Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=4[O:40][CH3:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(=O)Cc1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The flitrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[C:14]2([CH2:19][NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:7][N:6]1[C:2]([N:18]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:11][N:12]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:13]3)[CH2:19]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CCCNC2)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC2(CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 120 °C
Yield: 64.7 %

Procedure:
5-Chloro-1-methyl-4-nitro-pyrazole (0.16 g; 0.99 mmol) and tert-butyl 2,8-diazaspiro[3.5]nonane-2-carboxylate (0.2 g, 0.88 mmol) were suspended in butan-1-ol (2 mL), followed by the addition of DIPEA (0.7 mL; 3.9616 mmol). The reaction mixture was heated at 120° C. for 2 days. Evaporated all solvent and purified the crude mixture by silica gel eluting with a gradient of 0-30% ethyl acetate in dichloromethane. Tert-butyl 6-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate (200 mg) was obtained a yellow oil in a 57% yield. MS (ESI) m/z: 352.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1cccc(-c2ccccn2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccccn3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-2-yl)benzoic acid (1.69 g, 8.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give 3-(pyridin-2-yl)benzoyl chloride. 1.66 g of crude product was obtained. To a solution of methyl 3-amino-2-hydroxybenzoate (0.84 g, 5 mmol) and pyridine (790 mg, 10 mmol) in toluene (50 mL) were added crude 3-(pyridin-2-yl)benzoyl chloride (1.6 g, 7.37 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(3-(pyridin-2-yl)benzamido)benzoate (1.48 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:39])[C:30]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=3[F:38])[N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[F:36][C:35]1[CH:34]=[C:33]([F:37])[CH:32]=[C:31]([F:38])[C:30]=1[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[N:23]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Add trifluoroacetic acid (20 mL) to a solution of 4-[6-(2,4,6-trifluoro-benzoylamino)-pyridin-2-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (preparation 92, 2.482 g, 5.5 mmol) in methylene dichloride (50 mL) and stir for 30 min. Remove volatiles, dissolve the residue in methylene dichloride, adjust pH>11 with 1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Recrystallization (ethanol-H2O) provides 1.625 g of the title compound as a white solid. Concentrate themother liquor and further purify by chromatography (silica gel, eluting with 5.5% 2M NH3-methanol in CH2Cl2) to provide another 200 mg (total yield 94%) of the title compound: mass spectrum (ion spray): m/z=352.0 (M+1); 1H NMR (CDCl3, ppm): 8.35 (br, 1H), 7.68 (d, br, 1H), 7.46 (t, 1H), 6.60 (m, 2H), 6.34 (d, 1H), 4.84 (m, 1H), 2.93 (m, 2H), 2.59 (m, 2H), 1.85 (m, 2H), 1.46 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:8])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd](Cl)Cl.CCO>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)=[O:8])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(CNC(=O)c1ccc(Cl)s1)OCC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)s1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
Add 5-chloro-thiophene-2-carboxylic acid (2,2-diethoxyethyl) amide (50.15 g, 0.18 mol), 4-chlorophenylboronic acid (29.84 g, 0.18 mol), potassium carbonate (50 g, 0.36 mol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)(3-chloropyridyl)] palladium (II) dichloride (4.40 g, 0.006 mol), and EtOH (1000 mL) to a 2 L three-necked round bottom flask equipped with a overhead stirrer, reflux condenser, nitrogen inlet/outlet, addition funnel, and thermocouple. Heat the resulting slurry for 35 minutes, then add activated carbon (5.8 g) and heat for an additional 0.5 h. Filter the resulting slurry through glass microfibre filter and rinse solids with EtOH (500 mL). Remove solvent from the filtrate under reduced pressure until 15-20% solvent remains. To this filtrate, add water (1300 mL) and stir the resulting slurry at room temperature for 1 h, then at 0-5° C. for 0.5 h. Filter the slurry, rinse the solids with water (1000 mL), and dry to afford 66 g of crude 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide. Reflux the crude 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide in heptane (1625 mL) for 1 h then filter through a glass microfibre filter. Transfer the filtrate to a round bottom flask and remove solvent until 725 mL of solvent remained. Stir the mixture under chilled conditions for 40 min. Filter the resulting slurry, rinse with heptane (100 mL), and dry to afford 41 g (64%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.54 (d, J=9.0 Hz, 2H), 7.45 (d, J=4.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.24 (d, J=4.5 Hz, 1H), 6.20 (bs, 1H), 4.62 (t, J=5.5 Hz, 1H), 3.73-3.79 (m, 2H), 3.57-3.62 (m, 4H), 1.25 (t, J=7.0 Hz, 6H),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](I)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23]>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.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](/[CH:23]=[CH:22]/[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: C=Cc1ccncc1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21

