Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH3:8][S:9]([O:7][CH2:1][CH2:2][CH2:3][CH:4]=[CH:5][CH3:6])(=[O:11])=[O:10]
Reactant: CC=CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=CCCCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
This example illustrates a synthesis of 1-(4,5-Oxohexyl)-3,7-dimethylxanthine (inventive compound no. 1555). To a solution of 4-hexen-1-ol (1.22 g, 12.2 mmol) and methanesulfonyl chloride (1.04 mL, 13.4 mmol) in dichloromethane (15 mL), cooled in an ice bath, was added triethylamine (2.55 mL, 18.3 mmol) dropwise. After 5 minutes, the cooling bath was removed and the mixture stirred for an additional 45 minutes and then treated with saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic layers were dried over magnesium sulfate and the solvents evaporated under vacuum, yielding 1-methanesulfonyloxy-4-hexene as a viscous oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C2)ccc2c1COC2=O
Temperature: 148 °C

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (70 mg, 0.27 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (73 mg, 0.38 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 148° C. for 1.5 hours. LC showed formation of the product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:8][C:4]1[N:3]=[C:2]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2cccc(F)n2)cc1
Yield: 69 %

Procedure:
2,6-Difluoropyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (1.32 g) and potassium carbonate (3.60 g) were suspended in acetonitrile (10 mL), and heated under reflux for 21 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a colorless oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=10/0 to 7/3) to obtain the entitled compound (1.48 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][CH:8]=2)=[O:4].O.O.Cl[Sn]Cl.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(N)ccc2n1C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1-Methyl-5-nitro-1H-indole-2-carboxylic acid methyl ester (70 mg, 0.3 mmol) was dissolved in DMF (5 ml) and SnCl2.2H2O (339 mg, 1.5 mmol) was added as a solid. The resulting solution was stirred at 60° C. for 4 h. After cooling to room temperature, a pre-mixed aqueous solution of saturated Rochelle's salt (3 ml) and saturated NaHCO3 (3 ml) was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3×6 ml). The organic layer was washed with H2O (3 ml), 1:1 NaHCO3: Rochelle's salt solution (3 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CO>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CN(C)CCCCl
Solvent: CO
Solvent: O
Product: CN(C)CCCOc1ccc(C(=O)c2ccc(OCCCN(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of bis-(4-hydroxy-phenyl)-methanone (7.00 g) in methanol (130 mL) was added at room temperature t-Bu3OK (14.7 g) followed by (3-chloro-propyl)-dimethyl-amine (10.3 g). The reaction mixture was heated under reflux for 18 h and was allowed to cool down to room temperature. Water (50 mL) was added and the solvent was removed in vacuo. Methylene chloride (650 mL) was added and the organic layer was washed with water (2×150 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The crude products were separated and purified by flash chromatography on silica gel (chloroform/2 M ammonia in methanol) to give the title compound bis-[4-(3-dimethylamino-propoxy)-phenyl]-methanone as a colorless residue (250 mg). 1H NMR (400 MHz, CD3OD): 7.78 (d, 4 H), 7.09 (d, 4 H), 4.22 (t, 4 H), 3.37-3.40 (m, 4 H), 2.96 (s, 12 H), 2.24-2.31 (m, 4 H). And title compound [4-(3-dimethylamino-propoxy)-phenyl]-(4-hydroxy-phenyl)-methanone as a colorless residue (150 mg). 1H NMR (400 MHz, CD3OD): 7.88-7.99 (m, 4 H), 7.25-7.29 (m, 2 H), 7.08-7.13 (m, 2 h), 4.48 (t, 2 H), 2.69-2.76 (m, 2 H), 2.56 (s, 6 H), 2.23-2.30 (m, 2 H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[S:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[S:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)CSc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)CSc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.570 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.359 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]thiazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=6.14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[C:22]=1[F:31])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:17][CH2:16][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[C:23]([F:30])[C:22]=1[F:31])[CH3:19]
Reactant: Brc1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccc(C3CCC4(CC3)OCCO4)cc2)c(F)c1F
Temperature: 25 °C
Yield: 75.7 %

Procedure:
8-(4-Bromophenyl)-1,4-dioxaspiro(4.5)dec-7-ene (s71) (30.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (s70) (24.6 g), potassium phosphate (K3PO4; 64.7 g), dichlorobistriphenylphosphine palladium (II) (Pd(Ph3P)2Cl2; 2.1 g) and 1,4-dioxane (300 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and heated to reflux for 2 hours. After the reaction mixture had been cooled to 25° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (1.5 g) was added to the purified product, and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of toluene and heptane (toluene:heptane=1:1 by volume) to give 8-(4′-ethoxy-2′,3′-difluoro-(1,1′-biphenyl)-4-yl)-1,4-dioxaspiro(4.5)decane (s72) (28.8 g). The yield based on the compound (s71) was 75.7%.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.N[C:9](N)=[O:10].C(O)CCCC>>[NH:1]1[C:2]2=[CH:3][S:4][CH:5]=[C:6]2[NH:7][C:9]1=[O:10]
Reactant: Nc1cscc1N
Reactant: NC(N)=O
Solvent: CCCCCO
Product: O=c1[nH]c2cscc2[nH]1
Temperature: 130 °C

