Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[BH4-].[Na+]>CO>[Cl:3][C:4]1[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][CH2:1][NH2:2]
Reactant: CN
Reactant: CC(C)Oc1c(Cl)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1c(Cl)cccc1CCN
Reaction time: 72 h
Yield: 93 %

Procedure:
Methylamine (10.3 mL of a 2.0 M solution in MeOH, 20.6 mmol) was added to 3-chloro-2-isopropoxybenzaldehyde (0.500 g, 2.52 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The resulting light yellow oil was dissolved in EtOH (10.3 mL) and treated with NaBH4 (0.095 g, 2.52 mmol). After stirring for 18 h, the reaction mixture was concentrated under reduced pressure, dissolved in 1 N NaOH (20 mL) and extracted with Et2O (3×50 mL). The combined organics were washed with brine (2×75 mL), dried (Na2SO4) and concentrated to give the title compound (0.50 g, 93%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.31 (m, 2H), 7.08 (t, J=7.8 Hz, 1H), 4.42 (q, J=6.1 Hz, 1H), 3.66 (s, 2H), 2.25 (s, 3H), 2.02 (br s, 1H), 1.25 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[F:13][C:14]1[CH:15]=[C:16]([NH2:27])[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]([N:27]=[C:1]=[S:2])[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N=C=S)cc2F)CC1
Reaction time: 8 h

Procedure:
Thiocarbonyl diimidazole (3.00 g, 3.53 mmol) (Aldrich) was dissolved in N,N-dimethylformamide (10 mL) and the solution was cooled to −10° C. (ice/acetone bath). A solution of 3-fluoro-4-(4-methyl-1-piperazinyl) benzenamine (2.26 g, 10.8 mmol) (from Step B above) in N,N-dimethylformamide (30 mL) was added over a period of 30 minutes, then the cooling bath was removed and the solution was stirred overnight. Ice-water was then added (100 mL) and the mixture was extracted with ether (3×200 mL). The combined ether layers were dried (MgSO4), filtered, and evaporated to give 1-(2-fluoro-4-isothio-cyanatophenyl)-4-methylpiperazine as a yellow oil that solidified on standing (3.88 g, 92%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (0.903 g) was added portionwise to a stirred solution of 2-(4-fluorophenyl)ethanol (0.7 g) and imidazole (0.408 g) in DMF (20 mL) at 20° C. The reaction mixture was stirred for 3 hours at room temperature and then partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.99 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(I)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1c(Cl)cc(I)cc1Cl
Temperature: 130 °C
Yield: 87.9 %

Procedure:
Methyl 2,6-dichloro-4-iodobenzoate (46 g, 0.14 mol) was dissolved in pyridine (1380 mL) and water (230 mL). Lithium iodide (37.2 g, 0.28 mol) was added in one portion. The resulting mixture was heated at 130° C. for 30 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in 2N HCl (500 mL) and extracted with ethyl acetate (3×1 L). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in N-methyl morpholine (5 mL) and concentrated again. The residue was diluted with 2N HCl (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give 2,6-dichloro-4-iodobenzoic acid (39 g, yield: 88%). 1H NMR (DMSO-d6, 400 MHz) δ 14.26 (brs, 1H), 7.99 (s, 2H).
Reaction SMILES: C([NH:3][C:4](CC(C)=C)(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.[CH:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([CH2:31][CH:32]=[CH2:33])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[O:20]>C(Cl)Cl.CO>[NH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:33][CH:32]=[CH:31][CH:26]([NH:25][C:23](=[O:24])[CH2:22][NH:21][CH:19]=[O:20])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C=C(C)CC(NC=O)(C(=O)OCC)C(=O)OCC
Reactant: C=CCC(NC(=O)CNC=O)C(=O)OC
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(N)CC=CC(NC(=O)CNC=O)C(=O)OC

Procedure:
Using the procedure of preparation B of Example 1, diethyl (formylamino)-(2-methyl-2-propenyl)-propanedioate in Step 2 was replaced by methyl 2-[(N-formylglycyl)-amino]-2-(2-propenyl)ethanoate to obtain the expected product with an Rf=0.2 in a methylene chloride/methanol (9:1) mixture.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:18][CH2:19][CH2:20]Br>C(O)C.Cl>[NH:5]1[CH2:20][CH2:19][CH2:18][C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: BrCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCCN1
Temperature: 25 °C

