Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1CCNCC1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Solvent: CCO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 1.0 g (3.7 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 1.62 g (19 mmol) of piperidine, and 10 mL of ethanol. The resulting mixture was stirred at 80° C. for 5 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.02 g (reaction yield: 87%) of 6-methoxy-7-(3-piperidinopropoxy)quinazolin-4-one.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[CH3:16][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18]>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:18][N:17]([CH3:16])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: CN(N)c1ccccc1
Product: C=CCC(O)(CCNN(C)c1ccccc1)c1ccc(F)cc1
Temperature: 140 °C
Yield: 7.2 %

Procedure:
1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (20 mg, 0.088 mmol) and 1-methyl-1-phenylhydrazine (640 mg, 5.26 mmol) were combined and heated in a microwave for 10 min at 120° C. and for 20 min at 140° C. The crude mixture was purified by chromatography on a silica gel cartridge eluted with an EtOAc/hexanes gradient followed by preparative HPLC to afford 3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (2 mg). LC-MS Method 1 m/z=315 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]1[O:20][C:19]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=2[O:12]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:20]1[C:19]2[CH:18]=[CH:17][C:15]([NH:16][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:14][C:13]=2[O:12][CH2:11]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1Nc1ccc2c(c1)OCO2
Yield: 66.5 %

Procedure:
A 500 mL round bottom flask was charged with 2-chloro-3-nitropyridine (12.0 g, 76.0 mmol), 3,4-(methylenedioxy)aniline (12.97 g, 95.0 mmol), sodium acetate (7.76 g, 95.0 mmol) and acetic acid (200 mL). This was stirred at reflux for 6 h. The solvent was evaporated on a rotovap, and the crude product was column chromatographed with silica gel using a mobile phase gradient of 50-100% dichloromethane in hexane to give N-(benzo[d][1,3]dioxol-5-yl)-3-nitropyridin-2-amine (13.1 g, 67%) as a red solid.
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=4)[N:13]=3)=[CH:8][CH:7]=2)=[N:4]N=N1.[OH-:25].[Na+].OO>CS(C)=O>[CH3:24][O:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:4])=[O:25])=[CH:7][CH:8]=1)[CH:21]=[CH:20]2
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(C(N)=O)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(6-methoxyquinolin-2-yl)benzonitrile (5.00 g, 15.4 mmol, prepared following Scheme 2, Step 1 starting from Intermediate 1 and 4-cyanophenylboronic acid) in DMSO (40 mL) was added aqueous NaOH (1M, 10 mL). The mixture was cooled to 0° C. The aqueous H2O2 (30%, 30 mL) was added dropwise. After addition, the mixture was stirred at 0° C. for 30 minutes. The mixture was quenched with saturated Na2SO3 (100 mL) and filtered. The precipitate was washed with H2O (50 mL) and MeOH (50 mL). The filter cake was dried via high vacuum to give the desired (5.50 g, yield: 99+%) as a solid.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15])=[C:8]([F:17])[CH:7]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOCC>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[O:24])[CH2:15][C:14](=[O:16])/[CH:13]=[CH:12]/[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][C:8]=1[F:17])[CH3:23]
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1F
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1F
Temperature: -5 °C
Reaction time: 48 h
Yield: 86.5 %

