Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH2:19][C:20]([O:22]C)=O)[CH3:2].[NH4+:24].[OH-]>C1COCC1>[NH2:24][C:20]([CH2:19][C:4]1[C:5](=[O:18])[N:6]([CH2:15][C:16]#[CH:17])[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C:3]=1[CH2:1][CH3:2])=[O:22]
Reactant: [NH4+]
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(CC(=O)OC)c1=O
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(CC)c(CC(N)=O)c1=O

Procedure:
To a stirred solution of 1.75 g (5.7 mmol) of 6-ethyl-5-methoxycarbonylmethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 105) in 100 mL of THF was added 200 mL of concentrated aqueous NH4OH. The mixture was stirred for 2 weeks and the bulk of the THF was removed on the rotovap. The mixture was shaken with 100 mL of ethyl acetate and filtered. The solid collected was dried in a vacuum oven at 50° C. to afford 0.57 g of 5-aminocarbonylmethyl-6-ethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 275), m.p. 196°-198° C. 1H-NMR (d6 -DMSO) 1.15(3H,t), 2.5(2H,q), 3.2(1H,t), 3.4(2H,s), 4.55(2H,d), 6.9(1H,br s), 7.35(1H,br s), 7.55(3H,m), 7.7(2H,m). The aqueous layer of the filtrate was extracted with two additional 100 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4 and rotovaped to afford a further 0.54 g of Compound 275.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O-].[Na+].Cl.Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][N:11]=1>COCCO.COC(O)C.C1COCC1>[CH2:20]([C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]=[C:10]2[CH2:9][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCc1ccc2c(c1)C(CCl)=NCC2
Reactant: COCC[O-]
Agent: COC(C)O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCO
Product: CCc1ccc2c(c1)C(CCCOC)=NCC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Under cooling in an ice bath, a mixture of sodium hydride (suspension of 8 g of sodium hydride in mineral oil (60%) washed with hexane) in THF (10 mL) was added to methoxyethanol (100 mL) under stirring over 20 minutes to produce sodium 2-methoxyethoxide, followed by further stirring for 2 hours. A solution of sodium 2-methoxyethoxide in 2-methoxyethanol (55 mL) was added with stirring to a solution of 1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline hydrochloride (8.5 g) in methoxyethanol (50 mL) under cooling in an ice bath, for 5 minutes. The reaction mixture was heated at 60° C., followed by stirring for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and diluted with THF (150 mL), followed by filtration. The filtrate was concentrated under reduced pressure. To the resulting residue was added a saturated aqueous ammonium chloride solution and the residue was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain 7-ethyl-1-[(2-methoxyethyl)methyl]-3,4-dihydroisoquinoline (2.13 g).
Reaction SMILES: [CH:1]1([C:6]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:10][CH2:9][CH:8]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: O=CCC(C(=O)C1CCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCC2)c2ccccc2)CC1
Yield: 66.9 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde (1.36 mmol) and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with sodium triacetoxyboranehydride (1.77 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine (370 mg) in 67% yield. The di-hydrochloric acid salt was prepared as described above. m.p.=210-212° C.; MS (m/e): 406 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:14][C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.O[CH:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([N:14]([C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:22])[Cl:21])=[O:16])[C@H:24]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:26])[CH2:37][CH:38]([CH3:40])[CH3:39])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH:6]=1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C(=O)OC(C)(C)C)cc2Br)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 4-bromo-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1H-pyrazole-1-carboxylate (2.32 g, 5.3 mmol), 4-methoxybenzyl 2-hydroxy-4-methylpentanoate (2.02 g, 8.0 mmol, prepared as described in Example 16) and triphenyl phosphine (2.1 g, 8.0 mmol) in dry DMF (50 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (1.6 mL, 8.0 mmol) dropwise and the reaction was stirred overnight. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford 4-methoxybenzyl N-[4-bromo-1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]—N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([Si:27]([CH3:29])([CH3:28])[O:14][C:12]1[CH:13]=[C:8]([C:7]([CH3:17])([CH3:16])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=[CH:10][C:11]=1[F:15])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9 mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was added imidazole (1.34 g, 19.7 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.50 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.92 (s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H), 6.80-6.83 (m, 1H), 6.87-6.92 (m, 1H). MS (EI): 370.2 [M]+.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH:34]([C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2)=O>O1CCCC1.CCCCCC>[NH:40]1[C:41]2[C:37](=[C:36]([CH:34]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:28][CH:27]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:39]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(C=Cc2cccc3[nH]ccc23)cc1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
31 g of p-hydroxybenzyltriphenylphosphonium bromide ware suspended in 350 ml of tetrahydrofuran under an inert atmosphere, and over one hour 86 ml of a 1.6 M solution of butyllithium in hexane were added thereto. After stirring for 30 minutes, a solution of 5 g of 4-formyl-indole in 100 ml of tetrahydrofuran was added over 30 minutes, and the mixture was stirred for 24 hours. After dilution with 500 ml of water, the mixture was extracted with ethyl acetate. The fractions with an Rf=0.15 were isolated by chromatography on silica (eluent:methylene chloride) were triturated with petroleum ether (b.p. 60°-80° C.), filtered and dried under reduced pressure to obtain 7 g of 4-[(1H-indol-4-yl)-ethenyl]-phenol melting at ≃145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.CO.[C:26](Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:26])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:3]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Yield: 75 %

