Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=N)NC(=N)N
Yield: 83.3 %

Procedure:
10.00 g of metformin hydrochloride and 2.40 g of sodium hydroxide were stirred in 100 ml of ethyl alcohol at 70° C., and the produced inorganic salt was filtered. Then, ethyl acetate was added thereto, thus preparing metformin free-base. The produced crystal was filtered and dried in hot air, thus obtaining 6.50 g (yield: 83.4%) of metformin free-base.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].[CH:10](=O)[CH:11]([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH:6][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H](N)CO
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H](CO)NCC(C)C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
To a suspension of (D)-serine methyl ester HCl salt (2.13 g, 13.7 mmol) in 1,2-dichloroethane was added isobutyraldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol). The reaction mixture was stirred at room temp. for 24 h, then partitioned between Et2O (100 mL) and a saturated NaHCO3 solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (3×100 mL), dried (MgSO4), and treated with a 1M HCl solution in ether (25 mL). The resulting mixture was concentrated under reduced pressure to yield (R)-N-isobutylserine methyl ester HCl salt (2.27 g, 79%): NMR (DMSO-d6) δ0.94 (dd, J=6.7, 3.0 Hz, 6H); 1.97-2.11 (m, 1H); 2.76-2.91(m, 1H); 3.76 (s, 3H); 3.86 (dd, J=12.1, 4.1 Hz, 1H), 3.99 (dd, J=12.4, 3.2 Hz, 1H), 4.13-4.21 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:2]1[O:4][CH2:3]1.[OH2:11]>[OH-].[Na+].C(O)(=O)CCCCCCCCCCC>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:2]([CH2:3][OH:11])[OH:4]
Reactant: CCCCCOCC1CO1
Reactant: O
Agent: CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCOCC(O)CO
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
In a four-necked 300-ml flask, 100 g (0.69 mole) of amyl glycidyl ether obtained in Example 1, 25 g (1.39 mole) of water, 2.31 g (0.028 mole) of 48% sodium hydroxide and 5.54 g (0.028 mole) of lauric acid were charged, followed by heating to 90° C. while stirring under a nitrogen gas atmosphere. The stirring was continued for 8 hours. After excess water was distilled off, the residue was distilled under reduced pressure (100° C., 0.133 kPa), whereby 110 g (0.59 mole) of amyl glyceryl ether was obtained (yield: 86%, purity: 99%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O1CCCC1.C(OCC)C>[F:18][C:13]([F:19])([C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:23])[OH:21])=[CH:8][CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: COB(OC)OC
Reactant: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A 1.5 M solution of n-butyllithium in tetrahydrofuran (0.57 mL) was added to a solution of 1-bromo-4-pentafluoroethylbenzene (180 mg, 0.65 mmol) in diethyl ether (1.0 mL) at −78° C., and the mixture was stirred for 20 minutes. Thereafter, trimethyl borate (101 mg, 3.28 mmol) was added and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 30 minutes. 6 N aqueous hydrochloric acid (200 μL) was added to the reaction mixture, and the reaction was terminated. The mixture was then purified by silica gel column chromatography to give 4-pentafluoroethylphenylboronic acid as a white solid (111 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([C:15]#[N:16])[CH:3]=1.IN1[C:22](=O)[CH2:21][CH2:20][C:19]1=[O:24]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:15]#[N:16])[C:3]=1[C:22]1[O:24][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cccc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cccc2Cl)c(N)c1-c1ccco1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichlorophenyl)pyrazole (0.1318 g) in acetonitrile (5 ml) at room temperature was added N-iodosuccinimide (0.1469 g). Stirring was continued for 1 hour and the mixture was then evaporated to dryness. The residue was taken up in dioxane (5 ml). Furan-2-boronic acid (0.1232 g), tetrakis(triphenylphosphine)palladium(0) (0.0554 g) and a solution of potassium carbonate (0.4405 g) in water (2 ml) were added. The mixture was heated under reflux for 48 hours, then cooled and partitioned between ether and water. The separated aqueous layer was extracted with ether and the combined ether layers were washed with brine, dried and evaporated. The green oily residue was purified by column chromatography on silica gel (4 g) eluted with dichloromethane. Combination and evaporation of suitable fractions followed by recrystallisation from toluene gave the title compound as a light brown solid, m.p. 222.6° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: COc1cccc(F)c1C=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(F)c1C=NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with 2-fluoro-6-methoxylbenzaldehyde (Compound A, 2.43 g, 15.8 mmol) and hydroxylamine hydrochloride (“NH2OH. HCl”, 1.21 g, 17.3 mmol) in ethanol (60 mL) and H2O (120 mL) was added aq. NaOH (50% w/w 3.2 mL). The reaction mixture was stirred at room temperature for 1 hour. At the conclusion of this period, the reaction was neutralized with concentrated HCl to pH 7 and then extracted with methylene chloride (“CH2Cl2”, 3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide 2-fluoro-6-methoxybenzaldehyde oxime, Compound B, as a white solid (2.45 g, 92%). m/z (ES+) 169 (M+H).
Reaction SMILES: C([C:6]1[C:7](=[O:18])[NH:8][C:9]2[CH2:10][CH2:11][CH:12]([CH3:17])[CH2:13][C:14]=2[C:15]=1[OH:16])(OCC)=O.Cl>CC(O)=O>[OH:16][C:15]1[C:14]2[CH2:13][CH:12]([CH3:17])[CH2:11][CH2:10][C:9]=2[NH:8][C:7](=[O:18])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CCC(C)C2
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCc2[nH]c(=O)cc(O)c2C1