Procedure:
To a solution of sodium ethoxide (5.14 g) in absolute ethanol (75 mL) at 0° C. under a nitrogen atmosphere, a solution of diethyl aminomalonate (hydrochloride salt, 8 g) in absolute ethanol (75 mL) was slowly added. A yellow suspension was obtained at the end of the addition. 1,3-dibromo propane (7.7 mL) was then added and the resulting mixture was stirred at reflux temperature for 5 hours. The mixture was allowed to cool down to rt, then ethanol was removed in vacuo to give a yellow solid. This was dissolved in HCl (1M solution, 20 mL) and then washed with ethyl ether (2×50 mL). Phases were separated and the aqueous phase was brought to pH=9 by adding NaOH (1M solution). It was then extracted with ethyl ether (3×50 mL) and washed with brine (20 mL). The organic phase was dried and concentrated in vacuo to give the desired compound (2.35 g) as yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[C:20](=[O:21])[CH2:19][CH2:18][C:17]3=[O:22])[CH:11]=2)[C:6]2[N:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1.C([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)(=O)C>C(#N)C>[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[C:20](=[O:21])[CH2:19][CH2:18][C:17]3=[O:22])[CH:11]=2)[C:6]2[N:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1
Reactant: O=C1CCC(=O)N1c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Reactant: CC(=O)n1ccnc1
Solvent: CC#N
Product: O=C1CCC(=O)N1c1cccc(-n2c(=O)c(Cc3ncc[nH]3)nc3cccnc32)c1
Yield: 25.8 %

Procedure:
To a solution of 2-(bromomethyl)-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (420 mg) in acetonitrile (4 ml) was added 1-acetylimidazole (179 mg). The solution was refluxed for an hour. The mixture was evaporated. The residue was dissolved in water, and to the solution was added sodium carbonate. The mixture was extracted by ethyl acetate. The organic layer was evaporated. The residue was purified by column chromatography to obtain 2-(1-imidazolylmethyl)-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (105 mg) as yellow powder.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)[N:6]=1.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[ClH:32]>O>[Cl:32][C:2]1[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)[N:6]=1
Reactant: COC(=O)c1sc(N)nc1-c1nccc(N2CCCCC2)n1
Reactant: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(Cl)nc1-c1nccc(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of methyl 2-amino-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 62, 0.070 g, 0.219 mmol) in concentrated HCl (1 mL), sodium nitrite (0.045 g, 0.658 mmol) in water (1 mL) was added drop wise at 0° C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 5-10° C. and basified with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layer was washed with brine solution, dried and concentrated under reduced pressure to obtain methyl 2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate 0.040 g (54%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]3[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:23][C:22]3=[O:38])[CH3:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[NH2:12]>O.C(O)(=O)C>[N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]([N:21]4[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[O:23][C:22]4=[O:38])[CH3:20])=[CH:17][CH:18]=3)=[CH:7][C:6]=2[NH:5][N:1]=1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc3nn[nH]c3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A solution of NaNO2 (0.16 g) in water (2 mL) was added dropwise to an ice-cold solution of 3-[(S)-1-(3′,4′-diamino-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.43 g) in acetic acid (10 mL). The resulting mixture was stirred with cooling for 2 h and at room temperature for another 1 h. Then, water (100 mL) was added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaHCO3 solution, water, and brine and dried (Na2SO4). The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/MeOH 98:2→80:20) to afford the title compound as a foam-like solid.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([O:7][CH3:8])[CH3:6])[CH2:3][OH:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([C@H:5]([O:7][CH3:8])[CH3:6])[CH2:3][OH:4])[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CO[C@H](C)[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H](C)[C@@H](CO)Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.3 %

