Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+]>CS(C)=O>[N:40]([CH2:28][C@H:23]1[O:22][C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:25]([OH:26])[C@@H:24]1[OH:27])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1O[C@H](OCc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](O)[C@@H]1O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 32.14 g of benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolylsulfonyl)-α-D-glucopyranoside in 75 ml of dimethyl sulfoxide was treated at room temperature with 7.5 g of sodium azide and stirred at 90°C. for 3 hours. The mixture was then poured on to ice/water. Separated crystals were filtered off under suction, washed with water and dried. There was obtained benzyl 6-azido-2-benzyloxycarbonylamino-2,6-didesoxy-α-D-glucopyranoside, [α]+l 119.6° (c 0.5; dioxan), MS: mlz 428 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:7]([CH3:12])([N+:9]([O-])=O)[CH3:8])[CH2:3][CH2:2]1.N>C(O)C.[Ni]>[ClH:19].[CH:1]1([CH:4]2[CH2:5][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:7]([CH3:12])([CH3:8])[NH:9]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C(C(=O)CC1CC1)c1ccc(Cl)cc1)[N+](=O)[O-]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC1(C)NC(C2CC2)CC1c1ccc(Cl)cc1
Product: Cl

Procedure:
15.3 G of 1-cyclopropyl-3-(p-chlorophenyl)-4-methyl-4-nitropentanone in 200 ml of ethanol saturated with ammonia are hydrogenated for 7 hours 30 minutes under 100 atmospheres at 120° C in the presence of 8 g of Raney Nickel. After filtration and concentration of the filtrate in vacuo, the residue is diluted with ethanol-ether (50:50) and the base is neutralised with hydrogen chloride in ether. The precipitate so obtained is filtered off, washed with ether and recrystallized from isopropanol to give 9.5 g of 2-cyclopropyl-4-(p-chlorophenyl)-5,5-dimethyl-pyrrolidine hydrochloride as white crystals. Melting point = 235°-240° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)(=O)C.[CH3:18][NH:19][CH3:20].[CH2:21]=O.[ClH:23]>C(O)C>[ClH:23].[CH3:18][N:19]([CH2:21][C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[CH:13]=1)[NH:10][C:9](=[O:17])[CH2:8][CH2:7]2)[CH3:20]
Reactant: COc1ccc(OC(C)=O)c2c1NC(=O)CC2
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: COc1cc(CN(C)C)c(O)c2c1NC(=O)CC2

Procedure:
1.5 Grams of 5-acetoxy-3,4-dihydro-8-methoxy-2(1H)-quinolinone was suspended in 10 ml of ethanol, to this suspension were added 4 ml of 50%-dimethylamine aqueous solution and 2 ml of 37%-formalin, this mixture was refluxed by heating for 10 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by a silica gel flash column chromatography (eluent: methylene chloride: methanol=20:1→10:1). The oily product thus obtained was dissolved in ethanol, this solution was acidified by adding hydrochloric acid, concentrated to dryness, and recrystallized from ethanol, there was obtained 3.8 g of 6-(dimethylaminomethyl)-3,4-dihydro-5-hydroxy-8-methoxy-2(1H)-quinolinone hydrochloride as white powdery product.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:1]([O-:3])=[O:2])=[C:8]([CH3:12])[CH:7]=1
Reactant: Cc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 14 %
Yield: 39 %

