Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:30][S:31](O)(=[O:33])=[O:32].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:31]([Cl:30])(=[O:33])=[O:32])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC1CCNCC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCN(CC1CCN(S(=O)(=O)Cl)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine (0.2 grams, 0.66 mmole) and triethylamine (0.15 grams, 1.48 mmole) in dichloromethane (4 ml) at 0° C. was added dropwise a solution of chlorosulfonic acid (0.08 grams, 0.66 mmol) in dichloromethane (0.5 ml). The mixture was stirred at room temperature for 16 hours, and the solvent was removed under reduced pressure. To the residue was added benzene (4 ml) and phosphorous pentachloride (0.14 grams, 0.67 mmole). The mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-chlorosulfonylpiperidin-4-ylmethyl)amine as a viscous oil (0.18 grams, 70%), M+H 401.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[O:29][C:19]3=[C:20]4[C:25](=[CH:26][CH:27]=[C:18]3[O:17][CH2:16]2)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]4)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(OCC)C.CO>[CH3:28][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]3[O:17][CH2:16][CH:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[O:29][C:19]3=2)[N:24]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)O3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCNCC1)O3
Temperature: 35 °C

Procedure:
To an ice-cold solution of (2S)-4-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazine 1 carboxylic acid tert-butyl ester of Step A′ (0.550 g, 1.37 mmol) in ethyl acetate (8 mL) is added dropwise 1 M hydrochloric acid in diethyl ether (15 mL). The mixture is allowed to come to room temperature, diluted with methanol (10–15 mL) and warmed at 35° C. until the reaction is complete by TLC. The solvents are removed in vacuo and the residue is slurried in diethyl ether. The solid is collected and dried in vacuo. The free base is prepared by basifying an aqueous solution of the hydrochloride salt with concentrated aqueous sodium hydroxide, followed by extraction with dichloromethane. The title compound is obtained as a thick oil (quantitative yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]O)[CH3:2].[Br:10]P(Br)Br>ClCCl>[Br:10][CH2:8][C:7]1[S:6][CH:5]=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ncsc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCc1ncsc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-ethyl-1,3-thiazol-5-yl)methanol (740 mg, 5.2 mmol) in anhydrous dichloromethane (35 mL) was added tribromophosphane (550 μL, 5.7 mmol). The mixture was stirred at room temperature for 2 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-4-ethyl-1,3-thiazole. The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH:13]1[CH3:19])=[N:7][N:6]=[CH:5]2.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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.CCO>[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH:13]3[CH3:19])=[N:7][N:6]=[CH:5]4)[CH:26]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1C(=O)NCCN1c1nncc2cc(Br)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNC(=O)C3C)nncc2c1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
This compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of 4-(6-bromophthalazin-1-yl)-3-methylpiperazin-2-one (0.200 g, 0.62 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.245 g, 0.81 mmol), sodium carbonate (0.270 g, 2.5 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.040 g, 0.050 mmol) in DME (7 mL)/H2O (3 mL)/EtOH (2 mL) was heated at 90° C. The reaction was purified by flash chromatography eluting with 2M NH3 in MeOH/CH2Cl2 (0:1-1:19) to give 126 mg of a brown amorphous solid. The material was further purified by reverse phase HPLC (10→100% CH3CN [0.1% TFA]) to give the title compound as a light yellow amorphous solid. Found MS m/z: 416.2 [M+1].
Reaction SMILES: [CH2:1]([N:4]1[C:12]2C(Cl)=NC=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3].[H-].[Na+].CI.[CH3:18][N:19]([CH:21]=[O:22])[CH3:20]>O>[CH2:1]([N:4]1[C:12]2[C:21](=[O:22])[N:19]([CH3:20])[CH:18]=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCn1ccc2ncnc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: C=CCn1ccc2ncn(C)c(=O)c21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a room temperature solution of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (220 mg, 1.3 mmol, 1 equiv.) in 3 mL of DMF was added 60% NaH (100 mg, 2.5 mmol, 2 equiv.) followed by MeI (0.18 ml, 1.8 mmol, 1.5 equiv.). After 30 minutes, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-90% CH3CN/water+0.1% TFA). The desired fractions were combined and concentrated to remove CH3CN. The remaining aqueous mixture was extracted with EtOAc, dried, filtered, and evaporated to provide 152 mg (64%) of 5-allyl-3-methyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([NH:48][C:49]([CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.CN(C=O)C>[CH2:41]([NH:48][C:49]([CH:51]1[CH2:56][CH2:55][N:54]([C:12]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:53][CH2:52]1)=[O:50])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(O)c1nccn1Cc1ccc(Cl)cc1
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)C1CCN(C(=O)c2nccn2Cc2ccc(Cl)cc2)CC1
Reaction time: 14 h

