Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2]
Reactant: CCC1(c2cccc(O)c2)CCCCNC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC1(c2cccc(OCc3ccccc3)c2)CCCCNC1=O

Procedure:
To a solution of 3-ethyl-3-(3-hydroxy-phenyl)-azepan-2-one (Example 8, Step B) (1.28 g, 0.0055 mol) in DMF (50 mL) was added Cs2CO3 (1.79 g, 0.055 mmol) and benzyl bromide (0.653 mL, 0.0055 mmol) at ambient temperature. After 1.5 h the reaction was concentrated to remove most of the DMF and the residue was partitioned between EtOAc and H2O. The aqueous layer was washed with EtOAc, the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([CH2:48][C:49](O)=[O:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:49](=[O:50])[CH2:48][C:45]2[CH:46]=[CH:47][C:42]([CH3:52])=[CH:43][CH:44]=2)[C:7]1=[O:12]
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CC(=O)Nc2cccc3c(=O)n(CCN(C)C)ccc23)cc1
Yield: 27.5 %

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), p-tolylacetic acid (39 mg, 0.26 mmol) and DIPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 18 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2 gradient) gave N-[2-(2-Dimethylamino-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-2-p-tolyl-acetamide as a white solid (20 mg, 0.055 mmol, 27%).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][NH:7][C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>CC(O)C>[CH3:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S,5S)-tert-butyl 2,5-dimethyl-4-(3-nitropyridin-4-yl) piperazine-1-carboxylate. To a solution of (2S,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate hydrochloride (1.17 g, 4.67 mmol, Acesys Pharmatech, A1653, Sample ID 119-99-18) in 2-Propanol (20 mL) was added 4-chloro-3-nitropyridine (1.11 g, 7.00 mmol, Alfa Aesar, Ward Hill, Mass.) and DIPEA (4.06 mL, 23.33 mmol). The mixture was heated and stirred at 85° C. for 2 h. Additional DIPEA (0.81 mL, 4.67 mmol) was added and the heat was raised to 90° C. The mixture was stirred at this temperature for 18 h. The mixture was then cooled to RT and concentrated. The residue was diluted with EtOAc (150 mL) and washed with water (15 mL) followed by brine (15 mL) and then dried over MgSO4. The crude material was purified by silica gel chromatography (30-70% EtOAc in hexanes) to afford (2S,5S)-tert-butyl 2,5-dimethyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (918 mg, 2.73 mmol, 59% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 337.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1 H), 8.38 (d, J=5.9 Hz, 1 H), 6.99 (d, J=6.1 Hz, 1 H), 4.12 (dd, J=14.0, 4.4 Hz, 1 H), 3.99-4.07 (m, 1 H), 3.94 (dt, J=10.8, 5.5 Hz, 1 H), 3.23 (dd, J=13.5, 9.4 Hz, 1 H), 2.98 (dd, J=14.1, 10.8 Hz, 1 H), 2.77 (dd, J=13.5, 5.7 Hz, 1 H), 1.46 (s, 9 H), 1.16 (d, J=6.3 Hz, 3 H), 1.13 (d, J=6.1 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[NH:4][C:5](=[O:21])[CH:6]([C:8](=[O:20])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:18][CH3:19])=[CH:11][CH:10]=1)Br.[K].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12>CN(C)C=O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[NH:4][C:5](=[O:21])[CH:6]([C:8](=[O:20])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:18][CH3:19])=[CH:11][CH:10]=1)[N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37]
Reactant: COc1ccc(C(=O)C(Br)C(=O)Nc2ccccc2Cl)cc1[N+](=O)[O-]
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C(C(=O)Nc2ccccc2Cl)N2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]

Procedure:
A mixture of 30 g of 2'-chloro-4-methoxy-5-nitro-α-bromo-benzoylacetanilide and 39 g of phthalimide potassium was stirred in 400 ml of dimethylformamide for 3 hours at room temperature. The reaction product was treated as in Synthesis example 1. Upon recrystallizing the product from methyl cellosolve, 14 g of the Coupler 33 having a melting point of 203°-205° C. was obtained.
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[N:5]=[C:4]1[CH3:12]>CO>[CH3:2][N:3]1[CH:7]=[C:6]([S:8]([NH2:1])(=[O:10])=[O:9])[N:5]=[C:4]1[CH3:12]
Reactant: N
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: CO
Product: Cc1nc(S(N)(=O)=O)cn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A 7 mol/L solution of ammonia in methanol (2 mL) was added to 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (200 mg, 1.7 mmol) and the mixture was stirred at room temperature for 4 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and thereby 1,2-dimethyl-1H-imidazole-4-sulfonamide (Compound FG) (54 mg, yield: 60%) was obtained.
Reaction SMILES: C=CCCCCCC.[C:9]([OH:24])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCCCC.OO>>[CH2:9]1[O:24][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: OO
Solvent: C=CCCCCCC
Product: CCCCCCC1CO1
Yield: 51 %

