Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:63][C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH2:76])[CH2:72][CH2:71]1)=[O:69])([CH3:66])[CH3:65]>ClCCl.CN(C)C=O>[C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH:76][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:7]4[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]=4[N:19]=3)=[C:22]([O:30][CH3:31])[CH:23]=2)[CH2:72][CH2:71]1)=[O:69])([CH3:63])([CH3:65])[CH3:66]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
A mixture of 0.095 g (0.22 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.066 g (0.33 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.078 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 0.078 g (0.013 mmole) of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.055 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-5).
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[C:10]3[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12](S)[C:11]=3[CH:18]=[CH:19][CH:20]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.N1C=CC=CC=1.[N:41]1([CH:46]([CH3:50])[CH2:47][CH2:48][NH2:49])[CH:45]=[CH:44][N:43]=[CH:42]1>C(O)C>[CH2:1]([C:8]1[C:9]2[C:10]3[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:49][CH2:48][CH2:47][CH:46]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[CH3:50])[C:11]=3[CH:18]=[CH:19][CH:20]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SC1=Nc2ccc(Cc3ccccc3)c3cccc1c23
Reactant: CC(CCN)n1ccnc1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Solvent: c1ccncc1
Product: CC(CCNC1=Nc2ccc(Cc3ccccc3)c3cccc1c23)n1ccnc1

Procedure:
The Wolff-Kishner-Huang Minlon reductive procedure is applied to 6-benzoylbenz(cd)indol-2-one to yield 6-benzylbenz(cd)indol-2(1H)-one which is converted to 6-benzylbenz(cd)indol-2-thiol by P2S5 in refluxing pyridine. The reaction of the latter compound with 3-(1H-imidazol-1-yl)butanamine and mercuric acetate in refluxing ethanol, under the conditions of Example 55, leads to the title compound.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: c1cc[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1C=C(c2ccc[nH]2)C(=O)c2ccccc21
Yield: 18 %

Procedure:
Using the procedure described in Example 1, starting with 3.16 millimol of 1,4-naphthoquinone, 25 millimol of pyrrole and 3.16 millimol of copper acetate in 50 ml of acetic acid, the product 2-(1H-pyrrol-2-yl)-[1,4]-naphthoquinone was isolated in a yield of 18% after purification by chromatography on a column of silica.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[C:18]([C:24]#[N:25])=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>N1C=CC=CC=1>[C:24]([C:18]1[C:17]([NH:16][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:22][C:21]([CH3:23])=[CH:20][N:19]=1)#[N:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: Cc1cnc(C#N)c(N)c1
Solvent: c1ccncc1
Product: Cc1cnc(C#N)c(NS(=O)(=O)c2ccc(C)c(C(F)(F)F)c2)c1

Procedure:
Prepared from 2.92 g (11.3 mmol) of 4-methyl-3-trifluoromethyl-benzenesulfonyl chloride and 1.25 g (9.41 mmol) of 3-amino-5-methyl-pyridine-2-carbonitrile in 4 mL pyridine using procedure x. Yield: 1.13 g of a white solid. LC-MSD, m/z for C15H12F3N3O2S [M+H]+=356.0
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:12]1)=[O:9].C=O.[C:50](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:50])[C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:13][CH2:12]1)=[O:9]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C)c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Moisture was removed from a mixture of the compound (120 mg, 0.205 mmol) obtained in Example 43a and a 35% aqueous formaldehyde solution (85 μL, 1.02 mmol) azeotropically with toluene 3 times. The resulting mixture was dissolved in ethanol (6 mL), sodium triacetoxyborohydride (65 mg, 0.307 mmol) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (118 mg; yield, 96%) as a colorless oily substance.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH2:21])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[CH3:3].[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C=O)C.C1COCC1>[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH:21][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[CH3:23])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2)[CH3:3]
Reactant: CCOC(=O)C(N)C(=O)CCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)c1ccccc1C)C(=O)CCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
5-Adamantan-1-yl-2-amino-3-oxo-pentanoic acid ethyl ester hydrochloride (prepared using the method of T. W. von Geldem & C. Hutchins et al, J. Med. Chem. 1996, 39, 957) (3.30 g, 10.0 mmol) was suspended in DMF (15 ml) and a solution of 2-methylbenzoyl chloride (1.55 g 10.0 mmol) in THF (15 ml) was added. The mixture was stirred at room temperature and a solution of N,N-diispropylethylamine (3.48 ml 20.0 mmol) in THF (10 ml) was added dropwise over 30 min. After stirring for 2 h the THF was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with water, 2M HCl, brine, dried (MgSO4), and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/ethyl acetate 9:9:2) to afford the product as a pale yellow oil. (2.08 g, 60%). 1NMR (300 MHz, CDCl3) 7.49-7.23 (4H, m), 6.97 (1H, d), 5.45 (1H, d), 4.30 (2H, m), 2.77 (2H, m), 2.47 (3H, s), 1.97 (3H, s) 1.67 (6H, m), 1.47 (8H, m), 1.34 (3H, t).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH3:30])[CH:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[Si:23]([O:22][C@@H:13]1[C@H:12]([CH3:30])[NH:11][C:15](=[O:16])[C:14]1([CH3:21])[CH3:20])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].[Si:23]([O:22][C@H:13]1[C@H:12]([CH3:30])[NH:11][C:15](=[O:16])[C:14]1([CH3:21])[CH3:20])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)C(O[Si](C)(C)C(C)(C)C)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NC(=O)C(C)(C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: C[C@@H]1NC(=O)C(C)(C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %
Yield: 30.1 %

