Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](O)=O)=[N:16][CH:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O>CN(C=O)C>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][C:3]1[N:10]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][N:16]=2)[O:1][N:2]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: COC(CC(=N)NO)OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(Cc1noc(-c2ccc(F)cn2)n1)OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of N-hydroxy-3,3-dimethoxypropanimidamide obtained in Reference Example 19 (1.0 g, 6.8 mmol) in DMF (3 mL) was added to a solution of 5-fluoropyridine-2-carboxylic acid (1.0 g, 7.1 mmol) and carbonyldiimidazole (1.3 g, 8.1 mmol) in DMF (4 mL), which was stirred for 1 hour at 40° C., and the mixture was stirred for 30 minutes. The reaction solution was heated to 90° C. and stirred for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=75/25 to 0/100) to obtain the title compound (1.2 g) (colorless solid).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:36]([NH:39][C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)(=[O:38])[CH3:37]>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:42]3[CH2:43][CH2:44][C@@H:40]([NH:39][C:36](=[O:38])[CH3:37])[CH2:41]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1

Procedure:
Following the same procedure in Example 1, step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.74 mmol), N,N-diisopropylethylamine (0.5 mL, 3 mmol) and (3R)-(+)-3-acetamidopyrrolidine (142 mg, 1.1 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 15 mg (4% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.51-1.65 (m, 3 H), 1.69 (s, 9 H), 1.71-1.77 (m, 4 H), 1.78 (s, 3 H), 1.93-2.12 (m, 3 H), 2.21-2.33 (m, 1 H), 3.15 (dd, J=10.35, 4.69 Hz, 1 H), 3.21-3.28 (m, 1 H), 3.37-3.49 (m, 2 H), 4.00-4.11 (m, 1 H), 4.58 (d, J=7.42 Hz, 2 H), 7.91 (d, J=8.59 Hz, 1 H), 8.09 (d, J=8.79 Hz, 1 H), 8.12 (s, 1 H); MS (ESI) (M+H)+=496.6; Anal. Calc. for C24H34F2N4O3S+4.2 TFA+2.9H2O+2.4 CH3CN: C, 39.67; H, 4.58; N, 7.16. Found: C, 39.69; H, 4.61; N, 7.96.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH3:16][CH:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCCNc1ccc(N)cc1
Reactant: CCCCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCC(C)Nc1ccc(NCCCOC(C)C)cc1

Procedure:
A mixture of 50 g. of N-(3-isopropoxypropyl)-p-phenylenediamine, 50 g. of 2-octyl bromide, 200 ml. of 2N sodium carbonate and 1 liter of ethanol is stirred for 18 hours at 60°C. The reaction mixture is treated with 1 liter of water and extracted with 1 liter of ether. The ether layer is separated, washed with 1200 ml. of water, dried over sodium sulfate and evaporated in vacuo. A mixture of the residue in ether is treated with hydrogen chloride gas to yield the title product in dihydrochloride salt form, m.p. 200°-202°C.
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.I[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25].CN(C=O)C>C(OCC)(=O)C.[Cu]>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4]1
Reactant: FC(F)(F)C(F)(F)I
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(C(F)(F)C(F)(F)F)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (2.06 g), copper powder (0.95 g), iodopentafluoroethane (4.92 g) and DMF (13 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 130-135° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and an insoluble matter was filtered with Celite and washed with ethyl acetate. The filtrate was concentrated under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-pentafluoroethyl-3-trifluoromethyl-1H-pyrazole (1.39 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(NC(C)C)(C)C>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.[Cu](I)I.C(#N)C>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Methyl 2-bromoisonicotinate (216 g, 1 mol), dry acetonitrile (1.7 L), ethynyl(trimethyl)silane (117 g, 1.2 mol), diisopropylamine (122 g, 1.2 mol), and dichlorobis(triphenylphosphine)palladium (36 g, 0.05 mol) were placed into a well dried three necked flask which was twice purged with a stream of nitrogen. The reaction mixture was stirred for 0.5 hours, cooled to 10° C., and copper iodide (19 g, 0.1 mol) was added under a stream of nitrogen. At 20° C., the reaction mixture became thick and black and an exotherm was observed which was followed by formation of a precipitate. After the addition of copper iodide, the reaction mixture was stirred for further 2 hours at ambient temperature. The precipitated residue was separated by filtration and twice washed with diethyl ether (800 mL). The filtrate was washed with saturated ammonium chloride (2×300 mL) and brine (2×300 mL). After drying over sodium sulfate, the solvent was evaporated. The residue was purified using a silica gel column, eluting with hexane followed by 5% ethyl acetate in petroleum ether to yield 191 g (82%) of methyl 2-((trimethylsilyl)ethynyl)isonicotinate.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[OH:13])([O-:3])=[O:2].[Cl:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=1[C@@H:23](O)[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=1[C@H:23]([O:13][C:5]1[C:6]2[O:12][CH:11]=[CH:10][C:7]=2[CH:8]=[N:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:24]
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of 6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 7) (2.10 g, 11.6 mmol) and (S)-1-(2,6-dichloro-3-fluorophenyl)-ethanol (2.68 g, 12.8 mmol, prepared according to literature procedures: WO2006/021881A2) in THF (30 mL) were added PPh3 (4.31 g, 16.4 mmol) and diisopropyl azodicarboxylate (3.32 g, 16.4 mmol) at 0° C. After 10 min, the cold-bath was removed and the resulting mixture was stirred at rt overnight. LC-MS showed completion of the reaction. The reaction mixture was evaporated under vacuum to give an oil, which was purified by silica gel flash chromatography (DCM:Hexanes=2:1) to afford 4.2 g of the desired product as a light-yellow oil (yield: 97%). 1H NMR (CDCl3, 400 MHz): δ=1.94 (d, J=6.8 Hz, 3H), 6.69 (q, J=6.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 7.05 (t, J=8.3 Hz, 1H), 7.27 (dd, J=8.8, 4.8 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H), 8.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][C:12]1([NH2:15])[CH2:14][CH2:13]1.C[O-].[Na+]>CN1C(=O)CCC1.O>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][C:12]2([CH3:11])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: CC1(N)CC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(Nc2cc(Cl)nc(N)n2)CC1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
2-amino-4,6-dichloropyrimidine (508 mg, 3.1 mmol) was added to a suspension of 1-methylcyclopropylamine hydrochloride (1.0 g, 9.3 mmol) and sodium methoxide (502mg, 9.30 mmol) in NMP (3 ml). The resulting mixture was heated at 90° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and the resulting precipitate filtered off, washed with further water (20 ml) and dried in vacuo to give the title compound as a colourless solid (280 mg, 15%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4]#[C:5][CH3:6].[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH2:11]>C(O)C>[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH:11][C:5]([CH3:6])=[CH:4][C:3]([O:2][CH3:1])=[O:7]
Reactant: CC#CC(=O)OC
Reactant: NCC(O)CO
Solvent: CCO
Product: COC(=O)C=C(C)NCC(O)CO

