Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][CH:8]([NH2:14])[C:7]1=[O:15])[CH3:2].C(Cl)Cl.[C:20]1([C:30](O)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][CH:8]([NH:14][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:31])[C:7]1=[O:15])[CH3:2]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CCOC(=O)CN1CC(C)=CCC(N)C1=O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(C)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
The crude (3-amino-6-methyl-2-oxo-2,3,4,7-tetrahydroazepin-1-yl}-acetic acid ethyl ester, 10, obtained in the previous step is dissolved in 6 mL of 1:1 DMF:CH2Cl2 and treated with 1-isoquinolinecarboxylic acid (0.24 g, 1.2 mmol), 1-hydroxybenzotriazole (0.23 g, 1.5 mmol), and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (0.32 g, 1.5 mmol). The solution is stirred for 1 hour at room temperature, diluted with EtOAc, washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the crude isolate is purified by HPLC to afford 70 mg (30% yield) of the desired product. 1H NMR (CDCl3) δ 9.51–9.48 (d, J=8.1 Hz, 1H), 9.22–9.20 (d, J=6.9 Hz, 1H), 8.51–8.49 (d, J=5.4 Hz, 1H), 7.84–7.77 (m, 2H), 7.72–7.63 (m, 2H), 5.57 (bs, 1H), 5.48–5.40 (m, 1H), 4.775–4.715 (d, J=18 Hz, 1H), 4.24–4.19 (q, d, J=15.3, 7.5 Hz, 3H), 3.27–3.21 (d, J=18 Hz, 1H), 2.86–2.81 (d, J=16.5 Hz, 1H), 2.45–2.36 (d, d, J=15, 12.6 Hz, 1H), 1.79 (s, 3H), 1.30–1.25 (t, J=7.5 Hz, 3H); 13C (CDCl3) 172.8, 169.2, 165.6, 148.2, 140.8, 137.5, 131.8, 130.5, 128.7, 127.7, 127.0, 124.5, 123.4, 61.6, 52.3, 50.8, 49.6, 32.6, 25.0, 14.3; MS 382 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:25]([CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:2][C:3]=2[CH:9]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CCCCc3ccccc3)nc2cc1Cl
Yield: 11.1 %

Procedure:
To 25 ml of 6 N hydrochloric acid was added 5.5 g of 2-amino-4-chloro-5-sulfamylaniline and 6.6 g of 5-phenylvaleric acid and the mixture refluxed for twenty-four hours. The gummy solid was collected by concentration in vacuo and then added to concentrated ammonium hydroxide. The suspension was stirred for twenty minutes, collected by filtration, and suspended in water at 50° C. The solid was collected by filtration, dissolved in methanol, brought to a boil, and charcoal added. The suspension was then filtered through two sheets of filter paper, cooled, and filtered through Celite. Recrystallization from acetonitrile provided 1.0 g of colorless crystals, m.p. 176°-180°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]#[N:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CCN(CC)CC>C(Cl)Cl>[C:14]([CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:12])#[N:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CC#N)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CC#N)C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-cyanopropanoic acid (0.5 g, 2.334 mmol), HATU (0.986 g, 2.59 mmol) and cyclopentanamine (0.461 mL, 4.67 mmol) in DCM (10 mL) was added Et3N (0.651 mL, 4.67 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound (0.61 g, 93%). 1H NMR (400 MHz, CD3OD) δ 1.50 (s, 9 H) 1.57-1.73 (m, 4 H) 1.79-1.87 (m, 3 H) 1.89-2.02 (m, 1 H) 2.05-2.19 (m, 3 H) 2.76-2.95 (m, 1 H) 3.87 (t, J=7.07 Hz, 1 H).
Reaction SMILES: [PH4+].[CH:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=O.[CH2:15]1[O:19][CH2:18][CH2:17][CH2:16]1>>[O:19]1[C:18]2[CH:2]=[C:4](/[C:14](/[CH3:13])=[CH:2]/[C:4]3[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=3)[CH:5]=[CH:16][C:17]=2[CH2:8][CH2:7][CH2:6][CH2:15]1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: [PH4+]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)OCCCC3)cc1