Procedure:
To the 3,4-diaminothiophene obtained in Production Example 1 were added 1.1 equivalents of urea and amyl alcohol in an amount equivalent to 10 ml/mmol, and under argon gas atmosphere, a reaction was advanced by refluxing at 130° C. for 5 hours, then amyl alcohol was distilled off and the residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 1H-thieno[3,4-d]imidazol-2(3H)-one was obtained. The yield based on 3,4-diaminothiophene was 55%.
Reaction SMILES: [OH:1][C:2]1([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)C(=O)N[C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH-].[Na+]>>[C:16]1([C:13]2[O:12][C:11]([CH:2]3[O:1][C:5](=[O:9])[NH:4][C:3]3=[O:10])=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NC(=O)C(O)(c2ccc(-c3ccccc3)o2)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(c2ccc(-c3ccccc3)o2)O1
Yield: 16.8 %

Procedure:
5-Hydroxy-5-(5-phenyl-2-furyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (0.7 g.) was dissolved in 15 ml. of 1 N sodium hydroxide, stirred at room temperature for 15 minutes, extracted with ethyl acetate, made slightly acidic with about 1 ml. of glacial acetic acid, and extracted with 25 ml. of ethyl acetate. The latter ethyl acetate extract was back washed with about 6.5 ml. of water, filtered over a bed of anhydrous magnesium sulfate and evaporated to yield solid 5-(5-phenyl-2-furyl)oxazolidine-2,4-dione [100 mg.; m.p. 216°-218° C.; Rf 0.6 (1:1 hexane:ethyl acetate/5% acetic acid)].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1nc2ccc(O)cc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2nc(C)oc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A slurry of 2-methyl-1,3-benzoxazol-6-ol (7.1 g, 48.7 mmol) in THF (150 mL) was cooled to 10° C. and triethylamine (11.3 mL, 81.3 mmol) was added in one portion, followed by the addition of acetyl chloride (5.8 mL, 81.3 mmol) in small portions. After addition was completed the reaction mixture was stirred at room temperature over night, partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give sub-title compound (8.2 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13])=[O:4].C(Cl)(=O)[C:21](Cl)=[O:22]>C(Cl)CCl>[F:19][C:2]([F:18])([F:1])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([N:14]=[C:21]=[O:22])=[O:13])=[O:4]
Reactant: NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzamide (1.0 g, 3.6 mmol), oxalyl chloride (1.0 mL) and EDC (10 mL) to afford 0.750 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][S:11](=[O:13])(=[O:12])[NH2:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Yield: 71.5 %

