Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:27]([O:26][CH3:25])=[O:36])=[CH:30][CH:31]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C(=O)OCC(C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OCC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid 2,2-dimethylpropyl ester (Intermediate 48, 0.227 g, 0.70 mmol), 4-iodo phenyl acetic acid methyl ester (0.23 g, 0.83 mmol), triethyl amine (3 mL), copper(I)iodide (0.07 g, 0.39 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.21 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.198 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[Br:8][CH2:9][C:10]#[N:11]>>[Br-:8].[C:10]([CH2:9][N+:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=1)#[N:11]
Reactant: Cc1ncsc1C
Reactant: N#CCBr
Product: Cc1sc[n+](CC#N)c1C
Product: [Br-]
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 4,5-dimethylthiazole and bromoacetonitrile were heated with stirring at 95° C. for 1 hour. The product precipitated from the mixture within 30 minutes. After cooling to room temperature, the product a solution of 30% v/v of diethyl ether: CH3CN (10 mL) was added with stirring. The crude product was recovered by filtration, and recrystallized from a mixture of EtOH and CH3CN to yield 2.136 g of 3-(cyanomethyl)-4,5-dimethylthiazolium bromide as needles: mp 184-186° C. (dec.).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c3c2C)c1
Temperature: 100 °C
Yield: 34.6 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in water (1 mL) and 1,4-dioxane (2 mL) was added [3-(methyloxy)phenyl]boronic acid (52.8 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol), potassium carbonate (96 mg, 0.695 mmol) and the mixture heated to 100° C. for 15 min using a microwave reactor. The mixture was then filtered through celite, washing with ethyl acetate (30 mL) and DCM (20 mL). The organics were then combined, dried (phase separation cartridge) and concentrated. The residue was then purified by MDAP (basic conditions), to afford the title compound (36.8 mg). LCMS (A) m/z: 459 [M+1]+, Rt 1.32 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.N1C=CC=CC=1.O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>CN(C)C=O>[O:27]([C:25]([NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1)=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCNc1nc(N)ncc1C(=O)OCC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc(NC(=O)Oc2ccccc2)ncc1C(=O)OCC
Reaction time: 0.67 h

Procedure:
To a solution of ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 5.00 g) and pyridine (2.2 mL) in N,N-dimethylformamide (45 mL), phenyl chloroformate (3.1 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, pyridine (1.0 mL) and phenyl chloroformate (1.5 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was poured into water. The solid matter was taken by filtration, and dried under reduced pressure to obtain ethyl 2 -((phenoxycarbonyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E7, 2.89 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1n[nH]c2cc(Br)ccc12)N1CCOCC1
Temperature: 45 °C
Reaction time: 0.67 h

Procedure:
To a solution of 6-bromo-1H-indazole-3-carboxylic acid (500 mg, 2.07 mmol) in DMF (10 mL) was added CDI (403.62 mg, 2.49 mmol) and the reaction mixture stirred at 45° C. for 40 minutes. Morpholine (0.36 ml, 4.16 mmol) was then added and the reaction mixture stirred at RT. The reaction mixture was quenched by diluting with water. The product was extracted into EtOAc (×2) and the combined organic extracts were then washed with water and brine and dried (Na2SO4), filtered and concentrated in vacuo to give the crude (78% pure) title compound: 1H NMR (500 MHz, DMSO) delta 3.58-3.79 (6H, m), 3.96-4.13 (2H, m), 7.36 (1H, dd, J=8.59, 1.66 Hz), 7.86 (1H, d, J=1.10 Hz), 7.93 (1H, s), 13.66 (1H, br. s.); LC-MS: m/z=+311.70 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15]O)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C([N:19](CC)CC)C.[Cl-:24].[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O.O>[ClH:24].[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][NH2:19])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: [Cl-]
