Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)(O)[O-].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[NH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([O:18][C:15]4[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])=[CH:17][CH:16]=4)[C:20]=3[CH:27]=2)=[CH:33][CH:32]=1)[CH3:37]
Reactant: CCN(CC)CCCl
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1)Nc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)Nc5cccc(F)c5)cc4)ncnc3[nH]2)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
After dissolving 114 mg of 1-(3-fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yloxy]phenyl}urea in 2 ml of dimethylformamide, there were added 44 mg (ca. 1 equivalent) of 2-chloroethyldiethylamine hydrochloride and 63 mg (2.5 equivalents) of potassium bicarbonate, and the mixture was stirred at 50-60° C. for 16 hours. There were then added 17 mg of 2-chloroethyldiethylamine hydrochloride, 20 mg of potassium bicarbonate and 1 ml of dimethylformamide, and the mixture was stirred overnight at the same temperature. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 33 mg of a crude solid containing the title compound. This was washed with ethyl acetate to obtain 5 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Brc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 10.7 g of 3-bromo-1H-pyrazole, 11.8 g of 2,3-dichloropyridine, 57.3 g of cesium carbonate and 80 ml of N,N-dimethylformamide was stirred at 100° C. for 8 hours. The reaction mixture was allowed to cool to room temperature. After water was added, and the reaction mixture was extracted with methyl tert-butyl ether two times. The organic layers were combined, washed with sequentially with water and a saturated solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 12.9 g of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine.
Reaction SMILES: C([O-])(=O)C.[Cu+2:5].C([O-])(=O)C.[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>CO>[NH2:10][CH2:11][C:12]([O-:14])=[O:13].[Cu+2:5].[NH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: NCC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: NCC(=O)[O-]

Procedure:
1.8 g (9.8 mmoles) of copper(II) acetate are dissolved in 100 ml of hot methanol and a solution of 1.5 g (20 mmoles) of glycine in 50 ml of methanol is added with stirring to the resulting solution. The solution turns cloudy under the effect of precipitated product. After stirring for 2 hours at a falling temperature, the product precipitated is filtered off and dried. Yield: 2.5 g (96% of the theoretical), Mp.:>210° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=3[CH3:26])=[CH:13][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:29]=[CH:30][CH:31]=[N:32][C:4]1=2)[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:22])=[CH:19][C:18]=3[CH3:26])=[CH:13][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:29]=[CH:30][CH:31]=[N:32][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)Cl)cc3C)cc2C(=O)N(C)c2cccnc21
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN1c2ncc(CCOc3ccc(C(=O)Nc4ccncc4)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 103.7 %

Procedure:
A solution of 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoyl chloride (47.4 mg, 0.11 mmol), 4-aminopyridine (9.88 mg, 0.11 mmol) and Et3N (15.3 μL, 0.11 mmol) in CH2Cl2 (4 mL) was stirred at 25° C. for 5 h. The reaction mixture was diluted with EtOAc and the resulting solution was successively washed with aqueous saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (58 mg, 100% yield) as a colorless oil.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:14][CH2:15][CH2:16]Br.[OH-:18].[K+].Cl>O>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]([OH:12])=[O:11])=[CH:3][C:2]=2[CH2:16][CH2:15][CH2:14][O:18]1
Reactant: BrCCCBr
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCCOO2
Yield: 22.6 %

Procedure:
A mixture of 3,4-dihydroxyphenylacetic acid (5.0 g), 1,3-dibromopropane (7.2 g) and potassium hydroxide (7.3 g) in water (25 ml) was heated under reflux for 17 hours, acidified to pH 1 with 2M hydrochloric acid and extracted several times into methylene chloride. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (75 g) using methylene chloride plus 0-2% acetic acid as the eluant. Appropriate fractions were combined and evaporated and the residue was taken up in methylene chloride and extracted into 5% aqueous sodium carbonate solution. The basic extract was washed with methylene chloride, acidified to pH 1 with 5M hydrochloric acid and extracted into methylene chloride. The organic extract was dried over magnesium sulphate and evaporated to give the title compound as a colourless solid (1.4 g, 23%), m.p. 99°-101°.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[C:9]([F:15])=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:17]1C(C)=CC=CN=1>>[F:15][C:9]1[C:8]([C:3]2[C:2]([CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:14]
Reactant: Cc1cccnc1Br
Reactant: Nc1cccc(-c2ncccc2Cl)c1F
Product: Cc1cccnc1-c1cccc(N)c1F