Procedure:
To 5.0 g (0.051 m) methyl-2-butynoate in 25 ml absolute ethanol is added 5.0 g (0.055 m) 2,3-dihydroxypropylamine. This solution is heated at 75°-80° for 18 hours and the solvent is then removed at reduced pressure. The residue oil is chromatographed on silica gel, eluting with 10% methanol/chloroform to afford the desired product as a white solid. m.p. 109°-111°. The yield is 5.6 g (59%). ##STR4##
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:17]([CH:18]=2)[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:17]([C:18]=2[Br:23])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cccc(-c2cn3c(n2)sc2ccccc23)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cccc(-c2nc3sc4ccccc4n3c2Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 ml of chloroform were added 1.35 g of 2-(m-acetoxyphenyl)imidazo[2,1-b]benzothiazole and 0.94 g of N-bromosuccinimide and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and dried to provide 2-(m-acetoxyphenyl)-3-bromoimidazo[2,1-b]benzothiazole. The product was suspended in 50 ml of methanol and after adding thereto 4 ml of 0.84 normal methanol solution of potassium hydroxide, the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added acetic acid to acidify the mixture and then 50 ml of water was added to the mixture to form crystals, which were recovered by filtration and recrystallized from a mixture of methylcellosolve and water to provide 1.2 g of 3-bromo-2-(m-hydroxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:19]=[O:20])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nccc(Cl)c2s1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at −78° C. was added n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 20 min. Dry DMF (0.5 mL, excess) was added and the reaction mixture was stirred for an additional 2 hrs. The reaction mixture was quenched with methanol at −78° C. and water was added. The mixture was extracted with EtOAc and the organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the resultant yellow solid was triturated with hexane to afford 14 (250 mg, 100% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.2 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.61 (s, 1H), 7.78 (d, J=5.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=Cc1cc(O)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,5-dihydroxybenzaldehyde (10 g) in dichloromethane (50 ml) at 0° C. was added triethylamine (5 ml) and pivaloyl chloride (4.4 ml). The mixture was stirred at room temperature for 18 hours, filtered and the filtrates washed with 2M HCl (100 ml), brine (100 ml) and sodium bicarbonate (100 m), dried (magnesium sulphate) filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane:hexane (0:1 to 1:1 gradient) then ethyl acetate:hexane (1:9 to 3:7 gradient) as eluants to give 2-hydroxy-5-(t-butylcarbonyloxy)benzaldehyde (4 g) and some 2,5-dihydroxy-benzaldehyde.
Reaction SMILES: O[CH:2]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=[CH:10][C:9]=2[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:7]=1)[CH2:3][O:4]C.[H][H]>[C].[Pd].C(O)(=O)C>[OH:4][CH2:3][CH2:2][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[N:11]=[CH:10][C:9]=2[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:7]=1
Reactant: COCC(O)c1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Yield: 66.4 %