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(CN)cc2s1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.52 g, 10.7 mmol) and triethylamine (3.00 mL, 21.5 mmol) in anhydrous THF (80 mL) at 0° C. was added metahnesulfonyl chloride (1.24 mL, 16.0 mmol). The resulting mixture was allowed to stir at 0° C. for 30 min, diluted with EtOAc (400 mL), washed with saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was dissolved in anhydrous DMF (60 mL). After sodium azide (1.41 g, 21.6 mmol) was added, the mixture was heated at 50° C. for 30 min. After cooling to rt, the mixture was diluted with EtOAc (300 mL) and water (60 mL). The organic layer was further washed with water and brine, and then dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was dissolved in THF (60 mL) and water (6 mL). Triphenylphosphine (3.64 g, 13.9 mmol) was added and the mixture was allowed to stir at rt overnight and then concentrated. The residue was dissolved in ether (400 mL) and 4M HCl in dioxane (6 mL) was added dropwise. The solid formed was washed with ether (5×30 mL) and dried to give 6-aminomethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester, hydrochloride salt as a pale solid. 1H NMR (DMSO-d6, 200 MHz) δ 8.66 (brs, 2H), 8.24-8.10 (m, 2H), 8.06 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.4, 1.6 Hz, 1H), 4.34 (q, J=7.4 Hz, 2H), 4.13 (s, 2H), 1.32 (t, J=7.0 Hz, 3H). MS (EI): cal'd 236.1 (MH+), exp 236.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:24]2[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=2[S:22][CH2:21]1)[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:24]2[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=2[S:22][CH2:21]1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)CSc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
In a mixture of 40 ml of methanol and 25 ml of 1N aqueous sodium hydroxide solution is dissolved 0.6 g of tert-butyl 3(R)-[5-tert-butoxycarbonylamino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as obtaiend in Example 37, and 10 ml of water is further added to the solution, followed by stirring at room temperature for 2 hours. The methanol is evaporated off under reduced pressure, and the residual solution is made weakly acidified with phosphoric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.37 g of tert-butyl 3(R)-[5-tert-butoxycarbonylamino-1(S)-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless viscous material. This product is treated with ethyl acetate to yield a colorless crystalline powder, melting at 134°-135° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:29])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:10]=[C:9]([NH2:29])[C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(c1ccccc1)c1ncccc1Br
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Nc1nn2cccc(Br)c2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3-Bromo-pyridin-2-yl)-phenyl-acetonitrile (0.528 g, 1 eq) was dissolved in DCM (5 mL) and the solution cooled to 0° C. O-(Mesitylsulfonyl)hydroxylamine (0.540 g, 1 eq) was added portion-wise and the reaction was stirred at 0° C. for 2 h then stored at 4° C. for 16 h. An additional portion of 0-(mesitylsulfonyl)hydroxylamine (Intermediate 2, cf above) was added and the reaction mixture stirred at 0° C. for 2 h. The precipitate was collected by filtration and washed with pet ether 40-60 yielding the intermediate aminopyridine salt. The residue was re-dissolved in DCM/water and the aqueous was extracted with DCM (×3). The combined organics were dried and concentrated in vacuo to afford the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[N:6][CH:7]=1.[CH3:14][O:15]CC1COC(=O)O1.[C:23](=O)([O-])[O-].[K+].[K+].C1C2C(CCCC2)CCC1>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([CH3:23])[CH:11]([O:15][CH3:14])[O:10][C:9]2=[O:13])=[N:6][CH:7]=1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCC2CCCCC2C1
Product: COC1OC(=O)N(c2ccc(Br)cn2)C1C
Temperature: 160 °C
Yield: 308.1 %

Procedure:
A mixture of 9.3 g of ethyl 5-bromo-pyridin-2-yl-carbamate, 7.5 g of 4-methoxymethyl-1,3-dioxolan-2-one, 1.0 g of potassium carbonate and 10 ml of decahydronaphthalene was heated to 160° C. for 6 h. The mixture was cooled and treated with ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution. The organic phases were combined and dried with magnesium sulfate and then concentrated. Chromatography of the residue (20.2 g) with ethyl acetate/hexane mixtures (1:2-1:1) on silica gel yielded 6.4 g of (RS)-3-(5-bromo-pyridin-2-yl)-5-methoxy-methyl-oxazolidin-2-one which was recrystallized from diethyl ether. M.p.: 90°-92°.