Procedure:
4.9 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol were dissolved in 50 ml of acetonitrile and treated with 13 g of triphenylphosphine hydrobromide. The reaction mixture was stirred at 40° C. for 24 hours. Thereafter, the majority of the solvent was removed under reduced pressure and the residue was partitioned between hexane and ethanol/water (8:2). The heavy phase was evaporated and dried, whereby 11.96 g of white phosphonium salt were obtained. 6.29 g of Phosphonium salt were dissolved in 13 ml of butylene oxide, treated with 2.6 g of ethyl 4-formylbenzoate and heated to reflux for 18 hours. Thereafter, the majority of the solvent was removed under reduced pressure and the residue was partitioned between hexane and ethanol/water (8:2). The light phase was dried over magnesium sulfate and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate (97:3)) and recrystallization from hexane yielded 1.4 g of ethyl p-[(E)-2-(2,3,4,5-tetrahydro-1-benzoxepin-8-yl)propenyl]benzoate, m.p. 71°-72° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:22])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoic acid (10 g, 35 mmol) in DMF (50 mL) was treated with cesium carbonate (23 g, 70 mmol) followed by iodomethane (2.2 mL, 35 mmol). The mixture was stirred at rt for 1 h, after which time 50 mL of water was added. A yellow precipitate formed. The solid was collected by filtration, rinsed with water, and dried in vacuo. Desired methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate was obtained as a yellow solid (8.36 g, 27.8 mmol, 80% yield). 1H NMR (400 MHz, d6-DMSO): 8.12 (br s, 2H), 8.10 (d, 1H), 7.78-7.75 (m, 2H), 7.70 (m, 1H), 7.48 (dd, 1H), 7.10 (d, 1H), 3.64 (s, 3H); MS (EI) for C15H12N2O5: 323 (MNa+).
Reaction SMILES: ClC(OCC)=O.CN1CCOCC1.COC(C=C([NH:21][C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:23]([O-:25])=O)C)=O.[Na+].[CH3:34][C:35]1([CH3:47])[S:39][C@@H:38]2[C@H:40]([NH2:43])[C:41](=[O:42])[N:37]2[C@H:36]1[C:44]([OH:46])=[O:45].Cl>CC(C)CC(=O)C.O>[CH3:34][C:35]1([CH3:47])[S:39][C@@H:38]2[C@H:40]([NH:43][C:23]([C@H:22]([NH2:21])[C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)=[O:25])[C:41](=[O:42])[N:37]2[C@H:36]1[C:44]([OH:46])=[O:45]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: COC(=O)C=C(C)N[C@@H](C(=O)[O-])c1ccc(O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
Meanwhile, 4-methylpentan-2-one (70 ml) was stirred and cooled to 0° and ethyl chloroformate (2.0 ml, 0.0208 mole) and a 1% solution of N-methylmorpholine in 4-methylpentan-2-one (3 ml) was added. The solution was cooled to -5° and sodium (R)-N-(1-methoxycarbonyl propen-2-yl)-α-amino-p-hydroxyphenylacetate (5.87 g, 0.02 mole) was added. The suspension was stirred at 0° to -5° for 30 minutes, cooled to -30° and then added to the solution of 6-APA prepared above. The mixture was stirred at -30° for 45 minutes when water (50 ml) was added. The stirred two-phase mixture was acidified to pH 1.1 with concentrated hydrochloric acid and stirred at 0° to 2° for 75 minutes, during which time a white precipitate separated. The mixture was adjusted to pH 5.2 with 10% aqueous potassium hydroxide solution, and the white suspension was stirred and cooled to 0° for 1 hour and filtered. The filter was washed with ice-cold water (20 ml) and ethyl acetate (20 ml), and the solid was air dried at 35° to give amoxycillin trihydrate (6.33 g, 75.5% th.), [α]D25 + 237° (c 0.9; 0.1 N HCl).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:30]=[CH:29][C:14]([O:15]C2C=C(N3CC4CC3CN4)C=NC=2)=[CH:13][CH:12]=1.COC1C=CC([O-])=CC=1.[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:14]2[CH:29]=[CH:30][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(Oc2cncc(N3CC4CC3CN4)c2)cc1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1

Procedure:
In an alternative approach to the synthesis of pyridine-substituted pyridyl diazabicyclic compounds, 3,5-dibromopyridine can be converted into the corresponding 3-bromo-5-alkoxy- and 3-bromo-5-aryloxypyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This is exemplified by the preparation 2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with (1S,4S)-N-(tert-butoxycarbonyl)-2,5-diazbicyclo[2.2.1]heptane in the presence of sodium tert-butoxide and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl in toluene provides (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane. Removal of the N-tert-butoxycarbonyl group, using trifluoroacetic acid, produces (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[OH:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].CN1CCCC1=O>O>[F:20][C:17]1[CH:18]=[CH:19][C:14](/[CH:13]=[CH:12]/[CH:11]=[CH:10]/[CH2:9][O:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])=[CH:15][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccc(C=CC=CCBr)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OC/C=C/C=C/c1ccc(F)cc1
Reaction time: 24 h
Yield: 57 %

