Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7]CO)(=O)[C:2]([CH3:4])=[CH2:3].[C:10](N)(=O)[CH:11]=[CH2:12].[CH2:15]([C:19](=[CH2:23])[C:20](N)=[O:21])[CH2:16][CH2:17][CH3:18]>>[CH3:7][O:6][CH:1]([C:2]1[CH:3]=[CH:12][CH:11]=[CH:10][CH:4]=1)[C:20](=[O:21])[C:19]1[CH:23]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C)C(=O)OCCO
Reactant: C=CC(N)=O
Reactant: C=C(CCCC)C(N)=O
Product: COC(C(=O)c1ccccc1)c1ccccc1

Procedure:
30 g. of the resulting prepolymer were thoroughly mixed with 10 g. of 2-hydroxyethyl methacrylate, 2 g. of acrylamide, 1 g. of n-butyl acrylamide and 0.8 g. of benzoin methyl ether to give a uniform photosensitive composition. The resulting photosensitive composition was photopolymerized in the same manner as in Example 1 to give a photopolymerized article.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH2:67]([O:74][NH2:75])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:24])[NH:75][O:74][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[CH:25][CH:26]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
The acid compound 4 (0.6 g, 1.22 mmol) was dissolved in dry DMF (15 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.18 g, 1.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.22 mmol), and triethylamine (0.6 mL, 3.66 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.22 g, 1.34 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was extracted with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), water (1×25 mL) and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography using hexanes-ethyl acetate (1:1) yielded the desired benzyl hydroxamate 7 (0.4 g, 56%). 1H NMR (DMSO-d6): 11.73 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.29-7.47 (m, 13H), 6.99 (d, J=8.8 Hz, 2H), 6.99 (5.12 (s, 2H), 4.92 (s, 2H), 4.23-4.28 (m, 1H), 3.03 (dd, J=13.6 and 5.2 Hz, 1H), 2.90 (dd, J=13.6 and 10.0 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: CO[C:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])=O.[CH2:19](S)[CH2:20]C>CO>[CH2:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])[CH2:19][CH3:20]
Reactant: CCCS
Reactant: COC(=O)SSCC(=O)NC(CC(=O)O)C(=O)O
Solvent: CO
Product: CCCSSCC(=O)NC(CC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A flask was charged with 400 mg (1 eq., 1.5 mmole) of (methoxycarbonyldithio)ethylamidosuccinic acid dissolved in 5 ml methanol, cooled to 0° C., purged with argon, and then treated dropwise with a solution of 135.3 ml (114 mg, 1 eq., 1.5 mmole) propanethiol (purchased from Aldrich) in 4 ml of methanol over a 30 min. period. The reaction was then allowed to warm to room temperature and stirred for 18 hours. The volatiles were then removed by vacuum transfer and the residue applied to a flash silica gel column, eluting with 10% methanol/methylene chloride. 1H NMR (d6DMSO/TMS) δ: 0.92 (3H, t, CH3), 1.61 (2H, m, CH2), 2.30 (2H, m, CH2), 2.39 (2H, m, CH2), 2.69 (2H, m, 2× CH2), 3.31 (2H, m, 2× CH2), 8.03 (1H, t, NH), 12.05 (1H, br. s, CO2H). 13C NMR (d6DMSO/TMS) δ: 173.65 (Q), 170.97 (Q), 39.83 (CH2), 38.00 (CH2), 37.10 (CH2), 29.88 (CH2), 28.99 (CH2), 21.74 (CH2), 12.67 (CH3. 1H NMR (CD3OD/TMS) δ: 0.98 (3H, t, J=7.33 Hz, CH3), 1.69 (2H, h, J=7.22 Hz, CH2), 2.47 (2H, m with fine splitting, CH2), 2.56 (2H, m with fine splitting, CH2), 2.68 (2H, t, J=7.15 Hz, CH2), 2.77 (2H, t, J=6.84 Hz, CH2), 3.46 (2H, t, J=6.84 Hz, CH2). 13C NMR (CD3OD/TMS) δ: 176.72 (Q), 174.75 (Q), 41.87 (CH2), 39.87 (CH2), 38.42 (CH2), 31.77 (CH2), 30.72 (CH2), 23.47 (CH2), 13.40 (CH3).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[NH:11][CH2:12][CH3:13].C([CH:17]([C:21](Cl)=[O:22])[C:18](Cl)=[O:19])C.[CH2:24]([O:26]CC)[CH3:25]>>[CH2:24]([O:26][C:21]([C:17]1[C:18](=[O:19])[N:11]([CH2:12][CH3:13])[C:5]2[C:4]([C:3]=1[OH:14])=[CH:9][CH:8]=[C:7]([CH3:10])[N:6]=2)=[O:22])[CH3:25]
Reactant: CCNc1nc(C)ccc1C(=O)OC
Reactant: CCOCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.98 g. (0.02 mole) of 2-ethylamino-6-methylnicotinic acid methyl ester in 50 ml. of anhydrous diethyl ether was added 1.5 g. (0.01 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was added to a solution of 0.23 g. of sodium in 50 ml. of absolute ethanol and was warmed for 5 minutes. The mixture was cooled and the insoluble material was collected and was dissolved in water. Acidification of the water solution with glacial acetic acid afforded a precipitate which was collected, air dried and was recrystallized from heptane to give 1.2 g. of product, m.p. 147°-151° C.
Reaction SMILES: [H-].[Na+].[H][H].[Br-].[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:8])=[O:7].[CH:32]12[CH2:40][CH:39](O)[O:38][CH:37]1[CH2:36][CH2:35][CH:34]=[CH:33]2>CS(C)=O.O>[OH:38][CH:37]1[CH:32]([CH2:40]/[CH:39]=[CH:12]\[CH2:11][CH2:10][CH2:9][C:6]([OH:8])=[O:7])[CH:33]=[CH:34][CH2:35][CH2:36]1
Reactant: OC1CC2C=CCCC2O1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC/C=C\CC1C=CCCC1O
Temperature: 0 °C
Yield: 60.9 %

