Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](OCCCC)=[O:14]>C1COCC1>[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](=[O:14])[CH2:1][C:2]#[N:3]
Reactant: CCCCOC(=O)C1CC1(F)F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CC1(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of MeCN (1.1 g, 16.8 mmol) in THF (60 mL) was added dropwise n-BuLi in THF (11.2 mL, 40.3 mmol) at −78° C., and the reaction mixture was stirred at −78° C. under N2 for 30 min. Butyl 2,2-difluorocyclopropanecarboxylate (3.0 g, 16.8 mmol) was added at −78° C., and the reaction mixture was allowed to warm to RT over 3 h. The reaction mixture was quenched with water and adjusted to pH 7 with 1N HCl. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile. A mixture of crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile and hydrazine (2.0 g, 50.4 mmol, 85% pure) in EtOH (30 mL) was stirred at reflux for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by chromatography eluting with an EtOAc/petroleum ether gradient (12.5 to 100% EtOAc) to afford 2.1 g (78.5%) of 45 as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 11.40 (br s, 1H), 5.26 (s, 1H), 4.80 (br s, 2H), 2.78-2.66 (m, 1H), 2.04-1.75 (m, 1H), 1.73-1.21 (m, 1H); MS (ESI+) m/z=160.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:23][CH2:22][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:20]([F:21])=[C:12]3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]([N:10]2[CH2:23][CH2:22][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:20]([F:21])=[C:12]3[C:11]2=[O:24])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2c(F)c3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A mixture of 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (800 mg, 2.31 mmol), NaBH4 (263 mg, 6.92 mmol), and methanol (50 mL) was stirred at 0° C. for 1 h. Then the reaction mixture was quenched with water (30 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×30 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified by silica-gel chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 231a (650 mg, 81%) as a yellow solid. MS-ESI: [M+H]+ 340.1
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([C:42](=[O:44])[CH3:43])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: CC(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (200 mg, 0.41 mmol) was dissolved in methylene chloride (5 mL). Triethyl amine (0.173 mL, 1.24 mmol) and acetyl chloride (0.035 mL, 0.49 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and chromatography on silica gel with methylen chloride/triethyl amine 99:1 gave the desired product (122 mg, 56%) as a light yellow foam, MS: m/e=528.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:29](=[O:31])=[O:30]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:29]([OH:31])=[O:30])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A mechanically stirred solution of 63.67 g (300 mmol) of 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine, 115 mL of N,N,N′,N′-tetramethyl-ethylenediamine, and 1.8 L of dry diethyl ether was cooled to −78° C. in a Nestar refrigeration unit. n-Butyl lithium (72 mL of a 10 molar solution in hexanes) was added dropwise at such a rate so as to maintain the internal reaction temperature below −60° C. The resultant red-colored solution was stored at −40° C. for 16 hours, recooled to −78° C., then charged for ca. 20 minutes with dry carbon dioxide gas introduced via a spurge tube with the rate of bubbling adjusted so as to maintain the internal reaction temperature below −40° C. The reaction flask was removed from the bath and allowed to warm to room temperature over ca. 1 hour. The orange mixture was poured into 700 mL of cold dilute aqueous sodium hydroxide (final pH=12.5). The layers were separated, and the aqueous layer was further extracted with 2×400 mL of diethyl ether. The aqueous layer was ice cooled and acidified to ca. pH 6 with aqueous hydrochloric acid. A sticky precipitate was filtered off, then the filtrate was again ice cooled and further acidified to pH 3.0. A light yellow precipitate was collected by filtration, washed with 200 mL of water, then redissolved in 1 L of 5% aqueous sodium hydroxide. Insoluble matter was removed by filtration and the two-stage acidification/precipitation described above was repeated on the filtrate to provide 36.9 g (47%) of the dried product as a beige solid, mp 253-257° C. (dec). 1 H NMR in deuterated dimethylsulfoxide [(CD3)2SO]: δ9.83 ppm (s, 1H), 8.85 (s, 1H), 7.49 (d, JH-F=2.8 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[Cl-].[OH:12][NH3+:13].C(=O)(O)[O-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[N:13][OH:12])[NH2:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: [NH3+]O
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (7.2 mmol) of 3,4-difluorobenzonitrile was initially charged in 30 ml of ethanol, and a solution of 0.5 g (7.2 mmol) of hydroxylammonium chloride and 0.6 g (7.2 mmol) of sodium bicarbonate in 11 ml of water was added at RT. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure and reacted without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[N:12][C:11]=2[CH2:10][CH2:9]1.ClCCl>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[N:12][C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1N1CCc2nnc3c(C)cccc3c21
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-n1ccc2nnc3c(C)cccc3c21