Procedure:
The following was added sequentially to DMF: 1-(4-chlorobenzyl)-1H-imidazole-2-carboxylic acid (71 mg, 0.298 mmol), DIPEA (0.16 mL, 0.894 mmol), EDC (69 mg, 0.358 mmol), and HOBT (55 mg, 0.358 mmol). This was allowed to stir at rt for 30 min, at which time N-benzylpiperidine-4-carboxamide hydrochloride (76 mg, 0.298 mmol) was added and stirring continued at rt for 14 h. Addition of water caused precipitation, which was collected over a filter and washed with water and small amount of diethyl ether and EtOAc to give the title compound as a white solid. (Yield: 37 mg, 0.085 mmol, 28%) 1H NMR (400 MHz, CDCl3) 7.34-7.23, 7.13, 7.11, 7.04, 6.93, 5.79-5.65, 5.36, 4.63, 4.43, 3.14, 2.82, 2.42-2.32, 1.95, 1.83, 1.70-1.59
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]([OH:22])[CH2:12][NH:13][CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(CC)(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:11]([OH:22])[CH2:12][N:13]([CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[S:45]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:44][CH:43]=2)(=[O:47])=[O:46])[CH2:4][O:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
{(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl}-carbamic acid[1,3]dioxan-5-yl ester (14.8 mg, 0.04 mmol) was combined with 4-benzyloxybenzenesulfonyl chloride (12.0 mg, 1.2 eq.) in anhydrous DMF (1 mL). Solution was chilled to 0° C. and N(i-Pr)2Et (18.4 μL, 3 eq.) was added. Reaction was allowed to warm to room temperature and stirred for 5 hours. Reaction mixture was diluted in EtOAc (10 mL) and washed with sat. NaHCO3 (10 mL), 0.5 N KHSO4 (10 mL) and brine (10 mL). Organic phase was dried with MgSO4 and solvent was removed in vacuo. Purification by preparative TLC (1:1, EtOAc:Hex). Recovered 4.2 mg (18%) of the product as a colorless residue. MS(ES); 666.2 (M+1), HPLC; tR=13.24 min. (98%).
Reaction SMILES: [S:1]([O-])([O-])(=O)=[S:2].[Na+].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][S:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=S([O-])([O-])=S
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCCCCCSSCCCCCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
Sodium thiosulfate (55.3 g, 350 mmol) is added to a suspension of 11-bromo-undecanoic acid (92.8 g, 350 mmol) in 50% aqueous 1,4-dioxane (1000 ml). The mixture is heated at reflux (90° C.) for 2 h until the reaction to the intermediate Bunte salt was complete (clear solution). The oxidation to the corresponding disulfide is carried out in situ by adding iodine in portions until the solution retained with a yellow to brown colour. The surplus of iodine is retitrated with 15% sodium pyrosulfite in water. After removal of 1,4-dioxane by rotary evaporation the creamy suspension is filtered to yield product 11,11′-dithiobis(undecanoic acid). Recrystallization from ethyl acetate/THF provides a white solid (73.4 g, 96.5%): mp 94° C.; 1H NMR (400 MHz, CDCl3/CD3OD 95:5): δ 2.69 (t, 2H, J=7.3 Hz), 2.29 (t, 2H, J=7.5 Hz), 1.76-1.57 (m, 4H), and 1.40-1.29 (m, 12H); FAB-MS (Cs+, 20 keV): m/z (relative intensity) 434 (100, M+). Anal. Calcd. for C22H42O4S2: C, 60.79; H, 9.74; S, 14.75. Found: C, 60.95; H, 9.82; S, 14.74. To a solution of 11,11′-dithiobis(undecanoic acid) (1.0 g, 2.3 mmol) in THF (50 ml) is added N-hydroxysuccinimide (0.575 g, 5 mmol) followed by DCC (1.03 g, 5 mmol) at 0° C. After the reaction mixture is allowed to warm to 23° C. and is stirred for 36 h at room temperature, the dicyclohexylurea (DCU) is filtered. Removal of the solvent under reduced pressure and recrystallization from acetone/hexane provides 11,11′-dithiobis(succinimidylundecanoate) as a white solid. Final purification is achieved by medium pressure liquid chromatography (9 bar) using silica gel and a 2:1 mixture of ethyl acetate and hexane. The organic phase is concentrated and dried in vacuum to afford 11,11′-dithiobis(succinimidylundecanoate) (1.12 g, 78%): mp 95° C.; 1H NMR (400 MHz, CDCl3): δ 2.83 (s, 4H), 2.68 (t, 2H, J=7.3 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.78-1.63 (m, 4H), and 1.43-1.29 (m, 12H); FAB-MS (Cs+, 20 keV): m/z (relative intensity) 514 (100), 628 (86, M+). Anal. Calcd. for C30H48N2O8S2: C, 57.30; H, 7.69; N, 4.45; S, 10.20. Found: C, 57.32; H, 7.60; N, 4.39; S, 10.25.
Reaction SMILES: [F:1][N+]1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1S([O-])(=O)=O.[OH:20][C:21]1[C:31]2[CH2:30][CH2:29][N:28]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(O)(C(F)(F)F)C(F)(F)F>C(Cl)Cl>[F:1][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:30][C:31]=2[C:21]=1[OH:20]
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)[n+]1F
Solvent: ClCCl
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C(N1CCc2ccc(F)c(O)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
Add N-fluoro-4,6-bis(trifluoromethyl)-pyridinium 2-sulfonate (3.02 g, 9.6 mmol) to a stirred mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.5 g, 9.6 mmol) and hexafluoro-2-propanol (10 mL) in DCM (150 mL). Stir at ambient temperature for 16 h. Concentrate the reaction mixture and partition the residue between EtOAc and 1N aqueous HCl. Wash the organic fraction with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 6:1, 5:1 and 3:1) to give 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (1.8 g, 68%). Dissolve 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.5 g, 5.41 mmol) in a mixture of DCM (20 mL) and pyridine (2 mL) and cool in an ice bath. Add dropwise to the stirred solution a mixture of trifluoromethanesulfonic anhydride (1.64 mL, 9.74 mmol) in DCM and stir the reaction for 1.5 h at ambient temperature. Dilute the reaction with DCM (300 mL) and wash with 2.5N aqueous HCl. Dry the organic fraction over Na2SO4, filter and concentrate to give the title product as a white solid (2.2 g, 99%). MS (ES+) m/z: 410 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:1]1([NH:5][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Cyclobutylamine (370 mg) was added to an ice-cold suspension of tert-butyl bromoacetate (1.0 g) and potassium carbonate (700 mg) in acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was then extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure to afford tert-butyl N-cyclobutylglycinate (949 mg) as the residue.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1C)[CH:7]=[O:8])[CH3:2].[OH:13][C:14]1C=C(C=C(O)[CH:21]=1)C=O.C(I)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:11]=1)[CH:7]=[O:8])[CH3:21]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cc(C=O)cc(OCC)c1