Procedure:
2-(4-Chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (54; 500 mg, 1.46 mmol) was suspended in CH2Cl2 (15 mL). Methanol (2 mL) was added to solubilize. To the reaction solution was added dropwise oxalyl chloride (130 μL, 1.46 mmol). After having stirred the reaction at room temperature overnight, the reaction was concentrated. The residue was taken up in EtOAc and washed successively with saturated NaHCO3 and then brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (EtOAc/pentane) afforded methyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate as an orange solid (structure not shown) (390 mg, yield: 75%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][NH:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:27][CH2:26]1>C(#N)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][N:14]([C:35]1[CH:36]=[C:37]3[C:32]([C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29][N:28]3[CH:25]3[CH2:27][CH2:26]3)=[CH:33][C:34]=1[F:39])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCNCC12CNCC1C2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNCC12CC1CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 30.6 %

Procedure:
A mixture of 1-[N-(tert-butoxycarbonyl)ethylamino-methyl]-3-azabicyclo[3.1.0]hexane (45.3 mg, 0.18 mmol) and triethylamine (50 μl, 0.36 mmol) in acetonitrile (5 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50.0 mg, 0.18 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid (26.8 mg, 0.055 mmol, 31% yield). 1H NMR (CDCl3): 8.67 (s, 1H), 7.90 (d, J=15 Hz, 1H), 6.89 (d, J=7 Hz, 1H), 3.87 (bs, 2H), 3.5 (m, 5H), 3.3 (bs, 2H), 1.6 (m, 1H), 1.49 (s, 9H), 1.33 (m, 2H), 1.14 (m, 5H), 0.83 (m, 1H), 0.68 (m, 1 H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:2]([NH:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:3]([NH:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:7]=2)=[O:4])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
103.1.B (905 mg, 2.65 mmole), 5 ml of DMF and 0.69 ml of DIEA. The reaction mixture was cooled to 0° C., and then ethyl bromoacetate (0.49 g, 2.92 mmole) was added to the mixture. The reaction was stirred at room temperature overnight. After then, the solution was poured into saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 103.1.C (552 mg, 49% yield) as orange syrup.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:13]([CH3:15])=[O:14].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O.Cl>O>[CH3:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[C:3]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:4]1
Reactant: COS(=O)(=O)OC
Reactant: CS(=O)Cc1cnc2ccccc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(CS(C)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxy-3-methylsulphinylmethylquinoline (4.4 g.) and potassium hydroxide (1.68 g.) in water (20 ml.) at 0°-5° was added dimethyl sulphate (2.52 g.). The solution was stirred at room temperature for 30 minutes, then neutralised with 5 N aqueous hydrochloric acid. The resultant sticky solid was triturated with industrial methylated spirit to give a solid product. The product was purified by high pressure liquid chromatography over silica gel, eluting with isopropanol: dichloromethane 95:5 at a flow rate of 200 ml. per minute. This procedure gave the novel 1-methyl-3-methylsulphinylmethyl-4-quinolone, m.p. 94°-96°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][CH:8]=1.O1CCC[CH2:32]1.CI>>[CH3:32][N:6]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][CH:8]=1)[C:5](=[O:30])[O:4][CH3:3]
Reactant: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)N(C)c1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (1.6 mg, 0.000041 mol) was added to a solution of methyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate (8.0 mg, 0.000021 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) at rt. After stirring for 5 min., methyl iodide (2.6 μL, 0.000041 mol) was added and the reaction mixture was stirred for 1 h at rt. The crude product was purified by prep-HPLC. LC-MS: 402.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:7]1.[C:41](OC(=O)C)(=[O:43])[CH3:42].CO>N1C=CC=CC=1>[C:41]([NH:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:7]1)(=[O:43])[CH3:42]
Reactant: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(3-amino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (50.5 mg)in pyridine (1 mL) was added acetic anhydride (1 mL). The reaction mixture was stirred at room temperature overnight and methanol was added. The mixture was evaporated, and 1 N NaOH solution was added. The mixture was extracted with ethyl acetate and the organic layer was concentrated. Preparative TLC gave (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[CH:27][C:28]=1[Br:36]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (intermediate i-13a, 214 mg, 0.559 mmol) in DMF (2 mL) cooled to 0° C. via ice/water bath was added NBS (100 mg, 0.559 mmol) and the resulting solution stirred for 1.5 h allowing to warm to rt. The mixture was evaporated under vacuum and the residue purified via Biotage Horizon MPLC using a gradient of 0-40% ethyl acetate in hexane to afford the product (232 mg, 90%) as a white foam. LC-MS: m/z (ES) 483 (MNa)+and 485 (MNa+2)+.
Reaction SMILES: [C:1]([N:4]=[C:5](OCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13])(=O)[CH3:2].Cl.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C:5]1[N:4]=[C:1]([CH3:2])[N:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:29])[F:28])[N:27]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: CCOC(=NC(C)=O)c1ccc(F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(F)cc2Cl)nn1-c1ccccc1C(F)(F)F

