Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CC[CH:17]([N:20]=[C:21]=NC2CCCCC2)CC1.CNC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:11])[N:20]([CH3:21])[CH3:17])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a solution of (R)-2-tert-Butoxycarbonylamino-propionic acid (1.78 g, 9.43 mmol) in DCM (7.85 mL) was added portion wise DCC (2.14 g, 10.37 mmol) cooled in an ice bath. After stirring at room temperature for 30 min, dimethylamine (2 M in THF) (6.13 mL, 12.25 mmol) was added. The resulting solution was stirred overnight (18 h) until reaction was completed. The reaction mixture was filtered through silica gel and eluted with Ethyl acetate. Then the filtrate was evaporated off. The solvent was removed to yield (1.71 g, 7.12 mmol, 76% yield, 90% purity) ((R)-1-Dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:13]1([CH2:12][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Reaction time: 4 h

Procedure:
A solution of 6-hydroxyindan-1-one (1.60 g, 10.8 mmol (M. Phialas, P. G. Sammes, P. D. Kennewell, R. Westwood, J. Chem. Soc. Perkin Trans. 1: 687 (1984)), benzyl alcohol (1.23 mL, 11.9 mmol), triphenylphosphine (4.25 g, 16.2 mmol) under a N2 atmosphere in THF (100.0 mL) was treated with diethyl azodicarboxylate (2.55 mL, 16.2 mmol). The mixture was allowed to stir for 4 h then quenched with H2O. The mixture was then extracted with hexane (3×50 mL), the organic layers combined, dried with Na2SO4, and the solvent removed in vacuo. The residue was then submitted to column chromatography (SiO2 260-400 mesh, 4:1 hexanes: ethyl acetate) to provide the title compound (1.852 g, m.p. 99°-101° C.) as a solid. 'H NMR (400 MHz, CDCl3) δ 7.445-7.305 (m, 6H), 7.272-7.247 (m, 2H), 5.084 (s, 2H), 3.079 (m, 2H), 2.723-2.694 (m, 2H) .
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](O)(=O)[CH3:17]>O1CCCC1.C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH2:16][CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.1 g of 3-phenoxybenzaldehyde in 23 ml of an anhydrous tetrahydrofuran is added dropwise to 60 ml of 3-N-ethylmagnesium bromide in ethyl ether, cooled in an ice bath under a nitrogen atmosphere, over a period of about 1 1/2 hours. The reaction mixture is stirred overnight and warmed to room temperature, after which time it is poured over ice containing 12 ml of acetic acid. The organic and aqueous phases are separated and the aqueous phases extracted twice with ethyl ether. The ethereal extracts are combined and washed with a solution prepared from 3 g of sodium carbonate and 40 ml of water. The aqueous wash layers are extracted further with ethyl ether and the combined ethereal extracts are dried over anhydrous sodium sulfate and filtered. The ether is removed under reduced pressure to yield 29.45 g of 1-(3-phenoxyphenyl)propan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CC(C)=O.O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CC)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (2.2 g, 10 mmol) and potassium carbonate (2.2 g, 16 mmol) in a mixture of acetone (30 mL) and water (2.5 mL) was added benzyl chloroformate (2.0 mL, 2.4 g, 14 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solid was filtered off, the solvent was evaporated, the residue was stirred with cold aqueous sodium hydroxide solution [prepared from ice (20 g) and aqueous sodium hydroxide solution (1N, 40 mL)] and extracted with ethyl acetate (40 mL). The aqueous layer was acidified with an aqueous solution of hydrochloric acid 1/1 (20 mL) and the mixture was extracted with ethyl acetate (40 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine (1.66 g, 47%) was obtained as a yellow oil which can be used in the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24].N1C2C(=CC=CC=2)[C:27]2([CH2:37][O:36][C:35]3[CH:38]=C4C(=C[C:34]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:38][C@H:35]5[CH2:34][CH2:27][CH2:37][O:36]5)[C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione was obtained (69%) as an off-white solid: mp 79-81° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.16-7.04 (m, 3H), 6.63-6.62 (m, 1H), 6.39-6.32 (m, 1H), 4.96-4.92 (m, 1H), 4.72-4.67 (m, 1H), 4.54 (s, 2H), 4.37-4.26 (m, 1H), 3.98-3.85 (m, 2H), 3.82-3.70 (m, 2H), 3.15 (s, 3H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.78-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.7 (2C), 163.9 (2C), 157.4, 157.3, 146.9 (2C), 143.1, 142.6, 132.2, 131.9, 129.2, 129.1, 124.4 (2C), 123.8 (2C), 123.5, 123.1, 122.8, 109.8, 109.7, 109.6, 100.1 (2C), 80.8, 80.6, 76.9, 76.2, 68.4, 68.2, 67.7, 58.1 (2C), 44.9, 44.6, 29.3, 29.1, 28.5, 28.4, 25.7 (2C); MS (ES+) m/z 429.1 (M+23), 407.1 (M+1).