Procedure:
2-Chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (prepared by procedures analogous to those described in Example 1a-g) (0.5 g, 1.2 mmol) was coupled with 4-vinylpyridine in the presence of bis(triphenylphosphine)palladium(II) chloride and triethylamine as described in example 1h to give 0.28 g of the title compound as brown crystals, m.p. 150°-152° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH2:3]1.CS(C)=O.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(OCC)(=O)C>[C:45]([O:1][C:2]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH:3]=1)(=[O:47])[CH3:46]
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1c(C)cnc(Cn2nc3cc(OC(C)=O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (778 mg), dimethyl sulfoxide (10 mL) and acetic anhydride (1 mL) was stirred in a nitrogen atmosphere at room temperature for 12 hours. After confirming that the raw material disappeared, the reaction mixture was diluted with ethyl acetate and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (507 mg, 61%) as an oil.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].[OH-].[Na+]>C(O)C.O>[CH2:28]([O:30][NH:31][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])[CH2:2][CH2:3][CH3:4])[CH3:29]
Reactant: CCCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(NOCC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.6 Gram of 2-butyryl-5-[2-(5-trifluoromethyl-2-pyridylthio)ethyl]cyclohexane-1,3-dione was dissolved in a mixed solvent of 10 ml of ethanol and 1 ml of water, and 0.2 g of ethoxyamine hydrochloride and 0.07 g of sodium hydroxide were added to the resulting solution which was then stirred at room temperature for 2.5 hours. The reaction solution was poured into water, weakly acidified and extracted with ethyl acetate. After removing ethyl acetate, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.45 g of 2-(1-ethoxyaminobutylidene)-5-[2-(5-trifluoromethyl-2-pyridylthio)-ethyl]cyclohexane-1,3-dione.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.[Cu]I.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>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:7][N:6]2[N:8]=1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Temperature: 50 °C

Procedure:
To a stirred solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (500 mg, 1.78 mmol, see Examples 1 and 2 above) and (trimethylsilyl)acetylene (1.5 mL, 10 mmol) in a mixture of THF (10 mL) and TEA (5 mL) was added copper(I) iodide (68 mg, 0.36 mmol, 20 mol %) and PdCl2(PPh3)2 (190 mg, 0.27 mmol, 15 mol %). The reaction vessel was degassed and heated at 50° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to yield a crude product, which was purified by flash chromatography (silica gel, elution with 20% to 40% EtOAc/Hexane in volume) to afford the resulting 2-furan-2-yl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine. The trimethylsilyl group was removed by treating a stirred solution of the crude material (2-furan-2-yl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine) in wet MeOH (20 mL) with-Amberlyst A26 resin (2 g) for 1 hour. The suspension was filtered, and the resin was washed, sequentially with MeOH and THF. The filtrate was concentrated in vacuo to yield the desired 6-ethynyl-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (0.34 mg, 84% overall yield), which was used in the subsequent transformation without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C[O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)=[CH:29][C:24]=2[O:23][CH:22]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=4)=[CH:29][C:24]=3[O:23][CH:22]=2)=[O:18])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1coc2cc(Oc3ccnc(N)n3)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)coc3c2)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 108 mg (0.60 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 10 ml toluene and cooled to 10° C. Then 900 μl Me3Al (2 M in toluene; 1.8 mMol) are added via syringe. After 1 h at rt, a suspension of 171 mg (0.599 mMol) 6-(2-amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester (Step 9.6) in 5 ml THF is added and the reaction mixture is stirred for 40 min in an oil bath of 110° C. The solution is cooled in ice and hydrolyzed with 20 ml of a sat. NH4Cl. After 10 min stirring, the mixture is filtered through Celite, the solid washed extensively with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc) and crystallization from EtOAc/hexane 1:1 gives the title compound: MS: [M+1]+=433; TLC(hexane/EtOAc 1:9): Rf=0.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19][CH2:20][CH3:21])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1.ClC1C=CC=C(C(OO)=[O:37])C=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19]([CH2:20][CH3:21])=[O:37])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(SCC)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)CC)c(F)cc2c1=O
Yield: 77.9 %