Procedure:
Sodium pellets (2.88 g, 0.125 mol) were slowly added to absolute ethyl alcohol (EtOH, 125 mL). After the sodium had reacted, the solvent was removed under reduced pressure, and anhydrous ether (200 mL) was added. The reaction mixture was cooled to −5° C., and a solution of (E)-4-(4-chloro-2-fluorophenyl)-but-3-en-2-one (1; 24.75 g, 0.125 mol) and diethyl oxalate (21.9 g, 0.15 mol) in anhydrous ether (25 mL) was added over 30 min. After stirring 2 days (d) at room temperature, the yellow solid was filtered and washed with ether. After 1 hour (h) of drying at room temperature, the solid was partitioned between CH2Cl2 (200 mL) and 1 N sulfuric acid (H2SO4, 150 mL). The organic layer was dried (MgSO4), and the solvent was removed to give (E)-6-(4-chloro-2-fluoro-phenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (3; 32.3 g, 86%) as a yellow solid. A small sample was recrystallized from EtOH to yield yellow crystals: mp 84-85° C.; 1H NMR (400 MHz, CDCl3) δ 14.72 (s, 1H), 7.76 (d, J=16.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.24-7.12 (m, 2H), 6.73 (d, J=16.1 Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H12ClFO44, 298.041. found, 298.041.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:22](OCC)=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29].[H-].[Li+].[Al+3].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][OH:23])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: CCOC(=O)C(CN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CC(CO)c3ccccc3)CC2)cc(=O)n(C)c1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
1.3 g of 1,3-dimethyl-6-[4-(2-ethoxycarbonyl-2-phenylethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione obtained in Example 4 was dissolved in 50 ml of tetrahydrofuran, and while the resulting solution was cooled to -20° C., 1.1 g of aluminum lithium hydride was divided into several portions and then added thereto separately. After stirring at -10° C. for 1 hour, 0.7 ml of water was added to the solution at the same temperature. The reaction solution was stirred for 2 or 3 hours, and 3 g of anhydrous sodium sulfate was added thereto, followed by allowing the solution to stand overnight. Afterward, insolubles were removed from the solution by filtration, and the filtrate was concentrated and the resulting residue was then dissolved in ethyl acetate. The obtained solution was washed with water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified through a silica gel column chromatograph (chloroform/methanol=100/1 to 30/1 in volume ratio), thereby obtaining 0.5 g of oily 1,3-dimethyl-6-[4-(3-hydroxy-2-phenylpropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]=[S:12]([CH3:24])([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=[O:13])=O>CO.C(OCC)(=O)C.[Cl-].[Na+]>[CH3:24][S:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)(=[NH:11])=[O:13]
Reactant: CS(=O)(Cc1cccc([N+](=O)[O-])c1)=NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=N)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Potassium carbonate (56.9 g; 411.8 mmol) was added to a solution of (rac)-2,2,2-trifluoro-N-[methyl(3-nitrobenzyl)oxido-λ6-sulfanylidene]acetamide (25.6 g; 82.4 mmol) in MeOH (1768 mL) at room temperature. The batch was stirred for 1 hour at room temperature before it was diluted with ethyl acetate and saturated aqueous sodium chloride solution. After extraction with ethyl acetate (2×) the combined organic phases were dried (sodium sulfate), filtered and concentrated to give the desired product (13.9 g; 65.1 mmol).
Reaction SMILES: C(NC(C)C)(C)C.C(=NC1CCCCC1)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33]([O:35]CC)[CH3:34]>C([Li])CCC.CCCCCC.O1CCCC1>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH:34][CH:33]=[O:35])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC=NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=CC=Cc1ccc(OCc2ccccc2)cc1

Procedure:
Other N-methyl-cinnamylamines can be prepared as follows: To the solution of 5.55 g of di-isopropylamine in 60 ml of diethyl ether, 35 ml of 1.6 molar n-butyl lithium in hexane are added dropwise while stirring at -20° under nitrogen. Thereupon the solution of 6.9 g of N-ethylidenecyclohexylamine in 50 ml of diethyl ether is added dropwise at -20°, followed by the solution of 10.6 g of 4-benzyloxy-benzaldehyde in 50 ml of diethyl ether and 10 ml of tetrahydrofuran at -70°. The mixture is stirred for 1 hour at room temperature, washed with 50 ml of water and stirred with 100 ml of water and 50 ml of acetic acid for 8 hours at room temperature. The ethereal layer is collected, washed with water, N hydrochloric acid, 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated, to yield the 4-benzyloxycinnamaldehyde.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1.CN(C)C=O>C(N(CC)CC)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][N:21]=[C:20]2[N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCN(c4ccc5c(c4)CCC(=O)N5)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a mixture of 6-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinone (1.28 g), 4-chloro-6,7-dimethoxyquinazoline hydrochloride (1.43 g) and N,N-dimethylformamide (50 ml) was added triethylamine (560 mg) and the mixture was stirred for 8 hours at ambient temperature. The solvent was removed under reduced pressure and to the obtained residue were added water (20 ml), tetrahydrofuran (10 ml) and ethyl acetate (10 ml). The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (80 g) and eluted with 10% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated. The obtained residue was subjected to a column chromatography on alumina (60 g) and eluted with 5% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated to give 6-[4-(6,7-dimethoxyquinazolin-4-yl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone (0.8 g).
Reaction SMILES: O1C2C(=CC=CC=2)C(=O)C(C(O)=O)=C1.S(Cl)(Cl)=O.[O:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[C:21]([C:30]([NH2:32])=O)=[CH:20]1>CN(C)C=O>[C:30]([C:21]1[C:22](=[O:29])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH:20]=1)#[N:32]
Reactant: NC(=O)c1coc2ccccc2c1=O
Agent: O=C(O)c1coc2ccccc2c1=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1coc2ccccc2c1=O
Yield: 75 %