Procedure:
Concentrated nitric acid (16 mL) was slowly added, at 0° C., to a solution of 3-chlorotoluene (3 mL, 25.4 mmol) and concentrated sulfuric acid (6 mL) in glacial acetic acid (20 mL) and the resulting mixture was stirred for 24 hours allowing the temperature to rise until room temperature. The reaction mixture was then poured into ice-water and partitioned between water and diethyl ether. The aqueous phase was separated and extracted twice with diethyl ether; the combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow oily residue was purified on a silica gel plug and twice by flash chromatography to give 1.22 g (14% yield) of 2-chloro-4-methyl-1-nitro-benzene as a yellow oil and 3.39 g (39% yield) of 4-chloro-2-methyl-1-nitro-benzene.
Reaction SMILES: C([OH:3])C.C[C:5]1[C:10]([OH:11])=C(C)[C:8]2[CH2:13][CH2:14][C@:15]([CH2:18][CH2:19][CH2:20][C@@H:21]([CH2:23][CH2:24][CH2:25][C@@H:26]([CH2:28][CH2:29]CC(C)C)C)C)(C)O[C:7]=2[C:6]=1C>O>[C:10]([OH:3])(=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:13][CH2:14][CH2:15]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:28][CH3:29]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: CCO
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
A negative control was prepared by adding, to the reaction liquid, only 2 ml of 99.5% ethanol and 2 ml of distilled water, without adding anything else. Positive controls were prepared in the same way as for the present compound at the same concentration, except that the present compound was replaced with α-tocopherol or BHA.
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][C:7](=[O:33])[CH2:8][NH:9][C@@H:10]([C:14]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22](=[O:31])[C:21]3[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=3)[N:15]=2)[CH:11]([CH3:13])[CH3:12])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.CCN(CC)CC.[C:47]1([CH3:56])[C:48]([C:53](Cl)=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1>C(Cl)Cl>[C:47]1([CH3:56])[C:48]([C:53]([N:9]([CH2:8][C:7](=[O:33])[CH2:6][N:5]2[C:4](=[O:34])[C:3]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]3[C:1]2=[O:39])[C@@H:10]([C:14]2[N:23]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22](=[O:31])[C:21]3[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=3)[N:15]=2)[CH:11]([CH3:13])[CH3:12])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(CC(=O)CN1C(=O)c2ccccc2C1=O)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To 2-[(R)-1-(3-phthalimido-2-oxo-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (7.22 g, 13.3 mMol) in CH2Cl2 (50 mL) was added Et3N (2.0 mL, 14.3 mMol) and toluoyl chloride (1.9 mL, 14.4 mMol). The reaction was stirred at RT for 18 h, concentrated under vacuum, taken up in EtOAc, washed with 1 N HCl, brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography on silica gel (1% MeOH/CH2Cl2) followed by trituration with (1:1) Et2O/pet. ether, filtration and drying under vacuum gave the title compound (6.41 g, 73%) as a white solid. A side fraction (1.20 g) which contained mostly product was also obtained: 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.6 Hz, 1 H), 7.69-7.78 (m, 5 H), 7.45-7.49 (m, 3 H), 7.34 (t, 2 H), 7.25-7.29 (m, 3 H), 7.15 (d, J=8.1 Hz, 2 H), 6.19 (d, J=15.9 Hz, 1H), 5.82 (d, J=10.6 Hz, 1H), 5.12 (d, J=15.9 Hz, 1H), 4.56 (d, J=18.8 Hz, 1 H), 4.26 (d, J=18.8 Hz, 1 H), 4.09 (d, J=17.6 Hz, 1 H), 3.90 (d, J=17.6 Hz, 1H), 2.62 (n, 1 H), 2.42 (s, 3 H), 0.93 (d, J=6.8 Hz, 3 H), 0.32 (d, J=6.4 Hz, 3 H); MS (ES) m/e 661.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].N#N>CCOCC.N1C=CC=CC=1>[N+:9]([C:4]1[CH:3]=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[CH3:8])([O-:11])=[O:10]
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(Oc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63.1 %