Procedure:
To a mechanically stirred suspension (50° C.) of immobilized C. antarctica lipase (1 g, according to example 1) in 1-octene (15 ml, ca. 95.4 mmol) containing myristic acid (4.356 g, 19.1 mmol) was hydrogen peroxide (8 ml 60% (w/v)) added in four equal portions after 0, 1.5, 3 and 4.5 hours (140 mmol in all). After 6 hours 51% octene oxide was formed as determined by gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([O-])=[O:13].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([CH:12]=[O:13])=[C:6]([F:8])[CH:7]=1
Reactant: O=C[O-]
Reactant: COc1cc(I)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1Cl
Yield: 29.7 %

Procedure:
A mixture of 36.3 g of 2-chloro-4-fluoro-5-iodo-1-methoxybenzene, 12.9 g of sodium formate, 1.78 g of dichlorobis(triphenylphosphine) palladium, and 113 ml of N,N-dimethylformamide was stirred, while bubbling carbon monoxide at 90° to 100° C. over 12 hours. After completion of the reaction, the reaction mixture was returned to room temperature, followed by dilution with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.09 g (yield, 30%) of 4-chloro-2-fluoro-5-methoxybenzaldehyde.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[CH2:16]([O:19][C:20]1([CH3:49])[CH2:25][CH2:24][N:23]([C:26]2[N:31]3[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Br:41])[CH:36]=4)[CH:34]=[C:30]3[N:29]=[C:28]([CH3:42])[C:27]=2[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22][CH2:21]1)[CH:17]=[CH2:18].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[CH2:16]([O:19][C:20]1([CH3:49])[CH2:25][CH2:24][N:23]([C:26]2[N:31]3[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Br:41])[CH:36]=4)[CH:34]=[C:30]3[N:29]=[C:28]([CH3:42])[C:27]=2[CH:43]([OH:14])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22][CH2:21]1)[CH:17]=[CH2:18]
Reactant: C=CCOC1(C)CCN(c2c(CC(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: C=CCOC1(C)CCN(c2c(C(O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1M KHMDS/THF (49.3 mL, 49.3 mmol) in THF (150 mL) at −78° C. was added dropwise a THF (100 mL) solution of ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (20 g, 37.9 mmol) over 5 min. After 30 min, a THF (100 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (12.88 g, 49.3 mmol) was added and stirred for additional 30 min at −78° C. Then, the resulting dark reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage(5-50% EtOAc/hexane) to afford ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (17 g, 31.3 mmol, 82% yield) as white foam. Impurities were present by NMR. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.16 (t, J=1.7 Hz, 1H), 7.99-7.92 (m, 1H), 7.58-7.50 (m, 2H), 7.34 (t, J=7.9 Hz, 1H), 6.83 (s, 1H), 6.18-6.06 (m, 1H), 5.57 (d, J=5.4 Hz, 1H), 5.48 (d, J=17.0 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.83 (br. s., 2H), 4.35 (dq, J=10.8, 7.1 Hz, 1H), 4.23 (dq, J=10.9, 7.1 Hz, 1H), 4.06-3.99 (m, 2H), 2.65 (s, 3H), 2.00 (d, J=14.2 Hz, 2H), 1.84 (d, J=13.4 Hz, 2H), 1.36 (s, 3H), 1.29-1.26 (m, 3H). LCMS (M+H)=545.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2sc1=O

Procedure:
7-(3,5-Bis-trifluoromethyl-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3,5-Bis-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.47 (d, 1H), 8.03 (s, 2H), 7.937 (s, 1H), 7.66-7.56 (m, 2H), 4.03 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:16](=[O:18])[CH3:17])[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Commercially available 2-amino-4-chloropyridine (50 g, 389 mmol) was dissolved in acetic anhydride (500 mL), triethylamine (271 mL, 1.94 mol) was added at 20° C., and the mixture was stirred at 60° C. for 12 hours. The mixture was cooled to 25° C. and then the solvent was evaporated. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1) and then the target fraction was concentrated under vacuum to obtain the title compound (66 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C@@H:33](O)[CH2:32]2>CC#N.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:33]1[CH:34]2[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]2)[CH2:32]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (2 g, 7.96 mmol) was dissolved in CH3CN (20 ml). Di(1H-imidazol-1-yl)methanone (1.936 g, 11.94 mmol) was added, and the reaction was stirred at RT for 1 hour. (R)-quinuclidin-3-ol (1.518 g, 11.94 mmol) was added, and the reaction was stirred at RT for 3 hours to achieve completion. The solvent was removed under vacuum to give a solid that was dissolved in ethyl acetate (300 ml). The precipitate was filtered, and the organic solution was washed with 60 ml of K2CO3 30%, dried over Na2SO4 and evaporated under vacuum to give a crude, that was crystallized in ethyl acetate to give (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-2-phenylacetate (1.67 g, 5.2 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](SCC)=[CH:6][C:5]2=[O:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:6][C:5]2=[O:15]
Reactant: CCSc1cc(=O)c2cc(Br)ccc2o1
Reactant: C1COCCN1
Product: O=c1cc(N2CCOCC2)oc2ccc(Br)cc12