Procedure:
Refluxing a suspension of 3-carboethoxy-4-hydroxy-6-methyl-5,6,7,8-tetrahydrocarbostyril (20 g; 0.08 mole) with 2N hydrochloric acid (300 ml) over 48 hrs. afforded the decarboethoxylated product isolated as in Example 1 m.p. (AcOH) > 365° C.
Reaction SMILES: C1(S)C=CC=CC=1.Cl[CH2:9][C:10]#[N:11].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>[OH-].[Na+].C(O)C.O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][CH2:9][C:10]#[N:11])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: N#CCCl
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(SCC#N)cc1

Procedure:
The substituted phenylthioacetonitrile starting materials can be prepared by the reaction of the corresponding thiophenol with chloroacetonitrile in alcoholic sodium hydroxide. In a representative procedure, a solution of 100 grams of 4-tert-butylthiophenol and 45.3 grams chloroacetonitrile in 225 milliliters of 95 percent ethanol is stirred at room temperature while a solution of 24 grams sodium hydroxide in 36 milliliters water is added dropwise until the mixture remains alkaline to phenolphthalein. Slight spontaneous warming occurs during the addition. The mixture is then diluted with an equal volume of water and extracted twice with ether. The ether extract is washed with water, dried over sodium sulfate, and distilled, yielding the 2-(4-tert-butylphenylthio)acetonitrile as a liquid boiling at 153°-6° C. under a pressure of 4 millimeters of mercury.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=12.[CH3:25]I>CN(C=O)C>[CH3:25][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:3]=[C:4]1[C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=12
Reactant: C#CCn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(-c3nc4ccccc4n3C)ncn2c1=O
Reaction time: 8 h
Yield: 62.8 %

Procedure:
Sodium hydride (60% in mineral oil, 8 mg, 0.189 mmol, 1.1 eq.) was added in one portion to a slurry of 8-(1H-benzo[d]imidazol-2-yl)-3-(prop-2-ynyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (50 mg, 0.172 mmol) in DMF (4.5 mL) at 0° C. and the mixture, which became red, was stirred for 5 minutes before the addition of MeI (21 μL, 0.344 mmol, 2 eq.). The mixture was then stirred overnight and concentrated under high vacuum. The product was absorbed on silica and purified by flash chromatography using DCM:MeCN (80:20) as eluent to give the title compound as a bright yellow/green solid (33 mg, 62% yield). The product was then suspended in ethyl acetate, filtered and washed successively with water, ethyl acetate and diethyl ether to remove any trace of DMF. δH (DMSO-d6): 9.07 (1H, s), 7.76-7.79 (1H, m), 7.67-7.70 (1H, m), 7.35-7.39 (1H, m), 7.29-7.33 (1H, m), 5.17 (2H, d, J=2.5), 4.14 (3H, s), 3.53-3.54 (1H, t, J=2.5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a yellow solid (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:11]([O-])=O)[C:3]=1[N+:14]([O-:16])=[O:15].[C:17](OCC)(=O)[CH3:18]>>[N:11]1([C:4]2[C:3]([N+:14]([O-:16])=[O:15])=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])[CH2:18][CH2:17]1
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Product: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1N1CC1
Reaction time: 3 h