Procedure:
4-Bromo-2-nitrotoluene (25.0g, 116 mmol), 4-fluorophenol (8.70g, 77.6 mmol), potassium carbonate (21.5g, 156 mmol) and pyridine (75 mL), were combined under N2 atmosphere and heated at 90° C. for 30 min. The reaction mixture was cooled to ambient temperature, CuO (15.4g, 194 mmol) was added under a stream of N2, and the resulting dark-brown suspension was heated at reflux for 17 hours. The reaction mixture was cooled to ambient temperature and diluted with ether. The solids were removed by filtration through celite. The ethereal solution was washed with 1.0M aqueous NaOH, 1.0M aqueous HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a dark-brown oil. The crude product was purified by chromatography on silica gel to give 2-nitro-4-(4-fluorophenoxy)-toluene (12.1 g, 63%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1(C)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:13]1([N:19]([CH2:25][CH3:26])[C:20]([NH:22]CC)=O)CCCC[CH2:14]1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O>[CH:6]1([N:22]=[C:20]([N:19]([CH2:25][CH3:26])[CH2:13][CH3:14])[N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCNC(=O)N(CC)C1CCCCC1
Reactant: Cc1ccccc1
Reactant: CCNCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCN(CC)C(=NC1CCCCC1)N(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (144 ml, 237 g, 1.55 mol) is added dropwise over a 1.5 hour period to a toluene (800 ml) solution of cyclohexyl-diethylurea (297 g, 1.5 mol). The reaction is stirred overnight at room temperature. Diethylamine (330 ml, 234 g, 3.2 mol) is added dropwise for over a 2 hour period, then stirred 3 hours at room temperature. The reaction mixture is poured into water (3000 ml). The water layer is extracted with toluene (3×200 ml). The organic layer and extracts are combined and dried over Na2CO3, filtered and concentrated. The residue is further distilled under vacuum (ca. 0.3-0.5 torr) collecting product, cyclohexyl-tetraethylguanidine, at 110°-112° C. (334 g, 88%) of 99% purity as judged by gas chromatography. 1H NMR (CD3CN) δ 3.13-3.23 (m, 1H), 3.07 (q, 4H), 2.97 (q, 4H), 1.13-1.77 (m, 10H), 1.0 (t, 6H), 0.98 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:7](=[O:19])[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)=[CH:4][CH:3]=1.[CH2:28]([C:30]([CH:33]=[N:34][C:35]([O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH2:36])=[CH:31][CH3:32])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:19])[C:6]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:36][C:35](=[O:37])[NH:34][CH:33]3[C:30]([CH2:31][CH3:32])=[CH:28][CH3:29])[C:5]2=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([Si:38]([CH3:39])([CH3:40])[CH3:41])[CH3:14]
Reactant: C=C(N=CC(=CC)CC)O[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CC=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: COC(C)[Si](C)(C)C
Yield: 84.9 %

Procedure:
In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (5.4 g, 12.8 mmol) prepared in example 55a was reacted with 1-(1-ethyl-propenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 g, 95 mmol) prepared in example 66a in toluene (200 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white gum (Yield 6.1 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([S:7][CH3:8])=[N:5][N:6]=1.[CH3:15][I:16]>>[I-:16].[CH3:15][N+:6]1[N:5]=[C:4]([S:7][CH3:8])[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[CH3:1]
Reactant: CI
Reactant: CSc1nnc(C)n1-c1ccccc1
Product: CSc1n[n+](C)c(C)n1-c1ccccc1
Product: [I-]