Procedure:
A mixture of 6.1 g (22 mmol) of ethyl N-acetyl-2-chloro-4-fluorobenzimidate and 6.7 g (25 mmol) of o-trifluoromethylphenylhydrazine hydrochloride in 100 ml of toluene is treated with 3.9 ml (28 mmol) of triethylamine and the whole is heated at reflux temperature for 18 hours. Thereafter, the reaction mixture is washed once with water and extracted twice with 50 ml of concentrated hydrochloric acid. The acidic aqueous phases are neutralized with ice-cold sodium hydroxide solution and extracted twice with diethyl ether, and the combined extracts are dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is subjected to a bulb-tube distillation, the fractions with b.p. 200° C./0.01 mmHg (9.33 Pa) being collected and finally crystallized from diisopropyl ether/n-hexane. In this manner there is obtained 3-(2-chloro-4-fluorophenyl)-5-methyl-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, m.p. 116° C.; 1H--NMR (CDCl3, 60 MHz): 2.37 (s,CH3); mass spectrum: 335 (48), 314(43), 159(100).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]1[C:30]2[C:22](=[CH:23][C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]=3[CH:29]=2)[CH:21]=[C:20]([CH3:32])[O+]=1)[CH2:7][CH3:8].C(C1C2C=CC=CC=2SC=1C=O)CC.O.[NH2:48][NH2:49]>CC(O)C>[CH3:32][C:20]1[CH2:21][C:22]2[CH:23]=[C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]3=[CH:29][C:30]=2[C:18]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH2:6][CH2:7][CH3:8])=[N:49][N:48]=1
Reactant: NN
Reactant: CCCc1c(-c2[o+]c(C)cc3cc4[nH]c(=O)oc4cc23)sc2ccccc12
Agent: CCCc1c(C=O)sc2ccccc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: CCCc1c(C2=NN=C(C)Cc3cc4[nH]c(=O)oc4cc32)sc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-(3-propyl-1-benzothien-2-yl)-7-methyl-2-oxo-1H,2H-isochromeno[6,7-d][1,3]oxazol-6-ium perchlorate (51 mmol) (obtained according to Steps A and B described in Example 1 using 3-propyl-1-benzothiophene-2-carbaldehyde instead of 2-naphthaldehyde) in 2-propanol (468 mL) there is added hydrazine hydrate (6.68 mL; 133 mmol), with vigorous stirring, at ambient temperature. The reaction mixture is stirred for 20 hours at ambient temperature. The crystals obtained are then filtered off and then stirred in warm water (1900 mL) for 30 minutes. After filtration and drying, the solid is purified by chromatography over a silica gel column (eluant: dichloromethane/ethyl acetate) to yield the title product.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[C:22]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:21]=1)[CH3:18]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCCC2)c1
Temperature: 150 °C
Yield: 46.5 %

Procedure:
A microwave flask was charged with 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (48 mg, 0.17 mmol), 1-[3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (54 mg, 0.17 mmol), and K2CO3 (59 mg, 0.43 mmol). Dioxane (2.1 ml) and water (0.5 ml) were added, and the solution was vacuum degassed under argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (14 mg, 0.02 mmol) was added, and the reaction mixture was heated (150° C.) in a microwave reactor for 45 minutes. The reaction mixture was filtered through a plug of celite using ethyl acetate. The filtrate was transferred to a separatory funnel and shaken with water (20 ml). The organic phase was collected and the aqueous phase back extracted with ethyl acetate (2×15 ml). The organic phases were combined, dried (MgSO4), filtered and stripped to provide a viscous semi-solid. This material was purified by preparative TLC, eluting with 4.8% methanol in methylene chloride to afford 31 mg of 1-[2-(3-ethoxy-5-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow powder. MP 236-237° C., M+H=393.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=[C:5]([O:13][CH3:14])[CH:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]2)[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=1
Reactant: COc1cc(CBr)c2c(c1)C(=O)CO2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
A solution of 7-(bromomethyl)-5-methoxybenzofuran-3(2H)-one (0.040 g, 0.16 mmol) in methylene chloride (2.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.032 g, 0.17 mmol), and triethylamine (0.021 g, 0.20 mmol), and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl 4-[(5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.008 g, 14%).