Procedure:
In 10 ml of methylene chloride was dissolved 1.00 g of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and 580 mg of m-chloroperbenzoic acid (purity: 80%) was added thereto, after which the resulting mixture was subjected to reaction with ice-cooling for 5 hours. The precipitates were removed by filtration, and to the filtrate thus obtained was added 10 ml of water, after which the pH thereof was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was thereafter separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene-ethyl acetate (10:1 by volume)] to obtain 810 mg (yield 77.9%) of ethyl 1-(2,4-difluorophenyl)-7-ethylsulfinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 150°-151° C. The physical properties of this compound were identical with those of the compound obtained in Example 44.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[CH:13]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:11]=2)=[N:4]1)[CH3:2]>[Pd].C1COCC1.C(O)C>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:11]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:13]=[C:14]([OH:16])[CH:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reaction time: 16 h

Procedure:
10% Palladium on carbon (1.9 g, 50% wet) was added under argon to N-(1-ethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide (19.1 g, 46.7 mmol) in dry THF (100 mL) and ethanol (100 mL). The reaction mixture was degassed, placed under a hydrogen balloon and stirred for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was evaporated to give a brown oil. The residue was purified by column chromatography on silica, eluting with 40-65% ethyl acetate in hexanes, to give the desired product as a clear oil which crystallized on standing (11.35 g). 1H NMR δ (CDCl3): 1.21 (d, 6H), 1.38 (t, 3H), 3.32 (s, 3H), 3.39-3.51 (m, 3H), 3.98 (q, 2H), 4.44-4.51 (m, 1H), 6.54 (s, 1H), 6.72 (d, 1H), 6.92 (s, 2H), 7.26 (d, 1H), 8.18 (s, 1H), 8.85 (s, 1H); m/z 320 (M+H)+ 318 (M−H)−
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]1[CH2:11][CH:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][CH:10]1[CH2:9][CH:8]([CH2:7][OH:6])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(OC2CCCCO2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1CC(OC2CCCCO2)C1
Yield: 83.7 %

Procedure:
tert-Butyl dimethyl-[3-(tetrahydropyran-2-yloxy)-cyclobutylmethoxy]-silane (1.62 g) was dissolved in tetrahydrofuran (11 mL) and treated with a solution of 1.0M tetrabutylammonium fluoride in tetrahydrofuran (8.08 mL) for 2 hours. The reaction mixture was diluted with dichloromethane and the mixture was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 2:3 by volume) to give the title compound (0.84 g). 1H NMR (300 MHz, CHCl3-d): δ 4.62-4.54 (m, 1H), 4.29-4.20 (m, 1H), 3.88 (d, 1H), 3.68-3.60 (m, 2H), 3.53-3.42 (m, 1H), 2.30-2.20 (m, 2H), 2.19-2.08 (m, 2H), 1.86-1.72 (m, 3H), 1.58-1.47 (m, 4H), 1.34 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21]>C1COCC1>[CH:12]([C:11]1[C:2]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2)=[O:13]
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CC(=O)NCCN
Solvent: C1CCOC1
Product: COc1ccc2nc(NCCNC(C)=O)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (2.00 g, 9.0 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-aminoethyl)acetamide (2.76 g, 27.1 mmol) and the reaction mixture was stirred for 1 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up with CH2Cl2 (100 mL). This organic solution was washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was finally purified by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) to give N-(2-(3-formyl-6-methoxyquinolin-2-ylamino)ethyl)acetamide SLA 41168 as an orange solid (601 mg, 23% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([O-])=[O:13].[Na+].Cl>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH:12]=[O:13]
Reactant: COc1cc(I)c(Cl)cc1Cl
Reactant: O=C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(Cl)cc1Cl
Yield: 44.1 %

Procedure:
A mixture of 22.6 g of 2,4-dichloro-5-iodo-1-methoxybenzene, 7.61 g of sodium formate, 1.05 g of dichlorobis(triphenylphosphine) palladium, and 60 ml of N,N-dimethylformamide was stirred, while bubbling carbon monoxide at 90° to 100° C. over 12 hours. After completion of the reaction, the reaction mixture was returned to room temperature, followed by dilution with diluted hydrochloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 6.75 g (yield, 44%) of 2,4-dichloro-5-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([OH:10])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:18][S:19]([O:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH:2]([CH3:3])[CH3:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(O)CC(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CC(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a one liter three-neck flask was mixed 100 g (0.69 moles) of 2,6-dimethyl-4-heptanol and 580 g chloroform. Triethylamine (77.1 g; 6 moles) was added and the reaction mixture cooled to 0° C. Methanesulfonyl chloride (83.4 g; 0.73 moles) was added dropwise, keeping the reaction temperature about 0° C. After holding at about 0° C. for one hour, gas chromatograph (GC) showed less than 5% residual alcohol.