Procedure:
To 40 ml of acetic acid solution containing 2.30 g (4.90 mmol) of 3-(1-hydroxy-2-methoxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(d) was added 1.0 g of 10% palladium-carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at 80° C. for 2.5 hours. After completion of the reaction, insoluble material was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. Water was added to the residue, the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=3:7 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.43 g of the title compound as a colorless oil. (Yield: 66%)
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=1.CI>O>[Br:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][O:16][CH3:3])[CH:10]=1
Reactant: CN(C)C=O
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1cncc(Br)c1
Reaction time: 1 h

Procedure:
Sodium hydride (61% in oil) (11 mg) was added to a DMF (0.9 ml) solution containing (5-bromopyridin-3-yl)methanol (34 mg) under ice cooling, followed by stirring for 1 hour. Then, methyl iodide (17 μl) was added, followed by stirring at room temperature for 13 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and a light yellow solid of 3-bromo-5-(methoxymethyl)pyridine (26.5 mg) was thus obtained.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4].[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A mixture of 1,3-dibenzyl-8-cyano-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.071 mmol), glycine (2.82 g, 37.6 mmol) and NaOMe solution (56 mL, 28.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 31 mg of the title compound. MS: (−) m/z 467.10 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>ClC=CCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:41])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClC=CCl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2c(C)nn(C)c2OC(=O)c2ccncc2)c(C)c2c1S(=O)(=O)CCC2(C)C
Yield: 76.9 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of 1,2-dichloroethene, and further, 0.26 g (3.2 mmol) of pyridine, 0.57 g (3.2 mmol) of isonicotinic acid chloride hydrochloride and 10 mg of benzyltriethylammonium chloride were added. The mixture was allowed to react at room temperature for 3 hours. The extraction of the reaction mixture was carried out by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution. The solvent was removed by filtration under reduced pressure, and the resultant oily substance was washed with an ethyl acetate/n-hexane mixed solvent (1:1 (V/V)) to form a solid. The mixture was filtered to give 1.0 g (yield 80%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(pyridin-4-yl)carbonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 42).
Reaction SMILES: [F:1][CH:2]1[CH2:4][C:3]1([CH3:8])[C:5](Cl)=[O:6].[CH2:9]([OH:11])[CH3:10]>S(=O)(=O)(O)O>[F:1][CH:2]1[CH2:4][C:3]1([CH3:8])[C:5]([O:11][CH2:9][CH3:10])=[O:6]
Reactant: CCO
Reactant: CC1(C(=O)Cl)CC1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1F
Yield: 85 %

Procedure:
40 ml of ethanol are added dropwise at 20° C. and with stirring to 20 g (0.12 mol) of 2-fluoro-1-methylcyclopropane-carbonyl chloride (cis/trans mixture). After the addition of 2 drops of concentrated sulphuric acid, the reaction mixture is refluxed for one hour. Excess ethanol is subsequently distilled off, and the residue is dried and distilled under reduced pressure. In this manner, 18.4 g (85% of theory) of ethyl 2-fluoro-1-methyl-cyclopropanecarboxylate (cis/trans mixture) are obtained in the form of a liquid of boiling point 42-45° C. at 18 mbar.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)(=O)[CH3:2].[OH:20][CH2:21]CCO.S(=O)(=O)(O)O>O>[C:14]1([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([O:4][CH2:1][CH2:2][CH2:21][OH:20])=[CH:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)Oc1cn(-c2ccccc2)c2ccccc12
Reactant: OCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: OCCCOc1cn(-c2ccccc2)c2ccccc12
Temperature: 80 °C

Procedure:
A mixture of 3-acetyloxy-1-phenylindole (24 g), 1,3-dihydroxypropane (240 ml), and conc. sulfuric acid (10 ml) was heated to 80° C. for 2 h. Water was added followed by extraction with ether. The ether phase was dried over magnesium sulfate followed by removal of solvent in vacuo giving 3-(1-phenyl-3-indolyloxy)-1-propanol, sufficiently pure for use in the next step.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 9.8 %

Procedure:
A mixture of methyl 4-fluorobenzoate (1.00 g, 6.49 mmol), 4-methylimidazole (559 mg, 6.81 mmol), potassium carbonate (941 mg, 6.81 mmol) and DMF (30 ml) was stirred at 110° C. for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was subjected to column chromatography using basic silica gel and eluted with ethyl acetate-methanol (1:0-1:1, v/v) to give the title compound (137 mg, 10%) as a colorless oil.