Procedure:
A 12.5 g (296 mmol) portion of sodium hydride (57% oil dispersion) was heated with 95 ml of dry dimethylsulfoxide (DMSO) under argon at 65°-75° for ca. 2.5 hr until hydrogen evolution had ceased. The mixture was stirred with ice-water cooling as 48.3 g (109 mmol) of 4-carboxybutyltriphenylphosphonium bromide (Aldrich) was added as a solid. The resultant deep red mixture was stirred at 0° for several minutes, then at room temperature until most of the salts had dissolved (1 hr.). A solution of 12.2 g (87.1 mmol) of 7-oxabicyclo[4.3.0]non-2-en-8-ol in 10 ml of dry DMSO was added dropwise over 2 hr to the vigorously stirred ylide solution. The resultant dark mixture was stirred for 20 hr at room temperature. Water (200 ml) was added then and the resultant mixture was extracted three times with ethyl acetate and these extracts were discarded. The remaining aqueous phase was acidified with concentrated hydrochloric acid and then extracted four times with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated in vacuo. The resultant residue was evaporated at 0.1 mm as the pot was warmed to 50° and the receiver flask was cooled in an acetone-dry bath. The yield of crude orange oil was 32.5 g (theoretical yield 19.5 g) and contained in addition to the desired product, considerable aromatic byproduct as evidenced from an nmr spectrum of this oil. This oil was extracted several times with warm ether-pentane (1:1). The combined extracts were dried (MgSO4) and evaporated in vacuo to give 11.9 g of 7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid. A portion of this product was purified by column chromatography on silicic acid-Celite (85:15) using benzene to ethyl acetate gradient elution to obtain pure 7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH2:28][CH2:29][CH3:30])[NH2:26])([CH3:22])([CH3:21])[CH3:20]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:26][C@@H:25]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: CCCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and the norleucine tert-butyl ester hydrochloride, the title compound was prepared as a semi-solid. The reaction was monitored by tlc (Rf=0.41 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent, followed by preparative plate chromatography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH2:12][CH3:13].[Li]C(C)(C)C.[C:19](=[O:21])=[O:20]>C(OCC)C.CCCCC>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=2)[NH:7][N:6]=1)[CH2:12][CH3:13]
Reactant: O=C=O
Reactant: CCCc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCCc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To 5-bromo-3-propyl-1H-indazole (1.00 g, 4.18 mmol) in diethyl ether (60 mL), 1.3 M t-BuLi (10.9 mL, 14.2 mmol) in pentane was added slowly at −78° C. under N2 atm. After 1 hour, CO2 gas was passed through the reaction mixture at −78° C. for 1 hour and allowed to slowly warm to room temperature. The reaction mixture was quenched with saturated NH4Cl solution and the ether layer was separated. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate to afford the title compound (350 mg, 40.8%) as an off white solid. 1H NMR (DMSO-d6): δ 11.8-13.0 (br, 1H), 8.4 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 3.0 (q, 2H), 1.8 (q, 2H), 0.9 (t, 3H). mp: 296-299° C.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].[CH2:14]([SH:16])[CH3:15]>>[CH2:14]([S:16][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13])[CH3:15]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: CCS
Product: CCSc1c(C=O)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method D was followed. 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.303 g, 1.50 mmol) and ethanethiol were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (1:1) as the eluent.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:34])[CH2:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:34])[CH2:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(COc1ccc(C(=O)OCc2ccccc2)cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added benzyl 4-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 215 mg of the title compound (77%) as a orange powder in 98.3% purity by HPLC (Rt: 5.16, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH:24]=[N:23][C:22]2[CH:29]=[CH:30][CH:31]([CH3:34])[C:32](=O)[C:21]1=2.C[OH:36].C(Cl)(Cl)Cl>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]2[C:26](=[O:36])[C:25]([CH3:28])([CH3:27])[CH:24]=[N:23][C:22]3[CH:29]=[CH:30][CH:31]([CH3:34])[CH2:32][C:21]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CO
Reactant: CC1C=CC2=C(C1=O)C(N)CC(C)(C)C=N2
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1C=CC2=C(C1)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)C(C)(C)C=N2