Procedure:
was prepared by using the same procedures as described for the preparation of 3-(3-chloro-pyridin-2-yl)-2-fluoro-phenylamine in Scheme C6, starting from 2-bromo-3-methylpyridine [3430-17-9]. MS (LC-MS): 203 [M+H]+; tR (HPLC conditions k): 1.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:12]([O-:15])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]([O:15][CH3:12])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1ccc(Cl)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
5-Chloro-2-hydroxy-benzamide (1.5 g, 8.7 mmol) was dissolved in DMF (120 mL) and to the stirred solution K2CO3 (1.38 g, 10 mmol) and benzylbromide (1.71 g, 10 mmol) were added. The mixture was stirred at room temperature overnight. The suspension was concentrated in vacuo, and the residue was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was separated and extracted with ether (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 90/10), to give 75 as a white solid (2.15 g, 95%). 1H NMR (CDCl3, 300 MHz) δ8.20 (d, J=3 Hz, 1H), 7.67 (br s, 1H), δ7.44-7.38(m, 6H), 7.99 (d, J=9 Hz, 1H), 5.85 (br s, 1H), 5.17 (s, 2H). MS (m/e) (positive FAB) 262.1 (M+H)+. m.p. 110-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:26])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH2:11][CH2:10][C@@H:9]1[CH2:27]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:26])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:23])[F:25])[CH:16]=2)[CH2:11][CH2:10][C@@H:9]1[CH2:27][N:33]=[N+:34]=[N-:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](COS(C)(=O)=O)CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CN=[N+]=[N-])CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-2-methanesulfonyloxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (465 mg, 0.97 mmol) in DMF (3 mL) was added a solution of sodium azide (313 mg, 4.82 mmol) in water (0.5 mL) and the mixture was stirred at 80° C. under nitrogen atmosphere overnight. EtOAc and a saturated aqueous solution of NaHCO3 were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the desired compound. MS (LC-MS): 330 [MH−Boc]+; tR (HPLC conditions b) 5.75 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:36]=[C:37]([C:45]([F:48])([F:46])[F:47])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)c1cc(Sc2ccc(Br)cc2)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Yield: 37.8 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-bis-trifluoromethyl-benzene (0.29 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-bis-trifluoromethyl-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.115 g, 37%) as a solid.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([C:15](=O)[CH3:16])[CH:12]=[CH:13][CH:14]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][C:9]1[CH:10]=[C:11]([C:15](=[N:7][S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: 70 °C

