(2H)-dione with m.p. 204°-206° .
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17].F[B-](F)(F)F.[C:27]1(=[O:41])[N:31](OC(N(C)C)=[N+](C)C)[C:30](=[O:40])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][N:31]1[C:27](=[O:41])[CH2:28][CH2:29][C:30]1=[O:40])=[O:17]
Reactant: COC(=O)CCCCCCCCCCCCCCC(=O)[O-]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 20 h
Yield: 96.8 %

Procedure:
Mono-methyl hexadecandioate (275 mg, 0.91 mmol) was dissolved in THF (3 ml) and treated with succinimidyl tetramethyluroniumtetrafluoroborate (331 mg, 1.1 mmol) and N,N-diisopropylethylamine (188 μL, 1.1 mmol), and the mixture was stirred for 20 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate and washed with 0.1 M HCl (twice) and water. The organic phase was dried over MgSO4, filtered and evaporated in vacuo to give 350 mg (96%) of methyl succinimidyl hexadecandioate.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:36])[C@@H:20]([NH:28]C(=O)OC(C)(C)C)[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCO>[NH2:28][C@@H:20]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C@H:19]([OH:36])[CH2:18][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:38][CH:37]=1)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN(Cc1ccc(C#N)cc1)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOC(=O)N(Cc1ccc(C#N)cc1)C[C@@H](O)[C@@H](N)CC1CCCCC1
Temperature: 65 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl (2S,3R)-4-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (921 mg, 1.68 mmol) was dissolved in EtOH (10 mL) and treated with toluenesulfonic acid monohydrate (337 mg, 1.77 mmol, 1.05 equiv). The mixture was allowed to stir at 65° C. for 40 min. LC-MS analysis showed that the starting material had been consumed and converted to the desired product. The solvent was removed and the residue was dissolved in CH2Cl2 (20 mL). The solution was treated with 1.0 M aq NaOH (20 mL) and the biphasic mixture was stirred for 0.5 h. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated to afford (2R,3S)-3-amino-1-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)-4-cyclohexylbutan-2-ol.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C1C=CC=CC=1>[CH3:23][N:24]([CH3:28])[C:25]([N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:26]
Reactant: CN(C)CCNc1nc2ccccc2[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)CCN(C(=O)N(C)C)c1nc2ccccc2[nH]1

Procedure:
Following the procedure of Example 1C, using 9.4 g. (0.046 moles) of N,N-dimethyl-N'-(2-benzimidazolyl)-1,2-ethane diamine, 6.0 g. (0.06 moles) of triethylamine, 5.7 g. (0.053 moles) of N,N-dimethylcarbamoyl chloride and 150 ml. of benzene, there is obtained N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-benzimidazolyl)urea, which, after chromatographic separation on 375 g. of silica gel, and elution with a mixture of 500 ml. of chloroform, 100 ml. of isopropanol, 100 ml. of toluene and 10 ml. of triethylamine, affords 9.4 g. of oil. This is treated with hydrogen bromide and recrystallized from ethanol to give 8.2 g. of dihydrobromide salt, m.p. 193°-195° C.
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([C:11]1[N:15]2[C:16]([CH2:20]Cl)=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)([O:8]CC)=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:20][C:16]3[N:15]4[C:11](=[CH:12][N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:8])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCCN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 60 %

Procedure:
A solution prepared by dissolving 3.59 g (10.66 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine sulfate, 3.10 g (12.79 mM) of 3-(1-tert-butoxycarbonylpiperidin-4-yl)-1-propylamine, and 5.94 ml (42.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of chloroform. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=50:1) to provide 2.55 g (yield 62.1%) of the title compound as yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](=[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:11][OH:12])([CH3:9])[CH3:8].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:12][CH2:11][C:10](=[C:7]([CH3:9])[CH3:8])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=CCC(CO)=C(C)C
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC(=O)OCC(CC=C(C)C)=C(C)C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
In a nitrogen atmosphere, 64.0 g of butyryl chloride was added dropwise to a mixture of 94.1 g of 2-isopropylidene-5-methyl-4-hexenol (3) having a purity of 81.1% and an α,β-isomer purity of 98.1%, 50 g of pyridine and 500 ml of acetonitrile over 55 minutes which was stirred under cooling with ice. The reaction mixture was stirred for 2 hours under cooling with ice. To the reaction mixture was added an aqueous solution of saturated sodium bicarbonate, followed by extraction with diethyl ether. The diethyl ether solution was subjected to work-up including washing, drying and concentration to obtain 131.22 g of the crude product. The crude product was purified by distillation under reduced pressure to obtain, as the intended product, 23.54 g of a fraction having a purity of 92.8% and an α,β-isomer purity of 97.0% and 82.05 g of a fraction having a purity of 92.2% and an α,β-isomer purity of 98.3%. The yield of fractions including the other fractions was 95%.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=O)[CH:9]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[CH:9]=[C:8]([C:7]([F:20])([F:19])[F:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=c1cc(C(F)(F)F)c2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Cl)nc2ccccc12
Temperature: 90 °C
Yield: 29 %

Procedure:
DMF (cat.) was added to a solution of 4-trifluoromethyl-1H-quinolin-2-one 465 (160 mg, 0.75 mmol) in POCl3 (2 ml) and the mixture was heated at 90° C. for 1 h. After cooling, the mixture was concentrated in vacuo and the residue was poured into an ice cold solution of NaHCO3 solution. The aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (50 mg, 29%) which was used in the next step without further purification.