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3) and crystallization from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:13][CH2:14][C:15]2([CH3:31])[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]3)[CH2:16]2)[C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[CH:32](OC)(OC)OC.C(O)=O.C(O)(C(F)(F)F)=O>CO.[Fe]>[Cl:1][C:2]1[C:9]2[N:10]=[CH:32][N:13]([CH2:14][C:15]3([CH3:31])[CH2:30][CH2:29][CH2:28][C:17]4([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:18]4)[CH2:16]3)[C:8]=2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CNc3cc(C#N)cc(Cl)c3[N+](=O)[O-])C2)OC1=O
Agent: [Fe]
Solvent: CO
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CN1CC2(CCCC(C)(Cn3cnc4c(Cl)cc(C#N)cc43)C2)OC1=O
Temperature: 65 °C
Reaction time: 26 h
Yield: 80.1 %

Procedure:
To an orange suspension containing 3-chloro-5-(((7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.132 g, 0.294 mmol) in MeOH (5.44 mL) was added iron (325 mesh) (0.164 g, 2.94 mmol), trimethyl orthoformate (0.325 mL, 2.94 mmol), and formic acid (0.113 mL, 2.94 mmol). The resulting solution was stirred at 65° C. for 26 h. Additional trimethyl orthoformate (0.325 mL, 2.94 mmol) and formic acid (0.113 mL, 2.94 mmol) was added, and stirring was continued at 65° C. for 24 h. The reaction was cooled to rt and concentrated. The resulting residue was suspended in MeCN (2 mL) and DMSO (4 mL) and filtered through a Hirsch funnel to remove any remaining solids. The filtrate was purified using reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 14 minute run; 25 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 40-90% solvent A) to provide the title compound (0.101 g, 62% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.41 (d, J=1.25 Hz, 1H), 7.81 (d, J=1.25 Hz, 1H), 4.15 (s, 2H), 3.29 (dd, J=9.03, 20.33 Hz, 2H), 2.87 (s, 2H), 1.80 (d, J=13.55 Hz, 1H), 1.49-1.74 (m, 4H), 1.22-1.48 (m, 3H), 1.02 (s, 3H), 0.85 (s, 9H). MS (m/z) 429.2 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH3:14])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH:15]2[CH2:16][CH2:17][CH2:18]2)[CH3:14])[N:12]=1
Reactant: CN(C)C=O
Reactant: CN(c1cncc(Cl)n1)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reaction time: 0.33 h
Yield: 66 %