Procedure:
This compound was prepared according to the procedure of Example 84 from a mixture of 16.3 g (0.10 mole) of 2,6-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene to obtain 17.3 g (71%) of the title compound after recrystallization from benzene, mp 114.5°-116° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>O1CCOCC1>[Cl:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:13]=[CH2:14])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccnc2ccc(Br)cc12
Solvent: C1COCCO1
Product: C=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med. Chem., 21, 268 (1978)), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and tetrakistriphenylphosphine palladium (0) (0.62 g, 0.54 mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOH:CH2Cl2) to give the title compound (5.1 g) as a pale yellow solid. MS (ES)+ m/e 190 [M+H]+. This material was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:22]2[N:23]=[CH:24]C=CC=2N=N1.Cl.C(N=C=N)C.CNC.C(O)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[N:23]([CH3:24])[CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=N
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (8.0 g, 35 mmol) was dissolved in dichloromethane (70 ml) and N,N-dimethylformamide (35 ml). 1-Hydroxy-7-azabenzotriazole (4.75 g, 35 mmol) was added. The solution was cooled to 0° C. N-3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.69 g, 35 mmol) was added. The reaction mixture was stirred for 20 min at 0° C. A 5.6 M solution of dimethylamine in ethanol (37 ml, 209 mmol) was added. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. It was diluted with ethyl acetate (400 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (400 ml). The aqueous phase was extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacua. The crude product was purified by flash chromatography on silica (300 g), using dichloromethane/methanol 20:1 as eluent, to give 4.56 g of 4-(dimethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(O[N:24]1[N:32]=N[C:26]2[CH:27]=CC=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(N)=CC=N1.CN1CCOCC1>CN(C=O)C.[OH-].[Na+].C(Cl)Cl.CO>[NH2:1][C:2]1[C:3]([C:13]([NH:30][C:25]2[NH:24][N:32]=[CH:27][CH:26]=2)=[O:15])=[N:4][C:5]([Cl:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccn[nH]1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1cc(C(F)(F)F)c(Cl)nc1C(=O)Nc1ccn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate 5) (0.143 g, 0.594 mmol) in DMF (5 ml) was treated with HATU (226 mg, 0.594 mmol), 1H-pyrazole-5-amine (74.1 mg, 0.892 mmol) and 4-methylmorpholine (0.118 ml, 1.189 mmol). The mixture was stirred at RT for 30 minutes followed by 80° C. for 2 hours before cooling to RT. The reaction mixture was diluted with 2M NaOH (20 ml) and the product extracted with EtOAc (2×60 ml). The organics were combined, washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to give a brown oil. This oil was taken up as a solution in DCM (2 ml), and after 5 minutes, a white precipitate was present. This was filtered under vacuum, washed with DCM and dried on high vacuum. The material was taken up in EtOAc (50 ml) and washed successively with 2M NaOH (2×20 ml), brine (10 ml), dried over MgSO4 and concentrated in vacuo to give a yellow solid. This was taken up in MeOH (3 ml) and loaded onto a 10 g SCX-2 cartridge, eluted with MeOH (50 ml), then a solution of 7M NH3 in MeOH (50 ml). The relevant fractions were combined and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:33])[C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH2:29][CH2:30][CH2:31][CH3:32])=[O:19])=[CH:7]2.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:36][N:35]=[N:34][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:33])[C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH2:29][CH2:30][CH2:31][CH3:32])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 61.8 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.3 g, 0.59 mmol), prepared in the previous step, sodium azide (0.116 g, 1.78 mmol) and ammonium chloride (0.095 g, 1.78 mmol) in 12 mL DMF was stirred under nitrogen at 100° C. for 6.5 h. The reaction was diluted with water, made basic with 1N NaOH, and extracted three times with ethyl acetate. The organic layers were combined, acidified with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give an oily residue. The oil was diluted with water and the solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (0.20 g, 63%) as an off white solid, mp 190-194° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[N:17][N:18]=2)[CH:7]=[CH:8][C:9]=1[O:10]C(=O)C.Cl>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[N:17][N:18]=2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc(OC(C)=O)c(F)c3)s2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCc1ccc(-c2nnc(-c3ccc(O)c(F)c3)s2)cc1
Yield: 63.7 %

Procedure:
0.90 g of 85%-potassium hydroxide was added to 40 ml of ethanol and heated to 60°-65° C. on an oil bath. Under stirring, 2.00 g (5.02 mM) of 2-(3-fluoro-4-acetoxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole was added thereto. To the mixture, 1.20 ml of hydrochloric acid was added (pH=about 3) and then common salt was added, followed by stirring at room temperature to precipitate a crystal. The crystal was recovered by filtration, followed by recrystallization from a mixture solvent (acetone/ethyl acetate) to obtain 1.14 g of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-hexylphenyl)- 1,3,4-thiadiazole (Yield: 63.7%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])[NH:27][C:28]3=[O:31])=[CH:23][CH:22]=2)[CH2:16]1.[Cl-].[NH4+]>C(Cl)Cl.CO.CCCCCC>[CH3:8][S:9]([O:13][CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:40])([F:39])[F:41])[NH:27][C:28]3=[O:31])=[CH:23][CH:22]=2)[CH2:16]1)(=[O:11])=[O:10]
Reactant: O=C1OC(CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)(=O)OCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Triethylamine (128 μl) and methanesulfonyl chloride (71 μl) were added to a solution obtained by dissolving the 7-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (186.7 mg, 0.462 mmol) obtained in step B in methylene chloride (2.3 ml), under cooling on ice. The obtained mixture was stirred for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1, and then methylene chloride:methanol=30:1), so as to obtain 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl methanesulfonate (169.1 mg; yield: 76%) in the form of a colorless foaming substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](O)(=O)C.C(=N)N>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:15]=[N:14][NH:13][C:11]2=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCCCO
Product: O=c1[nH]ncn1-c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of intermediate (2) and methanimidamide acetate (2.4 mol) in 1-butanol (1500 ml) was stirred and refluxed for 5 hours and then stirred further for 48 hours. The precipitate was filtered off and washed with DIPE, yielding 48 g of 2,4-dihydro-4-(4-nitrophenyl) -3H-1,2,4-triazol-3-one (intermediate 3).