Procedure:
Add Ti(OEt)4 (7 mL, 17 mmol) to a solution of (R)-(+)-2-methyl-2-propane sulfinamide (1.0 g, 8.3 mmol) and 1-(3-bromophenyl)ethanone (1.8 g, 9.1 mmol) in anhydrous THF (30 mL) at RT. Heat the mixture at 70° C. for 24 h. Allow the reaction mixture to cool to RT and pour into 30 mL of brine under vigorous stirring. Filter the suspension through a pad of Celite and wash the solid with EtOAc (2×20 mL). Wash the filtrate with brine (30 mL), dry (Na2SO4), and concentrate in vacuo. Chromatograph the residue on a silica gel column and elute with Et2O/hexanes to give (R)—N-(1-(3-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[NH:2]([C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1)[C:31]([NH2:30])=[S:32]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A solution of 10 g (48 mmol) 3-Amino-benzenesulfonamide hydrochloride in 100 ml THF and 8.2 ml (48 mmol) N,N-Diisopropylethylamine was treated with 6.45 ml (48 mmol) benzoyl isothiocyanate and allowed to stir at room temperature. After evaporation to dryness the residue was suspended in diethyl ether. The precipitate was filtered off, dried and suspended in 130 ml methanol and 100 ml THF. K2CO3 (130 mmol) in 45 ml water was added and the mixture was stirred for 60 h at room temperature. The mixture was evaporated to drynes and the residue was treated with water and extracted with ethyl acetate. The combined organic layers were dried with MgSO4 filtered and evaporated to dryness. After suspending the residue in diethyl ether, filtration and drying 8.4 g (76%) of the title compound was obtained as white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[N:26]=2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][N:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:29])[N:26]=2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: NNC(=O)Cn1nnc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(Cn1nnc(-c2cccc([N+](=O)[O-])c2)n1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[5-(3-nitrophenyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 80 mg of the title compound (77%) as a yellow powder in 97% purity by HPLC (Rt: 4.96, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Na].[CH3:10][O-:11].[Na+].F[C:14]1[C:18]([F:20])([F:19])[C:17]([F:22])([F:21])[C:16]([F:24])([F:23])[C:15]=1F>CO.O.CN(C)C=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:14]2[C:18]([F:20])([F:19])[C:17]([F:22])([F:21])[C:16]([F:24])([F:23])[C:15]=2[O:11][C:10]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Oc1ccc(O)cc1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Oc1ccc(OC2=C(Oc3ccc(O)cc3)C(F)(F)C(F)(F)C2(F)F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
100 g (1.0 mol) of hydroquinone were dissolved in 200 ml of methanol with heating and converted into the monosodium salt using 180 g of 30% strength by weight sodium methoxide solution. 132 g (1.0 mol) of the sodium salt were then added in portions at 5° C. to a mixture of 250 ml of dimethylformamide and 106 g (0.5 mol) of perfluorocyclopentene. After stirring at room temperature for 19 hours, the mixture was added to 500 ml of water, and the organic phase was separated off after addition of 1000 ml of methylene chloride and subsequently washed with 500 ml of water. After drying, the solvent was stripped off on a rotary evaporator. 177 g of a partly crystalline, oily material remained. For further purification, this was dissolved in 200 ml of ethanol and reprecipitated by addition of 100 ml of water. 143 g of a slightly oily product was obtained, which corresponds to 73% of theory. The spectroscopic data (mass spectrum and 19F nuclear magnetic resonance spectrum) corresponded to the product from Example 44a).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[CH:28]([N:31](C(C)C)[CH2:32]C)(C)C.CNC.O>CS(C)=O>[CH3:28][N:31]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2)[CH3:32]
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: CS(C)=O
Solvent: O
Product: CN(C)Cc1cc([N+](=O)[O-])c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester (1.0 g, 2.4 mmol) prepared in Preparation 41 was dissolved in dimethylsulfoxide (15 mL). Diisopropylethylamine (0.6 g, 4.9 mmol) and dimethylamine (0.2 g, 4.9 mmol) were added thereto, and the mixture was stirred for 6 h at room temperature. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (0.7 g, Yield 71%).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:26]2[N:27]=[N:28][NH:29][N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=2)[C:26]2[N:27]=[N:28][N:29]([CH2:2][CH2:3][OH:4])[N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6]
Reactant: OCCBr
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
Add 2-bromoethanol (0.093 mL, 1.25 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzyl-(2H-tetrazol-5-yl)amino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (653 mg, 1.045 mmol) and cesium carbonate (749 mg, 2.30 mmol) in dry dimethylformamide under an atmosphere of nitrogen and stir the mixture at 50° C. for 24 h. Cool to room temperature, add water, and extract with ethyl acetate. Dry the organic solvent over sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford a mixture of two compounds. Separate by normal phase HPLC eluting with standard hexane/ethanol gradient to afford (+/−)-trans-4-[(3,5-bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1carboxylic acid isopropyl ester (48 mg, 7%). 1H NMR (CDCl3, 300 MHz): δ 0.95 (t, J=7.7 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H), 1.35 (d, J=6.3 Hz, 3H), 1.55-1.69 (m, 2H), 2.31-2.47 (m, 3H), 3.98-4.00 (m, 2H), 4.49-4.73 (m, 5H), 5.09 (septuplet, J=7.5 Hz, 1H), 5.41 (dd, J=11.9, 7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.81 (s, 2H), 8.39 (d, J=8.6 Hz, 1H). MS (ES+): 670 (M+H).
Reaction SMILES: [Mg].[C:2]([CH2:21][CH2:22]I)([C:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3].Cl.C(Cl)(Cl)Cl>C(OCCC)CC.CI>[C:2]([CH2:21][CH2:22][CH2:22][CH2:21][C:2]([C:5]([C:8]([C:11]([C:14]([C:17]([F:18])([F:19])[F:20])([F:15])[F:16])([F:12])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3])([C:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Agent: Cl
Agent: [Mg]
Solvent: CCCOCCC
Solvent: ClC(Cl)Cl
Solvent: CI
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 63.4 %

Procedure:
In accordance with K. von Werner, DE 39 25 525 A1 (1989), in a four-necked flask of 250 cm3 capacity, which is equipped with a dropping funnel (with bypass for pressure equalization), vane stirrer, thermometer and reflux condenser with superimposed check valve, 1.82 g (0.075 mol) magnesium chips are placed under argon in 10 cm3 of anhydrous di-n-propyl ether and activated with a few drops of methyl iodide with gentle heating. The temperature is raised to 80° C. while a mixture of 23.7 g (0.05 mol) of C6F13CH2CH2I and 60 cm3 of anhydrous di-n-propyl ether is added drop by drop within one hour with vigorous stirring. Then the mixture is stirred with refluxing for 9 hours and then cooled to 10° C., hydrolyzed with 100 cm3 of 5 wt.-% aqueous hydrochloric acid until the excess magnesium has dissolved. Then the ether phase is separated and concentrated with a rotary evaporator. The oily residue thus obtained is treated with 30 cm3 of chloroform and let stand for 1 hour at 0° C. The solid product precipitated from the mixture is suction filtered and dried in the desiccator. 11.0 g of C6F13(CH2)4C6F13 is obtained as nearly colorless crystals which have a melting point of 48° C. The yield is 63.2% of the theoretical.