Procedure:
Prepared from 6-Bromo-2-ethylsulfanyl-chromen-4-one (0.375 g, 1.35 mmol) and morpholine (0.54 ml, 6.25 mmol), affording a pale yellow solid. (0.0354 g, 1.14 mmol, 84%); m.p. 147-149° C.; ES+(m/e)=310.24 (M++1); (200 MHz, CDCl3) δ3.44 (4H, m); 3.77 (4H, m); 5.42 (1H, s); 7.11 (1H, d); 7.57 (1H, dd); 8.20 (1H, d)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[O:18][C:17]([C:19]3([CH3:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:16][C:15]=2[CH3:26])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[NH:5].N1C=CC=CC=1.[C:33]1([O:39]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[O:18][C:17]([C:19]3([CH3:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:16][C:15]=2[CH3:26])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:33](=[O:39])[O:7][N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nc(C2(C)CCCCC2)oc1COc1ccc(C(=N)NO)c(Cl)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1nc(C2(C)CCCCC2)oc1COc1ccc(-c2noc(=O)[nH]2)c(Cl)c1
Temperature: 25 °C

Procedure:
1.39 g 2-Chloro-N-hydroxy-4-[4-methyl-2-(1-methyl-cyclohexyl)-oxazol-5-ylmethoxy]-benzamidine were dissolved in 10 ml dichloromethane. 0.36 ml pyridine and 0.56 ml phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 30 ml acetonitrile and 2.75 ml 1,8-Diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 950 mg 3-{2-Chloro-4-[4-methyl-2-(1-methyl-cyclohexyl)-oxazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C3CCSCC3)sc2CC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acid (1.00 g) synthesized above, ethyl β-alaninate hydrochloride (415 mg), 1-hydroxybenzotriazole monohydrate (414 mg) and triethylamine (376 μL) in N,N-dimethylformamide (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (518 mg), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (1.06 g, 87%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:21]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]3[CH2:18][CH:17]([CH2:20]3)[C:8]3[N:9]([CH3:22])[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1ccc(I)cc1-2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1ccc(I)cc1-2
Temperature: 40 °C
Yield: 18.1 %

Procedure:
To a solution of ethyl 9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (500 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) was introduced potassium carbonate (175 mg, 1.27 mmol) and methyl iodide (270 mg, 1.90 mmol). The reaction mixture was warmed to 40° C. for 3 hr. After concentration of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2×10 mL), water (10 mL) and brine (10 mL). The organic extract was filtered at this stage to furnish the title compound (94 mg, 0.23 mmol) as a colorless solid of high purity. Following drying over sodium sulfate, the filtrate was re-filtered and concentrated in vacuo to furnish additional title compound of slightly lower purity (395 mg at 93% purity LC-UV215). This material was carried through to the next synthetic step without further purification. The higher purity batch was analysed for characterisation purposes: 1H NMR (500 MHz, CDCl3) δ 1.49 (t, J=7.09 Hz, 3H), 1.68-1.74 (m, 2H), 2.89-2.99 (m, 2H), 3.50 (td, J=7.49, 3.94 Hz, 1H), 3.60 (td, J=8.28, 3.63 Hz, 1H), 3.95 (s, 3H), 4.47 (q, J=7.04 Hz, 2H), 6.80 (d, J=7.88 Hz, 1H), 7.41 (dd, J=7.88, 1.89 Hz, 1H), 8.82 (s, 1H); M+1=409.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[N:18]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:32].[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34]>O1CCCC1>[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH:24]=[C:37]([C:36]1[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=1[C:33]#[N:34])[OH:38])[N:18]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:32]
Reactant: Cc1ncccc1-n1c(C)nc2ccc(F)cc2c1=O
Agent: COC(=O)c1ccccc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ncccc1-n1c(C=C(O)c2ccccc2C#N)nc2ccc(F)cc2c1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28.
Reaction SMILES: [C:1]([C:4]1([OH:25])[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:23])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:22])=[C:8]([OH:24])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1CNC(=O)C1.[Br:32][Br-]Br>O1CCCC1>[Br:32][CH2:2][C:1]([C:4]1([OH:25])[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:23])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:22])=[C:8]([OH:24])[C:7]=2[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)C1(O)CCc2c(cc3c(c2O)C(=O)c2ccccc2C3=O)C1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2c1cc1c(c2O)CCC(O)(C(=O)CBr)C1
Yield: 92.2 %

Procedure:
Reaction of 9-acetyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (690 mg) with pyrrolidone hydrotribromide (1.15 g) was effected in tetrahydrofuran (70 ml) at room temperature for 40 hours. After removing insoluble matters by filtration, the solvent was distilled off under reduced pressure to give yellow crystals (785 mg, 92%) of 9-bromoacetyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 179°-180° C.