Procedure:
To a refluxing slurry of 10% Pd/C (0.4 g) in diphenyl ether (20 ml) was added 1-(2-methylphenyl)-6-methyl-2,3-dihydropyrrolo [3,2-c]cinnoline (1.25 g, 0.0045 mol). After 0.5 hour at reflux temperature the reaction mixture was cooled, diluted with chloroform and the catalyst was filtered off over hyflo. The product was isolated by column chromatography using dichloromethane (11) then chloroform. The oil obtained was crystallized from ethyl acetate, 0.42 g, m.p. 105-106°.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][O:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[F:14])[CH2:24][CH2:23]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1OCC1CCNCC1
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3F)CC2)n1
Yield: 11.8 %

Procedure:
After dissolving 262 mg of 2-tert-butoxy-6-vinylpyrazine and 401 mg of 4-(2-fluorophenoxymethyl)piperidine [CAS No.63608-34-4] in 3 ml of ethanol, the mixture was stirred for 2 days at 80° C. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (67 mg, 12% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:24]([O-])=O)=[C:11]([CH:13]=[CH:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][N:16]=3)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Sn].Cl>C(O)C>[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH:14]=[CH:13][C:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]=2[NH2:24])=[N:16]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1C=Cc1n[nH]c2ccccc12
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)cc1C=Cc1n[nH]c2ccccc12

Procedure:
In a similar manner to Example 1, (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.12 g, 0.25 mmol) was dissolved in methanol (6.0 mL) and crude 3-{2-[5-(morpholin-4-yl)-2-nitrophenyl]vinyl}-1H-indazole was obtained from 5-morpholino-2-nitrobenzaldehyde (65 mg, 0.25 mmol) and potassium carbonate (0.10 g, 0.75 mmol). In a similar manner to Example 2, crude 3-{2-[5-(morpholin-4-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.80 g, 2.3 mmol) was dissolved in ethanol (25 mL) and the solution was added with tin (0.82 g, 6.9 mmol) and concentrated hydrochloric acid (4.0 mL) and heated from room temperature to 40° C. to obtain 2-[2-(1H-indazol-3-yl)vinyl]-4-(morpholin-4-yl)phenylamine. Further, in a similar manner to Example 29, 2-[2-(1H-indazol-3-yl)vinyl]-4-(morpholin-4-yl)phenylamine (0.45 g, 1.4 mmol) was dissolved in THF (10 mL) and the solution was added with triethylamine (0.61 ml, 4.2 mmol) and 3-methylthiophenecarbonylchloride (0.20 g, 1.4 mmol) and stirred at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to obtain free base of Compound 225. Further, said free base was treated by 4 mol/L hydrogen chloride-methanol solution (1.0 mL) to obtain Compound 225 (0.40 g, 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.C([Li])CCC.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[C:32]1([NH:38][C:39]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.0 g (0.0029 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. The solution was cooled in a dry ice-acetone bath in an argon atmosphere and mixed with 1.9 ml of a 1.69M-hexane solution of n-butyl lithium (0.0029×1.1 mol; hereinafter referred to merely as “BuLi”), followed by stirring for about 10 minutes. After 0.86 g (0.0029×2.5 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of 1.2N aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH2:15]3)[C:12]=2[C:6]2[O:7][CH:8]([CH2:10][NH2:11])[CH2:9][C:5]=2[CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].CC1C=CC(S(OC)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH2:15]3)[C:12]=2[C:6]2[O:7][CH:8]([CH2:10][NH:11][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc2c(c3c1C1CCC3CC1)OC(CN)C2
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c3c1C1CCC3CC1)OC(CNC(=O)OCc1ccccc1)C2
Yield: 92.6 %

Procedure:
Treatment of (±)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine (2.5 g, 8.45 mmol) with diisopropylethylamine (2.73 g, 21.12 mmol) followed by benzyl chloroformate (1.73 g, 10.14 mmol) generally according to the procedure described for Intermediate 7 provided 3.08 g (93%) of (±)-benzyl (5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methylcarbamate as a colorless oil. Chiral HPLC separation of (±)-benzyl (5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methylcarbamate (Chiralcel OJ, methanol) provided two fractions. Fraction 1 (Rt=13.252 min, Chiralcel OJ, methanol); Fraction 2 (Rt=18.196 min, Chiralcel OJ, methanol). Treatment of 0.460 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methylcarbamate (Chiralcel OJ, methanol) with palladium on carbon (10 wt. %, 0.05 g) generally according to the procedure described for Example 2 provided 0.304 g (88%) of (+)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. [α]D5=+40.03 (c 9.99 in methanol); mp>220° C.; Anal. calcd. for C16H21NO2HCl: C, 64.97; H, 7.5; N, 4.74. Found: C, 64.62; H, 7.79; N, 4.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCCO)cc1OC
Product: COc1ccc(CCCCOS(C)(=O)=O)cc1OC
Yield: 78 %