Procedure:
8.3 ml (60 mmol ) of triethylamine were added dropwise at about 20° C. to a mixture of 10.4 g (43 mmol) of 1-bromo-5- (4-fluorophenyl)-2,4-pentadiene, 9.8 g (60 mmol) of N-hydroxyphthalimide and 45 ml of N-methyl-pyrrolidone. The mixture was stirred for 24 hours and then poured into 200 ml of water and extracted several times with ethyl acetate, after which the combined organic phases were washed with 5% by weight aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution. After drying with magnesium sulfate and removal of the solvent, the residue was recrystallized from 70 ml of ethanol. Yield: 57%. Melting point: 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].[N:12]1([CH2:17][C:18]2[CH:23]=[C:22](C3C=CC(O)=CC=3)[C:21]([C:31]#[N:32])=[CH:20][CH:19]=2)[CH:16]=[N:15][CH:14]=[N:13]1>>[N:12]1([CH2:17][C:18]2[C:23]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:22][C:21]([C:31]#[N:32])=[CH:20][CH:19]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(O)cc1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: N#Cc1ccc(Cn2cncn2)c(-c2ccc(O)c(Cl)c2)c1

Procedure:
The title compound was prepared from 15 and 3-chloro-4-hydroxyphenylboronic acid using similar conditions to those described for the synthesis of 19. Chromatography (EtOAc) eluted 52 as a white crystalline solid (0.089 g, 46%), mp 243-245° C.; 1H NMR δH (270 MHz, DMSO-d6) 5.46 (s, 2H), 7.05 (d, J=8.4 Hz, 1H), 7.15-7.23 (m, 2H), 7.44 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.80 (dd, J=1.7 Hz, 7.9 Hz, 1H), 7.98 (s, 1H), 8.43 (s, 1H) and 10.51 (br s, 1H); LCMS (APCI−) m/z (rel intensity) 311 (35, [37CIM+H]−), 309 (100, [35CIM+H]−); HRMS (ES+) m/z calcd. for C16H12ClN4O [M+H]+: 311.0694, found 311.0689.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[F:32][C:30]1[CH:29]=[CH:28][C:27]([N+:33]([O-:35])=[O:34])=[C:26]([CH:31]=1)[O:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
LiHMDS 1M solution in THF (6.4 ml) was added into a solution of (S)-1-Boc-3-hydroxypiperidine (1.3 g) in anhydrous THF (20.0 ml). The reaction was stirred at 0° C. for 0.5 h. Then 2,4-difluoro-1-nitro-benzene (703 μl) was added in a single portion. The reaction was allowed to warm to room temperature overnight when TLC indicated the consumption of the starting material. The reaction was quenched by addition of sat NH4Cl (5.0 ml) and diluted with EtOAc (100.0 ml). The organic layer was washed with sat. NH4Cl (50.0 ml) and the aqueous back extracted with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography to give the intended product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[Br:12][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:11])=[CH:6][C:7]=1[OH:10]
Reactant: CC(C)c1ccc(O)cc1O
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1cc(Br)c(O)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
4-isopropyl-benzene-1,3-diol (IMO-a: 9.13 g, 60 mmol) and benzyltrimethyl ammoniumtribromide (24.6 g, 63 mmol) and methylene chloride 250 mL were placed in a 500 mL three-neck flask and were stirred at room temperature for 4 hours. After the reaction was finished, the reaction mixture was washed twice with saturated ammonium chloride and once with saturated sodium chloride, and then dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column chromatography to obtain the title compound (IM1-a: 10.5 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1nc(Cl)ccc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Temperature: 120 °C
Yield: 92 %