Procedure:
To a solution of ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoate (0.916 g) in methanol (20 mL) was added 10% palladium carbon (containing 50% water, 89 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in THF (15 mL). Diisopropylethylamine (1.5 mL) was added, and the mixture was fluxed for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound (yield: 161.8 mg, yield: 30.1%) and (4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (yield: 289 mg, yield: 53.7%), each as a colorless solid.
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([NH:13][C@:14]12[CH2:22][CH:21]1[CH2:20][C@H:19]1[C@@H:15]2[CH2:16][N:17]([C:23](=O)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>O>[C:6]([O:10][C:11]([NH:13][C@:14]12[CH2:22][CH:21]1[CH2:20][C@H:19]1[C@@H:15]2[CH2:16][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc(C(=O)N2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A 1M tetrahydrofuran solution (7.0 ml) of a borane-tetrahydrofuran complex (7.0 mmol) was added dropwise to a tetrahydrofuran (20 ml) solution of (1R,2R,6S)-1-t-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.02,6]nonane (970 ml, 2.60 mmol) while cooling with ice, and the mixture was stirred at room temperature for 1 hour. While cooling with ice, water was added to the reaction mixture to decompose the excess borane-tetrahydrofuran complex. A 1N sodium hydroxide aqueous solution (10 ml) was added thereto, followed by refluxing for 6 hours. After cooling to room temperature, the reaction mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 453 mg (1.26 mmol, 48%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH3:12])=[C:4]([OH:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O1CCOC[CH2:21]1>>[CH3:12][O:11][C:5]1[C:6]([O:9][CH3:10])=[C:7]([OH:8])[C:2]([CH3:1])=[C:3]([CH2:21][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:4]=1[OH:13]
Reactant: C1COCCO1
Reactant: C1COCCN1
Reactant: COc1c(O)cc(C)c(O)c1OC
Product: COc1c(O)c(C)c(CN2CCOCC2)c(O)c1OC

Procedure:
A solution of 2,3-dimethoxy-5-methyl-1,4-benzohydroquinone (2.2 g) 37% formaldehyde (2.4 ml) and morpholine (2.4 ml) in dioxane (11 ml) was refluxed at 100° C. for 2 hours. The reaction mixture was evaporated to dryness and the residue was suspended in water. The suspension was extracted with chloroform and the extract was treated in a conventional manner. The residue was recrystallized from ether-hexane to give 2,3-dimethoxy-5-methyl-6-morpholinomethylhydroquinone (2.23 g), melting at 127°-130° C.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([NH:19][CH2:20][CH:21]=[O:22])[C:17]#[CH:18]>C(O)C.O>[CH2:16]([N:19]([CH2:20][CH:21]=[O:22])[C:8]([NH:7][C:5]1[S:6][C:2]([I:1])=[CH:3][N:4]=1)=[O:9])[C:17]#[CH:18]
Reactant: C#CCNCC=O
Reactant: O=C=Nc1ncc(I)s1
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: C#CCN(CC=O)C(=O)Nc1ncc(I)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Iodothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-propargylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-iodothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([C:14]([NH2:16])=O)=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[Cl:7][C:8]1[C:13]([C:14]#[N:16])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: N#Cc1cnc(Cl)cc1Cl
Temperature: 60 °C
Yield: 88.4 %