Reaction SMILES: [FH:1].NC(N)=O.[O:6]1[C@H:8]2[CH2:9][C@H:10]3[C@:25]([CH3:27])([CH2:26][C@@H:7]12)[C@@H:24]1[C@H:13]([C@H:14]2[C@:21]([CH3:29])([CH2:22][C:23]1=[O:28])[C@@H:17]([C:18](=[O:20])[CH3:19])[CH2:16][CH2:15]2)[CH2:12][CH2:11]3>C(=O)(O)[O-].[Na+]>[F:1][C@H:7]1[CH2:26][C@@:25]2([CH3:27])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:24]2[C:23](=[O:28])[CH2:22][C@@:21]2([CH3:29])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[CH2:9][C@@H:8]1[OH:6]
Reactant: F
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](F)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrofluoric acid (50 ml.) was added slowly to urea (40 g.) to give a colourless liquid. To 11 ml. of the liquid was added 2α,3α-epoxy-5α-pregnane-11,20-dione (650 mg.), and the clear solution was stirred at room temperature overnight. It was poured into saturated sodium bicarbonate solution (250 ml), and the white precipitate was extracted into chloroform. The organic solution was washed with water, dried over sodium sulphate and evaporated to give a white foam (565 mg.). Recrystallisation from acetonepetrol gave the title compound m.p. 174°-178°, [α]D α+114°.
Reaction SMILES: Br[C:2]1C=CC(C(OC)=O)=C(C)C=1.[F:13][C:14]1[C:22]([I:23])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:24])[CH:15]=1>>[F:13][C:14]1[C:22]([I:23])=[CH:21][C:17]([C:18]([O:20][CH3:2])=[O:19])=[C:16]([CH3:24])[CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: Cc1cc(F)c(I)cc1C(=O)O
Product: COC(=O)c1cc(I)c(F)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 6.1, except 4-fluoro-5-iodo-2-methylbenzoic acid (compound 101.1) was used in place of 4-bromo-2-methylbenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)Nc2ccc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 191A (91.6 mg, 0.4 mmol) in DMF (4 ml) was added 2-aminoquinoline (64 mg, 0.44 mmol), ED AC (93 mg, 0.48 mmol), HOBT (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: CCCC[CH:5]([O:15][C:16]1(C(CC(O)=O)=O)[S:20][CH:19]=[CH:18][CH2:17]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](=[O:29])=[O:28].[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([O:28][C:27](=[O:29])[CH2:6][C:5]([C:19]1[S:20][C:16]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:17][CH:18]=1)=[O:15])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCCCCC(CCCC)OC1(C(=O)CC(=O)O)CC=CS1
Reactant: OCc1ccccc1
Reactant: O=C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)OCc2ccccc2)s1
Temperature: 25 °C

Procedure:
A mixture of 10.4 g (0.027 mole) of 2-(5-tetradecyloxy)thenoylacetic acid, 4.4 g (0.027 mole) of N,N'-carbonyldiimidazole, and anhydrous tetrahydrofuran is stirred until the evolution of carbon dioxide gas stops. The mixture is cooled on an ice bath, in 3.0 g (0.027 mole) of benzyl alcohol is added. The reaction is allowed to warm to room temperature and evaporated to dryness. The residue is extracted with ether-H2O. The ether layer is washed with 10% aqueous HCl, then water, then saturated sodium chloride, dried with sodium sulfate and evaporated to dryness to give 5-tetradecyloxythen-2-oylacetic acid benzyl ester.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]2=[O:3])=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2ccccc21