Procedure:
Then, 10 g of 5 methyl-3-methylthio-4-phenyl-1,2,4-triazole thus obtained was mixed with 40 g of methyl iodide and the mixture was heat-refluxed for 4 hours to precipitate crystals, which were collected by filtration and recrystallized from ethanol to provide 1,5-dimethyl-3-methylthio-4-phenyl-1,2,4-triazolium iodide.
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][C:12]=3Br)[O:7][C:6]=2[CH:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.C([Li])CCC.[OH-:30].[K+].[OH:32]O.Cl>CCCCCC.C1COCC1.O>[OH:30][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][C:12]=3[OH:32])[O:7][C:6]=2[CH:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)Oc1cc(C(C)(C)C)cc(Br)c1C2
Reactant: OO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)c1cc(O)c2c(c1)Oc1cc(C(C)(C)C)cc(O)c1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g (13.3 mmol) of 1,8-dibromo-3,6-di-tert-butylxanthene together with THF were placed in a reaction vessel under argon. At −50° C., 12.3 ml (30.7 mmol) of a 2.5 molar n-butyllithium solution in hexane were added. The reaction mixture was stirred for 2 hours, resulting in formation of a colorless suspension. At 0° C., 100 ml (100 mmol) of a 1 molar solution of BH3 in THF were added dropwise and the mixture was stirred overnight at 5–15° C. It was subsequently carefully hydrolyzed at 0° C. using 25 ml of water. 3 N KOH (7.4 g of KOH in 32 g of H2O) and 10.4 g of 30% strength H2O2 solution were carefully added to the reaction mixture and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, it was neutralized using 18% strength hydrochloric acid. After phase separation, the organic phase was washed twice with NaCl solution, dried over Na2SO4 and evaporated to dryness. 1,8-Dihydroxy-3,6-di-tert-butylxanthene was obtained in a yield of 4.7 g (100% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:15]=[N:16][C:17]([C:18]([O:20]CC)=[O:19])=[C:4]2[CH2:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:15]=[N:16][C:17]([C:18]([OH:20])=[O:19])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(C)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc2c1C(=O)N(C)Cc1c(C(=O)O)ncn1-2

Procedure:
25 g (85 mmol) of ethyl 5,6-dihydro-5,7-dimethyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate were heated to boiling under reflux for 1 hour with 3.40 g (85 mmol) of sodium hydroxide in 200 ml of ethanol and 15 ml of water. After evaporation of the ethanol the mixture was diluted with water and acidified with 21 ml of 4 normal hydrochloric acid. The suspension obtained was suction filtered and washed with water. After drying the suction filter cake there was obtained 5,6-dihydro-5,7-dimethyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 274-275°.
Reaction SMILES: [F-:1].[Cs+].COCCOCCOCCOCCOC.[C:18]([O:28][C:29]([C:35]([F:37])=[O:36])([C:31]([F:34])([F:33])[F:32])[F:30])([C:21]([C:24]([F:27])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19].[F:38][C:39]1(F)[O:49][C:40]1([C:45]([F:48])([F:47])[F:46])[C:41]([F:44])([F:43])[F:42]>>[C:18]([O:28][C:29]([C:35]([O:36][C:40]([C:39]([F:38])=[O:49])([C:41]([F:42])([F:43])[F:44])[C:45]([F:48])([F:47])[F:46])([F:1])[F:37])([C:31]([F:33])([F:34])[F:32])[F:30])([C:21]([C:24]([F:27])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19]
Reactant: FC(F)(F)C1(C(F)(F)F)OC1(F)F
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: [F-]
Agent: COCCOCCOCCOCCOC
Agent: [Cs+]
Product: O=C(F)C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
In vacuo a mixture of cesium fluoride (1.2 g, 7.90 mmol), tetraglyme (2.4 g) and C3F7OCF(CF3)COF (5.22 g, 15.72 mmol) was stirred at -20° C. for 1 hour and at 0° C. also for 1 hour. Subsequently, the reaction was cooled to -196° C. and octafluoroisobutylene oxide (3.39 g, 15.70 mmol) was condensed into it. Next the reaction mixture was stirred at -22° C. for 17 hours and then at -17° C. for 24 hours. Following this operation the volatiles were removed and fractionated in vacuo through traps cooled to 0°, -23°, -47° and -196° C. The product, C3F7OCF(CF3)CF2OC(CF3)2COF, (4.15 g, 48% yield); VP 0° C. 0.5 mmHg, (following refractionation of the 0, -23 and -47 fractions) was collected in the -23° C. trap. The material was characterized by mass spectrometry in the form of its methyl ester, C3F7OCF(CF3)CF2OC(CF3)2CO2CH3, MS(70 eV) m/e (intensity,ion): 541 (65.8%, M-F), 491 (10.7%, M-CF3), 375 (72.5%, CF(CF3)CF 2 OC(CF3)2CO2CH3), 335 (60.6%, C3F7OCF(CF3)CF2), 275 (46.6%, CF2OC(CF3)2CO2CH3), 209 (67.3%, C(CF3)2CO2CH3).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].C(=O)(O)[O-].[K+].[C:20](O)(=O)[CH3:21]>O>[CH3:20][C:21]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3
Reactant: CC(=O)O
Reactant: COc1ccc2c(NN)nccc2c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COc1ccc2c(ccn3c(C)nnc23)c1
Yield: 24 %