Procedure:
To a round bottom flask containing (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol) and a stir bar was added acetonitrile (100 mL) followed by the addition of 2,4-dichloropyrimidine (1.34 g, 9.0 mmol) and DIEA (4.7 mL, 27.0 mmol). Resulting reaction mixture allowed to stir 18 hr at room temperature. Volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol, 40% yield) which contains some unreacted 2,4-dichloropyrimidine. LCMS m/z 232.0 (M+H)+, Rt 0.38 min.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>CC#N>[Br:43][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCO)cc2O1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCBr)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a 100 ml CH3CN solution of ethyl 7-(3-hydroxypropoxy)-2-ethylchromane-2-carboxylate (2.88 g, 9.4 mmol) was added triphenylphosphine (3.21 g, 12.2 mmol) and carbon tetrabromide (4.05 g, 12.2 mmol) upon cooling in an ice-water bath. After stirring at rt for 1 hr, the solvent was removed under reduced pressure. The residue was suspended in dichloromethane and was charged onto a silica gel column. Elution with 10% AcOEt/hexanes gave the title compound 3.36 g (96%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]>ClC(Cl)C>[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH3:23])=[C:20]([CH3:22])[C:21]=1[C:5](=[O:7])[CH3:6])=[O:16])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c(C)c(C)c1C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of aluminum chloride (50.19 g, 0.376 mol) in dry dichloroethane (580 mL) at 25° C. was added slowly acetic anhydride (17.75 mL, 0.188 mol). The resulting mixture was stirred at room temp. for 10 minutes, then a solution of pyrrole 3b (10.49 g, 0.0627 mol) in dichloroethane (30 mL) was added and the reaction mixture was stirred at room temp. for 2 hours. After an additional 3 hours at 80° C., the mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo to an orange residue. Short plug filtration over silica gel (30% ethyl acetate/70% hexanes) gave 7.5 g (60%) of ethyl-3-acetyl-4,5-dimethyl-2-pyrrole carboxylate 4b. 1H NMR (CDCl3) δ 9.0 (bs, 1H), 4.3 (q, 2H), 2.7 (s, 3H), 2.1 (s, 3H), 1.9 (s, 3H), 1.3 (t, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=O)[O:9][C:8]([CH3:12])=[N:7]1.[NH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[N:7]=[C:8]([CH3:12])[NH:17][C:10]1=[O:9]
Reactant: N
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1C=C1N=C(C)NC1=O
Temperature: 80 °C

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (2.4 g) was dissolved in ethanol (50 ml) and aqueous ammonia (20 ml) and potassium carbonate (3 g) were added. The mixture was heated at 80° C. for 10 hr. After cooling, the solvent was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated yellow crystals were collected by filtration to give the title compound (2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([OH:14])=O)[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([N:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]4[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:21]([O:20][CH3:19])[CH:22]=4)[CH2:27][CH2:28]3)=[O:14])[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Reactant: COc1ccc2c(c1OC)CCCC(C(=O)O)=C2
Product: COc1cc(C(=O)N2CCN(C(=O)C3=Cc4ccc(OC)c(OC)c4CCC3)CC2)cc(OC)c1OC

Procedure:
In a manner as that described in Example 62, 3,4-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid and 1-(3,4,5-trimethoxy-benzoyl)piperazine are subjected to amidation to give 1-(3,4-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine. This product is recrystallized from ethyl acetate to give colorless prisms, m.p. 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1>O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: Clc1ccccc1CC1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(Cc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
A mixture of 4.8 grams (0.018 mole) of 8-(2-chlorophenylmethyl)-1,4-dioxaspiro[4.5]decane in 25 mL of water and 100 mL of acetic acid was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was carefully partitioned between diethyl ether and an aqueous solution saturated with sodium bicarbonate. The combined ether extracts were then washed with an aqueous solution saturated with sodium chloride. The organic layer was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.1 grams of 4-(2-chlorophenylmethyl)cyclohexanone, mp 48° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4])(=[O:31])=[O:30]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 1-(1-hydroxypropan-2-yl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 7) (0.110 g, 0.390 mmol) and Et3N (0.068 mL, 0.487 mmol) in CH2Cl2 (4 mL) was added methanesulfonyl chloride (0.038 mL, 0.487 mmol) dropwise. After stirring at rt for 2 h, the reaction mixture was concentrated to dryness. The residue was partitioned between EtOAc (30 mL) and 0.2N HCl (15 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 25-60% EtOAc-hexane gradient to give 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propyl methanesulfonate (0.145 g, 97% yield) as a colorless oil: MS (ESI): m/z 361 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=O)[CH3:12].C([O-])(O)=O.[Na+]>C(O)C>[CH3:12][C:11]1[N:8]=[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][N:6]2[CH:10]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(N)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2nc(C)ccc2n1
Temperature: 70 °C
Yield: 58.5 %