Procedure:
Pyridine (20.3 mL, 250 mmol) was added to a suspension of 4,6-dichloro-nicotinamide (8.00 g, 41.9 mmol) in acetonitrile (180 mL) at room temperature POCl3 (11.7 mL, 126 mmol) was added over 3 minutes at room temperature. The reaction mixture was heated at 60° C. with for 1.5 hours. The reaction solution was cooled to room temperature and poured into aqueous NaOH (0.8M, 600 mL) followed by extraction with EtOAc (6×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (30% ethyl acetate/hexanes) to give the title compound as a light orange solid (6.41 g, 88%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(Cl)nc1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), 3-fluorobenzylamine (0.15 ml, 1.2 mmole), PyBOP (0.67 gm, 1.3 mmole), and DIEA (0.43 ml, 2.6 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.3 gm, 85%); H1-NMR INOVA-500 (CDCl3) δ 3.562 (s, 2H), 4.429 (d, J=6.5 Hz, 2H), 5.868 (s, 1H), 6.929-7.015 (m, 3H), 7.300-7.333 (m, 2H), 7.668 (dd, J=8, 2.5 Hz, 1H), 8.280 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH3:10])[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[In]>C(O)C.O>[NH2:17][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](Nc1cccc(Br)n1)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@H](Nc1cccc(Br)n1)c1cccc(N)c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a solution of 6-bromo-N-[(1S)-1-(3-nitrophenyl)ethyl]pyridin-2-amine (100 mg, 0.31 mmol) in ethanol (5 mL) was added a solution of ammonium chloride (166 mg, 3.1 mmol) in water (2.5 mL), then indium powder (142 mg, mesh 100, 1.24 mmol). The mixture was heated at reflux for 4.5 hours, was allowed to cool to room temperature and was filtered through Celite. The filter cake was washed with water and ethanol and the combined filtrates were extracted with dichloromethane (2×30 mL) and the extracts washed with brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give N-[(1S)-1-(3-aminophenyl)ethyl]-6-bromopyridin-2-amine (70 mg, 77%) as a dark yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]P(=O)(OC)OC.O.[OH-].[Li+].[C:18]([O:21][C@@H:22]1[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:25]([CH:37]=O)[C@H:24]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:23]1)(=[O:20])[CH3:19]>COC(C)(C)C.O>[C:18]([O:21][C@@H:22]1[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:25](/[CH:37]=[CH:3]/[C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@H:24]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:23]1)(=[O:20])[CH3:19]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCC(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.178 g, 0.801 mmol) in t-butyl methyl ether (2 ml), lithium hydroxide monohydrate (32.5 mg, 0.775 mmol) was added and the mixture was stirred for two hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.213 g, 0.535 mmol) in t-butyl methyl ether (2 ml) and water (0.12 ml) were added thereto, and the mixed solution was stirred for one hour at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane =3:7), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (13) (0.255 g; 0.516 mmol; yield: 96.4%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.O(C1C=CC([B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)=CC=1C#N)C1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[C:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([B:33]3[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]3)=[CH:3][C:4]=2[N+:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c([N+](=O)[O-])c2)OC1(C)C

Procedure:
The title compound was prepared in a 56% from 4-bromo-2-nitro-1-phenoxybenzene in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.19(d, 1H), 7.91(d, 1H), 7.46(t, 2H), 7.27(t, 1H), 7.14(d, 2H), 7.06(d, 1H), 1.31(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.02 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:20]=[C:21]([NH:22][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(-c2nccs2)c1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2cccc(-c3nccs3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 2,4-dinitrofluorobenzene (1.14 ml, 9.1 mmol), 2t from Example 2 (1.6 g, 9.1 mmol) and potassium carbonate (1.51 g, 10.9 mmol) in dry N-methyl-2-pyrrolidone (10 ml) is heated to 80° C. for 2 hours. The cooled mixture is poured into ice-water. The precipitate is filtered off, washed with water and dried to yield: 3.05 g (98%). Mp 1 97-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[O:14][C:15]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[O:14][C:15]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccco2)c(-c2ccco2)o1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccco2)o1)c1cc(Br)ccc1O
Yield: 12.9 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-bis(furan-2-yl)oxazole as the raw materials, the same operation as the Example 16 gave the title compound.