Procedure:
A mixture of 3-amino-6-chloropicolinamide (2 g), potassium carbonate (3.2 g), tetrakis(triphenylphosphine) palladium (0.674 g) and 4-fluorophenylboronic acid (1.79 g) in DMF (50 mL) and water (10 mL) was heated to 120° C. for 16 hours. Solvents were removed and 1N HCl (30 ml) was added to the mixture. The resulting solid was filtered to provide 2.48 g of 3-amino-6-(4-fluorophenyl)picolinamide which was characterized by its mass spectrum as follows: MS (m/z) 232 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[C:3]([NH:5][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[NH:2])[NH2:4]
Reactant: N=C(N)N
Reactant: O=C(Cl)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A four neck flask (3 liters) equipped with a thermometer and a stirrer was charged with 573.2 g (6.0 mole) of guanidine hydrochloride and 1.5 liter of methanol and cooled to 20° C. Slowly dropwise added thereto was 324.1 g (6.0 mole) of sodium methoxide crystal at 20° C. or lower and stirred for 3 hours. Deposited crystals were filtered off. The mother liquor was charged to the four neck flask (3 liters) equipped with the above devices, and 337.4 g (2.4 mole) of benzoyl chloride was slowly dropwise added at 15° C. or lower and stirred for 12 hours. Deposited crystals were filtered off, and the mother liquor was concentrated under reduced pressure to obtain white crystals. The resulting crystals were sufficiently washed with 3 liters of deionized water and dried under reduced pressure, whereby the intended compound (white crystals) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@@H:10]1[CH2:13][C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH2:11]1.Cl.C(OCC)C>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@@H:10]1[CH2:11][C@H:12]([NH2:14])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](Oc2cccc(Cl)c2Cl)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@H]1C[C@@H](Oc2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 197 %

Procedure:
To 1,1-dimethylethyl {cis-3-[(2,3-dichlorophenyl)oxy]cyclobutyl}carbamate (5.21 g, 15.68 mmol) was added hydrochloric acid in dioxane (4M, 40 mL, 160 mmol) and the reaction mixture stirred in a sealed vessel at room temperature for 1 hour. The mixture was diluted with dioxane (300 mL) and stirred for a further 5 hours. Diethyl ether (300 mL) was then added and the solid collected by filtration and dried under high vacuum overnight to give the title compound (4.149 g)
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH3:13])(=O)C.[OH-].[Na+]>C(O)C.O>[CH3:14][CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5][OH:4]
Reactant: CCC/C=C\CC(C)CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC/C=C\CC(C)CCO
Yield: 91.8 %

Procedure:
In the next step, 55.0 g (278 mmol) of this (5Z)-3-methylnon-5-enyl acetate was dissolved in 600 mL of a 1:1 mixture of ethanol and water. With vigorous stirring, 55.5 g (1.39 mol) of sodium hydroxide was added, and the reaction mixture was subsequently heated to reflux for 3 h. After the reaction mixture had cooled to room temp., the ethanol was removed in a rotary evaporator under reduced pressure, and the resulting residue diluted with 300 mL of water. The crude product was extracted twice with 500 mL of ether each, and the combined organic extracts were washed twice with 300 mL of brine. After drying with sodium sulphate and removal of the solvent under reduced pressure, the resulting residue (51.2 g) was purified by flash chromatography (1.00 kg of silica gel, pentane/ether, 9:1, Rf=0.11) to provide 39.9 g (92%) of (5Z)-3-methylnon-5-en-1-ol as a colourless liquid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:41]2[CH:42]=[CH:43][C:38]([O:37][C:36]([F:48])([F:47])[F:35])=[CH:39][CH:40]=2)[CH:15]=1)[C:4]([OH:34])=[O:3]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(OC(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-trifluoromethoxy-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.87-0.98 (m, 6H), 1.56 (dt, J=13.39, 6.63 Hz, 1H), 1.75 (dt, J=13.76, 6.94 Hz, 1H), 1.98-2.08 (m, 1H), 3.84 (t, J=7.83 Hz, 1H), 7.36 (t, J=8.56 Hz, 2H), 7.64 (d, J=5.62 Hz, 2H), 7.70-7.80 (m, 5H), 7.84-7.89 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])#[N:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[N:1]=[C:2]3[CH:3]([C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]3)[CH:17]([C:16]3[CH:19]=[CH:20][C:13]([C:11]#[N:12])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: N#Cc1ccc(C=O)cc1[N+](=O)[O-]
Product: CC1(C)CC(=O)C2C(=NC3=C(C(=O)CC(C)(C)C3)C2c2ccc(C#N)c([N+](=O)[O-])c2)C1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-cyano-3-nitrobenzaldehyde in an analogous manner to that described in Example 1 gave 4-(2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-1,8-dioxo-1H-acridin-9-yl)-2-nitrobenzonitrile. Crystallization from methanol gave a yellow crystalline solid of melting point 274-275° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][N:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:40]=[C:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:38][N:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1noc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.24 g), potassium carbonate (0.94 g), 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (0.68 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.79 g, 45%).