Procedure:
Reaction of 4-chloro-2,3-dinitrobenzamide [Goldstein and Schaaf, Helv. Chim. Acta. 1957, 40, 369-376] in ethyl acetate generally as described in Example L, except that the reaction time was 3 hours, gave 2-(aziridin-1-yl)-4-chloro-3-nitrobenzamide (16) as a yellow powder, mp 216° C. 1H NMR [(CD3)2SO] δ8 16 (br s, 1H CONHH), 7 71 (br s, 1H, CONHH), 7 69 (d, J=8.3 Hz, 1H, H-6), 7.25 (d, J=8.3 Hz, 1H, H-5), 2.28 (s, 4H, aziridine-H) 13C NMR δ165.53 (s), 142.59 (s), 142.49 (s), 131 65 (d), 129.71 (s), 129.00 (s), 121.37 (d), 29.40 (t). Found. C, 44.90;H, 3.49; N, 17.39. C9H8ClN3O3 requires C, 44.73;H, 3.33; N, 17.39%.
Reaction SMILES: CC1C=C(C)NN=1.[CH3:8][C@@H:9]1[C@H:18]2[C:12](=[C:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:19]([CH3:21])=[CH2:20])[CH2:17]2)[CH2:11][CH2:10]1.[OH-:23].[Na+]>ClCCl>[CH3:8][C@@H:9]1[C@H:18]2[C:12](=[C:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:19]([CH3:21])=[CH2:20])[CH2:17]2)[C:11](=[O:23])[CH2:10]1
Reactant: [OH-]
Reactant: C=C(C)[C@@H]1CCC(C)=C2CC[C@H](C)[C@@H]2C1
Agent: Cc1cc(C)[nH]n1
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)[C@@H]1CCC(C)=C2C(=O)C[C@H](C)[C@@H]2C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
At −30° C., a solution of 3,5-dimethyl-1H-pyrazole (7.2 g, 74.9 mmol) in dichloromethane (40 ml) was treated with CrO3 (7.5 g, 74.9 mmol, added in two portions) while the reaction temperature rose to −20° C. The resulting mixture was stirred at −20° C. for 0.5 h and treated within 20 min. with a solution of α-bulnesene (3.0 g, 14.7 mmol) in dichloromethane (20 ml) while the reaction temperature rose to −10° C. The resulting mixture was stirred between −20° C. and −10° C. for 4 h before allowing the reaction temperature to slowly reach 20° C. (overnight), treated with 8M aqueous NaOH (70 ml), stirred at 20° C. for 20 h, and extracted with MTBE (400 ml). The aqueous phase was extracted with MTBE (150 ml) and the joined organic phases were washed twice with 2 M aq. HCl (100 ml), once with H2O (100 ml), once with aqueous saturated NaCl solution (100 ml), dried with MgSO4, filtered, and the solvent evaporated. FC (200 g 0.015-0.040 mm-SiO2, flow: 60 ml/min., hexane/methyl t-butyl ether 100:0 to 85:15 in 30 min.) of the crude product (2.4 g) gave (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-3,3a,4,5,6,7-hexahydroazulen-1(2H)-one (130 mg, 4%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:1][C@@H:2]([CH2:3][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: NC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: NC(=O)Nc1ccc(OC[C@@H](O)CN2CCN(c3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 70.8 %

Procedure:
A mixture of 0.1 g of (S)-1-(4-(oxiran-2-ylmethoxy)phenyl)urea, 0.14 g of N-phenyl-piperazine, and 6 mL of absolute ethanol was heated to 70° C. for 20 hrs. The reaction was cooled, and the resulting precipitate collected by filtration. The solids were washed three times with ethanol, and dried. 0.126 g of the title compound was obtained as a fluffy white powder was obtained. 1H NMR (d6-DMSO): δ 2.36 (dd, 1H, J=6 Hz, J=13 Hz), 2.48 (m, 1H), 2.55 (m, 4H), 3.08 (t, 4H, J=5 Hz), 3.78 (dd, 1H, J=6 Hz, J=9 Hz), 3.89 (m, 1H), 3.93 (m, 1H), 4.84 (d, 1H, J=5 Hz), 5.68 (s, 2H), 6.73 (t, 1H, J=8 Hz), 6.78 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=8 Hz), 7.16 (t, 2H, J=8 Hz), 7.24 (d, 2H, J=9 Hz), 8.27 (s, 1H); MS: 371 (M+H); HRMS: Observed: 371.20723; HPLC: 100% peak area composition; retention time=6.64 min.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]3[N:29]=[N:30][NH:31][N:27]=3)[CH:20]=2)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1c(Oc2cccc(CC#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(Oc2cccc(Cc3nn[nH]n3)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 90 °C