Reaction SMILES: [Na+].[Br-].Cl[CH:4]([CH3:8])[C:5](=O)[CH3:6].[NH2:9][C:10]1[C:11]([NH2:19])=[N:12][CH:13]=[C:14]([CH:18]=1)[C:15]([NH2:17])=[O:16]>C1(=O)CCCCC1>[NH2:9][C:10]1[C:11]2[N:12]([C:4]([CH3:8])=[C:5]([CH3:6])[N:19]=2)[CH:13]=[C:14]([C:15]([NH2:17])=[O:16])[CH:18]=1
Reactant: CC(=O)C(C)Cl
Reactant: NC(=O)c1cnc(N)c(N)c1
Agent: [Br-]
Agent: [Na+]
Solvent: O=C1CCCCC1
Product: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
NaBr (27.0 g; 0.259 mol; 1.33 equiv) was suspended in cyclohexanone (220 mL) and 3-chloro-2-butanone (25.7 mL; 0.242 mol; 1.24 equiv) was added in one portion. The mixture was heated to 80° C. and stirred for 3 h. The mixture was cooled to 50° C., the white solid was filtered off and washed with cyclohexanone (60 mL). 5,6-Diamino-nicotinamide (30 g; 0.1946 mol; 1.0 equiv) was added to the filtrate and the mixture was heated to 100° C. for 4 h, after which 98% conversion was determined by HPLC. The reaction mixture was cooled to 20° C., stirring was continued for 2 h at 20° C. The solid was filtered off, washed with TBME (220 mL) and dried to yield 46.6 g of the title compound. Yield: 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][N:8]=[C:9]([NH2:13])[CH:10]([OH:12])[CH3:11])=O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:8]=[C:9]([CH:10]([OH:12])[CH3:11])[N:13]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
27.2 g crude N′-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide was dissolved in ethanol (250 mL) and refluxed for 1 h, followed by addition of 14.0 g (170 mmol) sodium acetate in water (40 mL). After refluxing o.n., cooling to r.t. and addition of water (250 mL) the mixture was concentrated in vacuo to about ½ of its volume, resulting in a precipitate which was filtered off and recrystallized from EA/Hep to yield 6.45 g (25%) of the title compound. 1H NMR: 8.14 (s, 1H), 8.02 (d, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 5.04 -5.14 (m, 1H), 2.51 (d, 1H), 1.67 (d, 3H)
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:10]1[C:5]2[N:6]([C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:3][N:4]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#C[Si](C)(C)C)cnc12
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A mixture of 3-iodo-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 3) (4.02 g, 10 mmol), trimethylsilylacetylene (2.8 mL, 20 mmol), Et3N (2.1 mL, 15 mmol), PdCl2(PPh3)2 (70 mg, 1 mol %) and PPh3 (26 mg, 1 mol %) in THF (20 mL) was stirred for 10 min at 23° C. while being purged with Argon. Then CuI (19 mg, 1 mol %) was added. Stirring was continued for 16 h at 80° C. The reaction mixture was purified by column chromatography (heptane/AcOEt) to give the title compound as a yellow foam (3.15 g, 85%). MS (ISP) 373.2 [(M+H)+].