Procedure:
Phosphoryl chloride (4.3 mL) was added dropwise to DMF (20 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 6-chloro-N-cyclobutyl-N-methylpyrazin-2-amine (4.61 g) in DMF (5 mL), and the mixture was stirred at 50° C. for 15 hr. Water was added to the reaction mixture and the mixture was stirred for 2 hr and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10-450% ethyl acetate/hexane) and recrystallized from hexane-diisopropyl ether to give the title compound (3.46 g, 66%).
Reaction SMILES: [CH3:1][C:2]1([CH2:17][C:18]2[N:19]=[CH:20][N:21]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]=2[CH3:23])[C:15](=[O:16])[N:6]2[C:7]3[C:12]([C:13]([CH3:14])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[OH-].[Na+].C([OH:47])C>O1CCOCC1>[CH3:1][C:2]([CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:22]=1[CH3:23])([CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:15]([OH:47])=[O:16]
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C)(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(CCC(C)(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)C(=O)O)[nH]c2ccccc12
Temperature: 90 °C

Procedure:
A mixture of 8,9-dihydro-7,10-dimethyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (3.78 g), aqueous 3N sodium hydroxide solution (10 ml), ethanol (10 ml) and dioxane (5 ml) was heated at 90° C. for 30 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with aqueous oxalic acid solution, and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 2-methyl-4-(3-methylindol-2-yl)-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]butyric acid (3.3 g) as an amorphous powder. The product was used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([I:12])[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([I:12])[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2c1cc(F)c(O)c2I
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1c(F)cc2c(c1I)OCC2=O
Reaction time: 12 h
Yield: 23.7 %

Procedure:
A solution of 5-fluoro-6-hydroxy-7-iodobenzofuran-3(2H)-one (0.256 g, 0.871 mmol) in DMF (5 mL) was added with potassium carbonate (0.110 g, 0.796 mmol). The mixture was added with dimethyl sulfate (0.0803 g, 0.637 mmol) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 5-fluoro-7-iodo-6-methoxybenzofuran-3(2H)-one (0.0582 g, 21%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15]CC)C>CN(C)C=O.CO>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:15][CH3:13])=[CH:3][C:4]=1[CH3:12]
Reactant: CCOCC
Reactant: COC(=O)c1ccc(Br)cc1C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-2-methylbenzoate (19.0 mmol) was dissolved in dimethylformamide (2.7 mL) and methanol (1.1 mL), and the solution was heated at 80° C. and then added with CuBr (1.09 mmol). After stirring was continued for 2 hours under heating, the mixture was cooled to room temperature. The mixture was added with diethyl ether (25 mL) and filtered. The filtrate was washed four times with water, an aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfated. The drying agent was removed by filtration and the filtrate was concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:13])=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A mixture of 5-bromoindole-2-carboxylic acid (5 g, 21 mmol), and 1,1′-carbonyldiimidazole (4.39 g, 27 mmol) in tetrahydrofuran (60 mL) was stirred at room temperature overnight. Morpholine (3.63 mL, 42 mmol) was added and the mixture was stirred for an additional 40 min. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with hydrochloric acid (1N) and brine, then dried over sodium sulfate, filtered and evaporated in vacuo, to give 6.74 g (99%) of the desired compound as a yellow solid which was used without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[OH-].[K+].[CH3:16]I.[ClH:18]>CS(C)=O.O>[ClH:18].[F:1][CH2:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:16]
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C(=O)C(C)(C)CF)n1cncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
37.2 g (0.2 mol) of 1-fluoro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one were dissolved in 200 ml of dimethylsulphoxide, 11.2 g (0.2 mol) of potassium hydroxide, dissolved in 24 ml of water, were added and 28.4 g (0.2 mol) of methyl iodide were added dropwise at 20° C., whilst cooling. The reaction mixture was subsequently stirred at room temperature for 24 hours and poured onto 1,000 ml of water, the mixture was extracted twice with 200 ml of methylene chloride each time, the combined organic phases were washed five times with 100 ml of water each time and dried over sodium sulphate, the solvent was distilled off, the residue was taken up in 100 ml of acetone, the mixture was filtered and the solvent was distilled off from the mother liquor. The residue was taken up in 150 ml of ethyl acetate, and 14.4 g (0.2 mol) of hydrogen chloride were passed in. Thereafter, the mixture was allowed to crystallise out. 33.8 g (72% of theory) of 1-fluoro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one hydrochloride of melting point 142° C. were obtained. ##STR62##