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-phenyl]-acetonitrile (0.030 g, 0.078 mmol) was dissolved in toluene (1 mL) along with azidotrimethylsilane (44 μL, 0.33 mmol) and dibutyltin(IV) oxide (0.002 g, 0.008 mmol). The reaction was heated to 90° C. for 2 days then concentrated. The crude material was dissolved in DMSO and purified via preparatory HPLC to give the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:9]([C:20](O)=[O:21])=[CH:8]2.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:36][CH:34]1[CH2:35][N:32]([C:29]2[N:28]=[CH:27][C:26]([NH:25][C:20]([C:9]3[N:10]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[C:11]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[Si:2]([CH3:1])([CH3:23])[CH3:24])=[O:21])=[CH:31][CH:30]=2)[CH2:33]1
Reactant: C[Si](C)(C)c1cccc2cc(C(=O)O)n(Cc3cccc(F)c3)c12
Reactant: Nc1ccc(N2CC(O)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1cccc2cc(C(=O)Nc3ccc(N4CC(O)C4)nc3)n(Cc3cccc(F)c3)c12
Yield: 12.6 %

Procedure:
Compound No. 6 was prepared according to a process similar to that described in stage 5.4, by reacting 0.15 g (0.44 mmol) of 7-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 5.3, with 109 mg (0.66 mmol) of 3-amino-6-(3-hydroxyazetidin-1-yl)pyridine, prepared according to the protocol described in stage 2.2, in the presence of 87 mg (0.44 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and of 61 mg (0.44 mmol) of 1-hydroxybenzotriazole (HOBT) in 5 ml of dimethylformamide. 27 mg of the expected product are obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:34][CH2:35][CH2:36][CH2:37][F:38])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:18]3=[O:33])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:34][CH2:35][CH2:36][CH2:37][F:38])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:18]3=[O:33])=[N:15][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCF
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCF
Reaction time: 6 h

Procedure:
To a cooled (0° C.) solution of [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(4-fluoro-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (51 mg, 0.088 mmol) in DCM (2 mL) was added TFA (204 μL, 2.65 mmol). The solution was allowed to reach room temperature and stirred for 6 hrs. The volatiles were removed in vacuo and the residue was stripped with methanol. The TFA salt was dissolved in methanol followed by the addition of acetyl cloride (63 μL, 0.88 mmol) and concentrated. This procedure was repeated once. The product was dissolve in methanol and DCM then concenrated (twice). The remaining solid was triturated in diethyl ether to give 1-[5-Aminomethyl-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl]-3-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione; HCl salt (45 mg, 100%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cncn3)nc2c1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.10 g of 1H-1,2,4-triazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 2-[3-(1,2,4-triazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 63”).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([CH2:35][CH2:36]OS(C)(=O)=O)=[N:27]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([CH2:35][CH2:36][N:21]2[CH2:22][CH:23]3[O:25][CH:19]([CH2:18][N:17]([CH2:16][CH2:15][NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=4)(=[O:13])=[O:12])[CH2:24]3)[CH2:20]2)=[N:27]1
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Reactant: CS(=O)(=O)OCCc1noc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(S(=O)(=O)NCCN2CC3CN(CCc4noc5ccccc45)CC(C2)O3)cc1
Temperature: 160 °C
Yield: 41.5 %

Procedure:
To 4-cyano-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.123 g, 0.30 mmol, from prep E above), methanesulfonic acid 2-benzo[d]isoxazol-3-yl-ethyl ester (0.076 g, 0.315 mmol, from prep AD above) and potassium carbonate (0.145 g, 1.05 mmol; from Prep ) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 60 mg (41.5%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12]>N1CCCCC1.C(O)C>[CH3:21][C:20]1[NH:19][C:18]([CH:22]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:17]([CH3:24])[C:16]=1[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 234.3 mg of the 4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 3 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 244.6 mg (79%) of the title compound as a yellow solid.