Procedure:
The present invention concerns a novel method of preparing these 3-cyanochromones from chromone-3-carboxylic acids. The reaction mechanism of the present invention may best be described by the following reaction scheme: ##STR4## Referring to the reaction scheme, chromone-3-carboxylic acid is initially converted to the acyl chloride by treating with thionyl chloride as disclosed in U.S. Pat. No. 3,849,446 to Von Strandtmann, et al., issued Nov. 19, 1974. The acyl chloride is then converted to the corresponding chromone-3-carboxamide, as disclosed in U.S. Pat. No. 3,862,143. The critical feature of the present invention is the further dehydration of the chromone-3-carboxamide with thionyl chloride in N,N-dimethylformamide to give the desired 3-cyanochromone in a high yield of at least 75%. Generally, a molar excess of thionyl chloride and a 30-40 molar excess of N,N-dimethylformamide are employed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1)[CH2:19][CH2:20][O:21][C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3-fluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C1COCC1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[N:19]=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([N:20]3[C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:18]([C:17]([F:35])([F:34])[F:16])=[N:19]3)=[CH:33][CH:32]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
4-Chlorobenzoyl chloride (88 mg) and THF (2 ml) were added to a mixture of 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (150 mg), triethylamine (57 mg) and THF (2 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1 N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in that order. The organic lager was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, 4-chloro-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]benzanilide (105 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16](=[O:29])[N:15]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[C:14]=2[S:13][C:12]=1[C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][O:49][CH3:50])=[O:47])=[CH:41][CH:40]=1)C)C1C=CC=CC=1.[ClH:51]>C(O)C.[C].[Pd]>[ClH:51].[CH3:1][NH:8][CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:16](=[O:29])[N:15]([CH2:30][C:31]3[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=3[F:37])[C:14]=2[S:13][C:12]=1[C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:46]([NH:48][O:49][CH3:50])=[O:47])=[CH:43][CH:44]=1
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(OC)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(-c1ccc(OC)cc1)c(=O)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A mixed solution of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (2.0 g, 2.87 mmol) synthesized in Reference Example 19, 10%-palladium-carbon (200 mg), 1N hydrochloric acid (3 ml) in ethanol (40 ml) was stirred under hydrogen atmosphere at room temperature for 72 hours. The reaction mixture was subjected to filtration and the filtrate was concentrated to dryness to give the title compound (1.77 g, 96%) as white powders.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:16]([CH3:28])=[CH:17][C:18]2[CH2:19][C@H:20]3[C@@H:25]([C:26]=2[CH:27]=1)[CH2:24][CH2:23][CH2:22][NH:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]4[C:26]5[CH:27]=[C:15]([O:14][CH3:13])[C:16]([CH3:28])=[CH:17][C:18]=5[CH2:19][C@H:20]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1cc2c(cc1C)C[C@@H]1NCCC[C@H]21
Product: COc1cc2c(cc1C)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-methoxy-7-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. LC (method 7): tR=1.04 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCC>ClCCl>[C:4]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:3]
Reactant: C[Si](C)(C)C#C[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCCCC
Product: C#C[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
(S)-(trans)-4-[2-(trimethylsilyl)ethynyl]-2-oxo-3-[(triphenylmethyl)amino]azetidine (2.97 g) is dissolved in 30 ml of dichloromethane and 330 mg of tetrabutylammonium fluoride (containing 20-25% water) is added. After 20 minutes, the solvent is removed in vacuo. The residue is taken up in ethyl acetate and water. The organic layer is separated, washed once with water and once with saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. Removal of the solvent gives an oil which is stirred for 15 minutes with 60 ml of pentane to afford 2.35 g of the title compound as a powder (after drying in vacuo).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](O)=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([NH:63][S:64]([C:67]2([CH2:70][F:71])[CH2:69][CH2:68]2)(=[O:66])=[O:65])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].C(N(CC)CC)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](=[O:43])[NH:55][C@:56]1([C:61](=[O:62])[NH:63][S:64]([C:67]2([CH2:70][F:71])[CH2:69][CH2:68]2)(=[O:66])=[O:65])[CH2:58][C@H:57]1[CH:59]=[CH2:60])=[O:35])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(CF)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(CF)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
HATU (11.61 g, 30.5 mmol) was added to a DCM (220 mL) solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.50 g, 25.5 mmol), (1R,2S)-1-amino-N-((1-(fluoromethyl)cyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide HCl (8.37 g, 28 mmol), triethylamine (14.19 mL, 102 mmol). The reaction mixture was stirred at RT for overnight. The reaction was washed with 1N HCl (3×) and then with brine and evaporated on rotovap. The crude material was purified by silica gel chromatography using 20-40% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give the desired product tert-butyl((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (15 g, 90% yield). MS: MS m/z 657.3 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(pyridin-2-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: C(#N)C.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([NH:19][C:7]1[C:8]([F:12])=[C:9]([F:11])[N:10]=[C:5]([F:4])[C:6]=1[F:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1c(F)c(F)nc(F)c1F
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To 100 ml of acetonitrile was added 24.5 g of pentafluoropyridine, and the mixture was stirred in an ice bath simultaneously with the dropwise addition of 30 g of t-butylamine. When the mixture warmed to room temperature, 150 ml of chloroform was added, and the mixture was washed twice with 800 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 23 g of the title compound as a pale yellow oil.