Procedure:
1-Hydrazino-6-methoxyisoquinoline (9.6 g., 0.05 mol.) was dissolved in glacial acetic acid (190 ml.) and the solution was heated at reflux for four hours. Excess acetic acid was removed in vacuo to provide a brown oil. The oil was slurried in water and was treated with potassium bicarbonate to yield a solid. The solid was treated with decolorizing carbon and was recrystallized three times from benzene to give the productin a yield of 24%; m.p. 183°-184°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[C:44]1([C:50]2([C:56]([OH:58])=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:27][CH2:28][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([NH2:35])=[O:58])[CH2:55][CH2:54]3)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(4-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride to give the title compound: Rf =0.57 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[Br-].O1CCC[CH2:28]1>>[CH3:28][C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: C1CCOC1
Agent: [Br-]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(O)CC3)c(F)c2)C(=O)O1
Yield: 71 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.2 mmol) with methylmagnecium bromide (1.32 mmol) in tetrahydrofuran (20 ml) at a temperature 0° C. to 25° C. for twelve hours and by purifying the compound by silica gel column chromatography in 71% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20].CO.N>C(O)CCC>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: Fc1ccc(Nc2ccnc(Cl)n2)c(F)c1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(Nc3ccc(F)cc3F)n2)cc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
2-Chloro-4-(2,4-difluoroanilino)pyrimidine (Reference Example A-2; 174 mg, 0.72 mmol) was dissolved in n-butanol (2 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 198 mg, 0.72 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 100° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%): DCM:aqueous ammonia(1%). The resulting gum was recrystallized from acetonitrile to give the title product as a solid (124 mg, 41%). NMR (300 MHz): 2.18 (s, 6H), 2.34 (m, 2H), 3.78 (m, 1H), 3.88 (m, 2H), 4.75 (brd, 1H), 6.18 (d, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.32 (t, 1H), 7.48 (d, 2H), 7.88 (dd, 1H), 7.95 (d, 1H), 8.88 (s, 1H), 8.95(s, 1H); m/z: (ES+) 416.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[C:16]2[O:17]CC(C)(C)N=2)=[CH:4][CH:3]=1.Cl.[OH2:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[C:16]([OH:17])=[O:24])=[CH:6][CH:7]=1
Reactant: O
Reactant: CC1(C)COC(c2c(F)cccc2Sc2ccc(F)cc2)=N1
Agent: Cl
Product: O=C(O)c1c(F)cccc1Sc1ccc(F)cc1

Procedure:
The compound 2-[2-(4-fluorophenylthio)-6-fluorophenyl]-4,4-dimethyloxazoline (5.0 g, 15.66 mmol) is added to 310 ml of a 4.5N HCl solution in water and is refluxed overnight. The cooled reaction mixture is extracted twice with ethyl acetate. The extracts are washed with water and then brine and dried over MgSO4 to afford the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13](C=O)C>C(Cl)Cl.O.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.[C-]#N.[Zn+2].[C-]#N>[F:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[CH2:9][OH:10])[C:12]#[N:13]
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(F)c(CO)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of (4-bromo-2,6-difluorophenyl)methanol (1.12 g, 5.0 mmol), Pd(PPh3)4 (323 mg, 0.28 mmol) and zinc cyanide (587 mg, 5.0 mmol) was prepared in DMF (7 mL) under nitrogen atmosphere and heated at 90° C. for 18 hours. The mixture was diluted with DCM and water. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.28-7.21 (2H, m), 4.83 (2H, d, J=6.7 Hz), 1.95 (1H, t, J=6.7 Hz).