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:34])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:16]=1[N+:31]([O-:33])=[O:32])=O.CC(C[Al]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:16]([N+:31]([O-:33])=[O:32])=[C:15]([CH:20]=1)[C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C@H:5]1[CH:3]=[O:2])=[O:34]
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2c3ccccc3C[C@H]2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the methyl ester 5 (4.4 g, 9.5 mmol) in anhydrous dichloromethane (11 mL) and toluene (33 mL) was added dibal-H (19 mL, 1.0 M in toluene) dropwise via a syringe pump in 30 minutes at −78° C. The mixture continued to be stirred at −78° C. for 3 hours and TLC (hexanes/AcOEt, 1:1.5) showed that the starting material was almost consumed. The reaction was quenched with methanol (0.4 mL) and 5% HCl (30 mL) at −78° C. Ethyl acetate (100 mL) was added and the dry ice/acetone bath was removed. The mixture was stirred at room temperature for 30 minutes and then transferred to a reparatory funnel. The aqueous layer was extracted with AcOEt twice and the combined organic layers were washed with brine, saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. It was filtered through celite and the solvents were removed under reduced pressure (temperature<35° C.). The residue was purified by flash chromatography (Hexanes/AcOEt, 1.5:1, 1:1, 1:1.5) to give the aldehyde 6 as a yellow solid (2.85 g, y=69%). 1H NMR (400 Hz, CDCl3): the compound appears as three distinct rotomers. δ 10.02 (s, 0.3H), 9.85 (s, 0.5H), 9.45 (s, 0.2H), 8.32-8.31 (m, 0.2H), 7.93 (s, 0.3H), 7.83 (s, 0.5H), 7.79 (s, 0.2H), 7.53-7.34 (m, 5.2H), 7.26-7.14 (m, 1.3H), 7.08 (s, 0.5H), 7.01-6.94 (m, 1H), 6.91-6.82 (m, 1H), 5.78 (d, J=8.4 Hz, 0.3H), 5.71 (d, J=8.4 Hz, 0.5H), 5.52-5.48 (m, 0.5H), 5.35-5.21 (m, 2.3H), 4.53-4.50 (m, 0.2H), 4.06 (s, 1.5H), 3.98 (s, 0.6H), 3.94 (s, 0.9H), 3.63-3.17 (m, 2H); HRMS (ESI, m/z): calc. 433.1400 (M+H)+. found 433.1387.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[O:19][CH:16]1[CH2:15][CH2:14][C:11]2([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(OC2CCC3(CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
9-(3,4-Dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (340 mg, 0.82 mmol) was dissolved in dichloromethane (8 mL) and cooled on an ice bath. Trifluoroacetic acid (2 mL) was added and stirred for 2 h at room temperature. Evaporation followed by co-evaporation with toluene and ethyl acetate gave a solid compound. The compound was washed with diethyl ether to give 222 mg (63%) of 9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane trifluoroacetic acid salt as a white crystalline compound. Mp. 139, 6-141.2° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CO>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: Nc1ncc(O)cn1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCCCCC(=O)Nc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
5-Hydroxypyrimidin-2-amine (40 g, 360 mmol) was dissolved in pyridine (200 mL), the solution was added with hexanoyl chloride (121 g, 899 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was added with methanol (100 mL), the mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was dissolved in methanol (200 mL). The solution was added with saturated ammonia solution in methanol (250 mL) under ice cooling and stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=2:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (39.5 g, 52%) as colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([CH3:46])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[C:25]([C:37]([NH:39][C:40]3[S:44][N:43]=[C:42]([CH3:45])[N:41]=3)=[O:38])=[N:26][C:27]([S:30][C:31]3[N:35]([CH3:36])[CH:34]=[N:33][N:32]=3)=[CH:28][CH:29]=2)=[CH:19][CH:18]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:12][N+:13]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[C:25]([C:37]([NH:39][C:40]3[S:44][N:43]=[C:42]([CH3:45])[N:41]=3)=[O:38])=[N:26][C:27]([S:30][C:31]3[N:35]([CH3:36])[CH:34]=[N:33][N:32]=3)=[CH:28][CH:29]=2)=[CH:19][CH:18]=1)([CH3:46])[O-:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCCN(C)C)cc2)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCC[N+](C)(C)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