Procedure:
Ester 24 was prepared following procedure E from alcohol 23 (12.0 g, 57 mmol) and methanesulfonyl chloride (8.4 g, 74 mmol) in 78% yield. 1H NMR (300 MHz, CDCl3) δ 1.65 (m, 4H), 2.62 (m, 2H),3.05 (s, 3H), 3.88 (br s, 6H), 4.38 (m, 2H) 6.70-6.88 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12](C)([C:18](OCC)=O)[C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([CH3:18])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1c(F)cc([N+](=O)[O-])cc1F
Yield: 85.1 %

Procedure:
A solution of compound (26b) (7.8 g, 24.9 mmol) in acetic acid (28 mL), and concentrated sulfuric acid (8.0 mL), and water (20 mL) were treated in the same manner as in (b) in Production Example 1 to give 4.9 g (85%) of compound (27b) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:10]=[C:11]([CH2:18][OH:19])[N:12]([CH3:17])[C:13]=2[CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].C(=O)([O-])O.[Na+]>O1CCCC1>[C:22]([O:19][CH2:18][C:11]1[N:12]([CH3:17])[C:13]([CH:14]([CH3:16])[CH3:15])=[C:9]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)(=[O:23])[NH2:24]
Reactant: CC(C)c1c(Sc2cccc(Cl)c2)nc(CO)n1C
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(COC(N)=O)n1C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
In 5 ml of dry tetrahydrofuran was dissolved 200 mg (0.67 mmol) of [4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-38), and 190 mg (1.0 mmol) of trichloroacetylisocyanate was added to the mixture with cooling at -40° C. After 10 minutes, the mixture was warmed to 0° C., and stirred at the same temperature for 10 minutes. To the reaction mixture, ice-water was added, arid then, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and to the residue was added 5 ml of methanol, 0.5 ml of water and 0.5 ml of triethylamine. The mixture was stirred at 50° C. for 30 minutes. To the reaction mixture was added water, extracted with methylene chloride, the extract was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl ace-ate). The product was recrystallized from ethyl acetate/isopropyl ether to give 180 mg of the target compound (Compound I-59) (yield 79%). mp 145-146° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([N:39]1C2=C3C(=CC=[C:42]2[CH:41]=[N:40]1)C(=O)C(I)=C(C1C=CC=CC=1)O3)C>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:40]([CH2:41][CH3:42])[N:39]=[CH:37][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CCn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 84 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 1-ethyl-7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a colourless solid (44.4 mg, 84%). LCMS (Method H): RT=4.50 min, [M+H]+=536.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)c2snc(-c3ccccc3)c2c1O
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (53 mg, 0.139 mmol), Pd(PPh3)4 (16.1 mg, 0.0139 mmol), 4-fluorophenylboronic acid (29.3 mg, 0.209 mmol), K2CO3 (57.8 mg, 0.418 mmol), and 1,4-dioxane (1.39 mL) was heated at 140° C. in a microwave oven with stirring for 5 min. After cooling to r. t., the mixture was filtered and the filter cake was washed with CH2Cl2. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title compound as a white solid (27.6 mg): MS (m/z) 395.2 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[N:13]2)[CH2:10][O:9][CH2:8]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:26][NH:27][CH3:28]>C(#N)C.C(Cl)Cl>[CH3:26][N:27]([CH3:28])[CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[N:13]2)[CH2:10][O:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1(Cn2cc([N+](=O)[O-])cn2)COC1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)CC1(Cn2cc([N+](=O)[O-])cn2)COC1
Temperature: 70 °C
Yield: 14.7 %

Procedure:
(3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methyl methanesulfonate (0.225 g, 0.935 mmol) was suspended in acetonitrile (6 mL) with K2CO3 (0.297 g, 2.15 mmol) and dimethylamine (2M in MeOH, 1.87 mL, 3.75 mmol) in a microwave vial and sealed under Nitrogen. This was heated at 70° C. for 36 h then diluted with DCM (20 mL), washed with water (20 mL) and brine (20 mL). The organics were dried over Na2SO4, filtered and the solvent removed under vacuum. The crude product was purified by prep HPLC to give N,N-dimethyl-1-(3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanamine as a white solid (33 mg, 15% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][C:12](=O)[CH2:13][C:14](=O)[CH2:15][Cl:16])C.S(=O)(=O)(O)O>O>[Cl:16][CH2:15][C:14]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=2)[O:8][C:12](=[O:11])[CH:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2oc(=O)cc(CCl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a mixture of 4-methylphenol (21.6 g, 200 mmol) and 4-chloro-3-oxo-butyric acid ethyl ester (32.9 g, 200 mmol) is added dropwise during 30 min. at 0° C. a mixture of concentrated sulfuric acid (180 mL) and water (60 mL). The resulting clear solution is stirred for 18 h at room temperature, during which time a white precipitate is formed. The reaction mixture is poured over crushed ice (1 kg) and the formed precipitate is collected, washed with water and dried in vacuo at 50° C. to yield the title compound as a white powder (35.8 g, 172 mmol, 86%). 1NMR (400 MHz, CDCl3, 298 K): δ=7.45 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 4.69 (s, 1H), 2.46 (s, 3H).