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 367 mg) in N,N-dimethylformamide (15 ml) was added a solution of ethyl 2-(1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)-acetate (2.0 g) in N,N-dimethylformamide (35 ml) with stirring at room temperature under nitrogem atmosphere, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-chlorobenzyl chloride (1.48 g) with stirring at room temperature and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated in vacuo to give a residue, which was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried. Evaporation of the solvent gave a residue, which was washed with n-hexane to afford ethyl 2-[3-(4-chlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (2.55 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[C:37]([NH:44][CH2:45][CH2:46][CH2:47][NH2:48])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].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>C(Cl)Cl>[C:40]([O:39][C:37](=[O:38])[NH:44][CH2:45][CH2:46][CH2:47][NH:48][C:34]([C@H:16]1[C@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C@:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[C@H:18]([CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[NH:17]1)=[O:35])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2)[C@@]1(C#N)c1ccc(Cl)cc1
Yield: 87 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid prepared in Example 25a (1 g, 1.8 mmol) was reacted with N-Boc-1,3-diaminopropane (Aldrich) (0.7 g, 4 mmol), HATU (1.4 g, 3.7 mmol) and iPr2NEt (2.8 g, 21 mmol) in CH2Cl2 (100 mL) at room temperature for 60 h to give rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester as a white solid (0.92 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[O:26][C:27]([CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[NH:40][CH:41]2[CH2:46][CH2:45][N:44]([C@@H:47]3[CH2:52][CH2:51][NH:50][C@@H:49]([CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:48]3)[CH2:43][CH2:42]2)=[CH:28][N:29]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([N:50]1[CH2:51][CH2:52][C@@H:47]([N:44]2[CH2:43][CH2:42][CH:41]([NH:40][C:32]3[N:31]([CH2:30][C:27]4[O:26][C:25]([CH3:24])=[N:29][CH:28]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:46][CH2:45]2)[CH2:48][C@@H:49]1[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:13]
Reactant: Cc1ncc(Cn2c(NC3CCN([C@@H]4CCN[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc(Cn2c(NC3CCN([C@@H]4CCN(C(=O)c5oc6ccccc6c5C)[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Yield: 45.2 %

Procedure:
3-methyl-2-benzofurancarboxylic acid (0.100 g) and 1-hydroxy-1H-benzotriazole (0.070 g) were added to (±)-trans-1-[(2-methyl-5-oxazolyl)methyl]-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-1H-benzimidazol-2-amine (0.100 g) in CH2Cl2 (5 ml). The mixture was stirred under N2 atmosphere. A solution of triethylamine (0.5 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1:1) (0.080 g) in CH2Cl2 (10 ml) was added dropwise and the reaction mixture was stirred overnight at RT, under N2. Then, the compound was isolated and purified by column chromatography (eluent gradient: (0.5% ammoniumacetate in H2O)/CH3OH/CH3CN 70/15/15 upgrading over 0/50/50 to 0/0/100). The desired fractions were collected and the solvent was evaporated, yielding 0.060 g of (±)-trans-1-[(3-methyl-2-benzofuranyl)-carbonyl]-4-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-(phenylmethyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>O1CCCC1>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:18])=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 150 ml of absolute tetrahydrofuran by heating to 60° C., with stirring. The solution is allowed to cool to room temperature, 5.0 g (24.8 millimoles) of p-nitrophenyl chloroformate are added and the mixture is stirred first for 20 hours at room temperature and then for 5 hours under reflux. It is then concentrated to about 70 ml, 100 ml of water are added and the product is filtered off and recrystallized from dimethylformamide/water at room temperature, giving 6.5 g (72% of theory) of 4,5-dihydro-5-methyl-6-[p-(p-nitrophenoxycarbonylamino)-phenyl]-3(2H)-pyridazinone as yellow crystals, of melting point 177°-178° C.