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10, vide infra) by reaction of 3,5-dihydroxybenzaldehyde with ethyl iodide in DMF using K2CO3 as base.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>CN(C)C=O>[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: FB(F)F
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(Cc4ncc[nH]4)CC3)c(F)c2)C(=O)O1
Yield: 66 %

Procedure:
The compound was obtained by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.40 mmol), BF3 etherate (catalytic) and imidazole (1.80 mmol) in dimethylformamide (10 ml) at 80° C. for 8 hours, followed by silica gel column chromatographic separation to provide title compound in 66% yield. M.P. 130-132° C. and MS (M+1)=432 (MH+, 100%) for M.F.=C21H26FN5O4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([NH:20][CH3:21])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:23])=[O:22])=[CH:4][CH:3]=1.[CH2:24]([Li])CCC.CI.O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([N:20]([CH3:24])[CH3:21])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:23])=[CH:4][CH:3]=1
Reactant: CNc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CN(C)c1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-chlorophenyl)-4-methyl-6-(N-methylamino)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (55 mg) in dry THF (2 ml) was added a 1.5M solution of n-butyl lithium in n-Hexane (0.16 ml) at -78° C. The mixture was stirred at 0° C. for 30 minutes and added methyl iodide (0.05 ml) at the same temperature. After the mixture was stirred at 0° C. for 30 minutes, water was added. The mixture was extracted two times with ethyl acetate and the combined organic layers were washed with water and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by preparative thin layer chromatography (eluted with a mixture of benzene and acetone (9:1) to give 2-(4-chlorophenyl)-6-(N,N-dimethylamino)-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (8 mg) as colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(C)=O>[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: COC(CCBr)OC
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COC(CCOc1ccc(CCO)cc1)OC

Procedure:
A mixture of 4-(2-hydroxyethyl)phenol (1 g), 3-bromopropionaldehyde dimethyl acetal (1.02 mL), cesium carbonate (2.83 g) and a catalytic amount of sodium iodide in acetone (15 mL) was stirred at room temperature overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 3-[4-(2-hydroxy-ethyl)phenyloxy]propionaldehyde dimethyl acetal (1.22 g). This material was dissolved in methylene chloride (15 mL). To the solution were added triethylamine (0.85 mL) and methanesulfonyl chloride (0.43 mL) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with 0.5 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[4-(2-methanesulfonyloxyethyl)-phenyloxy]propionaldehyde dimethyl acetal (1.49 g). To a solution of 7-benzyloxy-1H-indole (1.04 g) in N,N-dimethyl-formamide (10 mL) was added sodium hydride (55% 0.25 g) under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture were added the above 3-[4-(2-methane-sulfonyloxyethyl)phenyloxy]propionaldehyde dimethyl acetal (1.49 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-5/1) to give 7-benzyloxy-1-{2-[4-(3,3-dimethoxypropoxy)phenyl]ethyl}-1H-indole. This material was dissolved in tetrahydrofuran (10 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.57 g).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:23]([F:24])=[CH:22][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:34]OC(OC)N(C)C>C1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]3[C:13]([C:14](=[O:15])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:34][N:25]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:22][C:23]=2[F:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 88.1 %

Procedure:
In 2 ml of benzene was suspended 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate, and 100 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 7 hours. Subsequently, the crystals thus deposited were collected by filtration and washed with 2 ml of diethyl ether to obtain 180 mg (yield 88.1%) of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 233°-236° C.