Procedure:
A 3 neck 1 L round bottom flask is charged with 6-methyl-pyridazin-3-ylamine (20 g, 0.18 moles), ethanol 2B (200 mL), and chloroacetone (23.7 g, 20.4 mL, 0.256 moles, 1.4 equiv). The reaction mixture is heated at 70° C. overnight. NaHCO3 (23.2 g, 0.276 moles, 1.5 equiv) is added portion wise. After most of bubbling subsides, the reaction is heated at 100° C. overnight. The solvents are removed in vacuo and the residue is taken up in dichloromethane and filtered through a filter paper. The solvent is again removed in vacuo. The residue is purified using silica gel chromatography with a hexanes:ethyl acetate gradient to obtain the title compound (15.5 g, 57%). 1H-NMR (DMSO-d6), δ 2.34 (s, 3H), 2.47 (s, 3H), 7.03, (d, J=10 Hz, 1H), 7.85 (d, J=10 Hz, 1H), 7.91 (s, 1H) ppm. MS (APCI): 148 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](=O)[CH3:14]>>[CH2:13]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:14]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC=O
Product: CCN[C@H](Cc1ccccc1)C(=O)O

Procedure:
According to a further embodiment of the present invention D-phenylalanine is submitted to hydrogenolysis in the presence of acetaldehyde, the resulting N-ethyl-D-phenylalanine is provided with a benzyloxycarbonyl protecting group, its 2,4,5-trichlorophenyl ester is formed, then it is condensed with L-proline. The N-benzyloxycarbonyl-N-ethyl-D-phenylalanyl-L-proline obtained is coupled by the mixed anhydride method to Nω -benzyloxycarbonyl-L-arginine lactam. The protected tripeptide lactam obtained is reduced by lithium aluminum hydride to N-benzyloxycarbonyl-N-ethyl-D-phenylalanyl-L-prolyl-Nω-benzyloxycarbonyl-L-arginine-aldehyde, the protecting groups are removed by hydrogenolysis in the presence of sulfuric acid and the resulting N-ethyl-D-phenylalanyl-L-prolyl-L-arginine-aldehyde sulfate is isolated.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(C)C=CC=CC=1>[F:22][C:23]([F:34])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc(I)cn2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cn2)CC1
Yield: 34.4 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.4.). Starting with 0.250 g (0.61 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-iodo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 5.5., 0.51 g (2.44 moles) of 4-(trifluoromethoxy)-phenylboronic acid, 0.61 g (˜8 mol %) of palladium catalyst on a solid support, prepared in step 2.1. of Example 2, and 2.9 ml (7.32 mmol) of aqueous sodium carbonate solution (2.5M) suspended in 12 ml of toluene and 3 ml of ethanol, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.092 g of product is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH2:17][CH3:18])=O>N1C=CC=CC=1>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:17][CH3:18]
Reactant: CCCOC(=O)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: c1ccncc1
Product: CCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with propyl chloroformate (3.0 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h, after which time the pyridine was removed in vacuo. The residue was washed with water (25 ml) and dried in vacuo to afford the desired product as an off-white solid (0.96 g, 66%); δH (400 MHz, DMSO-D6) 1.03 (3H, t, J 7, CH2CH3), 1.82 (2H, tq, J, J′7, CH2CH3), 2.46 (3H, s, CH3), 4.42 (2H, t, J 7, OCH2), 7.40 (1H, d, J 8, Ph), 7.71 (1H, d, J 8, Ph), 7.89 (1H, s, Ph); m/z (ES+) 219 (MH+).