At 0° C., 9.2 mg of m-chloroperbenzoic acid was added to a chloroform solution of 20 mg of 3-({4-[2-(dimethylamino)ethoxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Example 1, and stirred at 0° C. for 30 minutes. Aqueous sodium sulfite solution was added to it, extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid]. The solvent of the obtained fraction was evaporated away under reduced pressure to obtain 17.5 mg of the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:18][CH2:17][CH:14]1[CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: NCC1CC1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Product: CCOC(=O)c1cnc(Cl)cc1NCC1CC1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethyl ester synthesized according to the method described in US2006/0217417 and cyclopropylmethylamine in a manner similar to Example 339, the title compound was obtained as a slight yellow crystalline powder (yield 77%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1.[H-].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(CBr)cn1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 55 °C
Yield: 33.7 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (6.0 g, 0.018 mol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02 mol) in THF (50.0 mL) was added NaH (0.5 g) and heated at 55° C. under argon atmosphere for 3 h. The reaction mixture was cooled added acetic acid (1.2 ml) and concentrated under reduced pressure. The residue was triturated with water and filtered the solid. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (3.0 g, 78%)as alight brown powder: 1H NMR (CD3OD/400 MHz) δ9.10 (d. 1H, J=1.2 Hz), 8.77 (d, 1H, J=1.2 Hz), 7.61 (m, 1H), 7.01 (m 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J=6.8 Hz), 2.52 (s, 3H), and 1.39 (t, 3H, J=6.8 Hz); 19F NMR (CD3OD/400 MHz) δ−111.64 (m), and −116.04 (m); ES-HRMS m/z 494.0482 (M+H C21H19N3O4BrF2 requires 494.0522).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH2:7])[CH3:3].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][C:20](=[O:22])[C:19]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH:7][C:20]([C:19]1([NH:18][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:22])[CH3:3]
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(C)C
Reaction time: 72 h

Procedure:
30 ml of dimethylformamide was added to a flask in which 5 g (27 mmol) of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one were placed. Then, 3.53 g (27.4 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred for 3 days. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel chromatography to obtain 8.3 g (quantitative) of the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].CN1CCOCC1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[C:25](=[O:26])([O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1)[O:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)NCCc1c[nH]c2ccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)cc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To N-acetylserotonin (0.9 g; 4 mmol) was added N-methylmorpholine (0.92 ml, 8 mmol), and 4-nitrophenyl chloroformate (1.61 g; 8 mmol) dissolved in tetrahydrofuran. Reaction was carried out for 0.5 h under an argon atmosphere. The solvent was evaporated. The residue was purified by column chromatography (SiO2, methanol/methylene chloride) to give 0.92 g (yield 60%) of crystalline yellow product with a melting point 153-156° C.
Reaction SMILES: C(O[CH:5]1[N:9]([CH3:10])[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:13])=[N:7][C:6]1=[O:22])(=O)C.Cl.[CH2:24]([SH:26])[CH3:25]>CCOCC.C(#N)C>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[N:9]([CH3:10])[CH:5]([S:26][CH2:24][CH3:25])[C:6](=[O:22])[N:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Reactant: CCS
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCSC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Yield: 73.2 %

Procedure:
A solution of 3.00 g (9.20 mmol) of N-(5-acetyloxy-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl)-N'-(3-chlorophenyl)urea, the compound of Example 1a, in 75 ml of anhydrous ether was treated with anhydrous HCl until no more precipitation occurred. The solid was filtered, washed with anhydrous ether and suspended in a mixture of 1.8 ml (25 mmol) of ethyl mercaptan and 30 ml of acetonitrile. After heating under reflux for 1 hr, the reaction mixture was evaporated in vacuo. The crystalline residue was dissolved in THF/water and extracted with ether. The combined ether layers were washed with water to pH 5-6, dried (MgSO4) and evaporated in vacuo. Crystallization of the residue from methanol/water afforded 2.20 g (73%) of the title compound. Recrystallization from ether/hexane and finally ethanol/water gave an analytical sample mp 102°-104° C.