Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C=CC=1)CO[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[NH:12][CH2:11][CH2:10][C:9]=2[N:8]=1.C(Cl)Cl.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>CC([O-])=O.CC([O-])=O.[Cu+2].C(N(CC)CC)C>[F:24][C:25]1[CH:30]=[C:29]([N:12]2[CH2:11][CH2:10][C:9]3[N:8]=[CH:7][CH:16]=[CH:15][C:14]=3[C:13]2=[O:17])[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1NCCc2nc(OCc3cccc(F)c3)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2cccnc2CCN1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-((3-fluorobenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (30 mg, 0.11 mmol) was dissolved into DCM (2 mL) and treated with 3-fluorophenylboronic acid (30 mg, 0.22 mmol), Cu(OAc)2 (22 mg, 0.13 mmol), and triethylamine (50 μL). The reaction was stirred for 2 days at RT and concentrated to an oil and purified by RP-HPLC (10-90% gradient CH3CN in water with 0.1% TFA modifier) to give the compound, 24(3-fluorobenzyl)oxy)-6-(3-fluorophenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. LC-MS (M+H)=367.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[F:21][CH:22]([F:31])[O:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.CCN(CC)CC>C1COCC1>[F:21][CH:22]([F:31])[O:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A mixture of 4-chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (1.00 g, crude, 3.7 mmol, 1.0 eq.), 3-(difluoromethoxy)benzenamine (600 mg, 3.7 mmol, 1.0 eq.) and Et3N (1.00 g, 10 mmol, 3.0 eq) in THF (80 mL) was stirred at 75° C. for 18 h. After cooling, the volatiles were removed in vacuo and the residue was washed with H2O (100 mL×2). The solid was dried in vacuo to afford 1.40 g of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine as a black solid (90.2% of two steps). LCMS m′ z=411.0 (M+1) (Method A) (retention time=1.61 min).
Reaction SMILES: O.O.O.O.[Cl-].[Mn+2:6].[Cl-].C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:59]3[NH:60][C:56](=[CH:57][CH:58]=3)[C:55]([C:61]3[CH:66]=[CH:65][C:64]([C:67]#[CH:68])=[CH:63][CH:62]=3)=[C:54]3[N:69]=[C:51]([CH:52]=[CH:53]3)[C:50]([C:70]3[CH:75]=[CH:74][C:73]([C:76]#[CH:77])=[CH:72][CH:71]=3)=[C:49]3[NH:78][C:46]([CH:47]=[CH:48]3)=[C:45]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[CH:86])=[CH:81][CH:80]=3)[C:44]3=[N:87][C:41]=2[CH:42]=[CH:43]3)=[CH:36][CH:35]=1)#[CH:33]>CN(C=O)C>[C:76]([C:73]1[CH:72]=[CH:71][C:70]([C:50]2[C:49]3[NH:78][C:46](=[CH:47][CH:48]=3)[C:45]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[CH:86])=[CH:81][CH:80]=3)=[C:44]3[N:87]=[C:41]([CH:42]=[CH:43]3)[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[CH:33])=[CH:35][CH:36]=3)=[C:59]3[NH:60][C:56]([CH:57]=[CH:58]3)=[C:55]([C:61]3[CH:62]=[CH:63][C:64]([C:67]#[CH:68])=[CH:65][CH:66]=3)[C:54]3=[N:69][C:51]=2[CH:52]=[CH:53]3)=[CH:75][CH:74]=1)#[CH:77].[Mn:6]
Reactant: [Mn+2]
Agent: C#Cc1ccc(-c2c3nc(c(-c4ccc(C#C)cc4)c4ccc([nH]4)c(-c4ccc(C#C)cc4)c4nc(c(-c5ccc(C#C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: [Mn]

Procedure:
A solution of 5.5 g (27.8 mmol) of manganese chloride tetrahydrate (MnCl2.4H2O) in 160 ml of DMF was added portionwise to a solution of 1 g (1.4 mmol) of porphyrin TEPP (2) as obtained in step 2) above and dissolved in 200 ml of DMF. The mixture was refluxed for 72 hours. After a return to ambient temperature, the solvent was evaporated off under reduced pressure. The residue was taken up in 50 ml of chloroform and the manganese salts were eliminated by filtration over celite. The liquid filtrate was evaporated and the residue was subsequently dissolved in 100 ml of ethanol and washed with 3×100 ml of water in order to eliminate the TBAF. After evaporation, the residue was dissolved in chloroform and this organic phase was in turn washed with a saturated aqueous solution of sodium chloride (3×100 ml) in order to be sure that the axial ligand of the manganese is a chlorine, and finally washed with 2×100 ml of water in order to eliminate the traces of sodium chloride. The organic phase was subsequently dried over sodium sulfate and the solvent was evaporated off. During the first extraction with ethanol and water as solvents, a part of the porphyrin precipitated. This precipitate was filtered off and kept. It was subsequently redissolved in chloroform so that it could be added to the organic phase during the washing with sodium chloride. 700 mg (0.88 mmol; yield 63%) of manganese tetrakis(4-ethynylphenyl)porphyrin (MnCl-TEPP) (5) were obtained in the form of a purple/black-colored powder which is green in solution in chloroform.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[C:8]([OH:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=[CH2:2])[C:8]=1[OH:15]
Reactant: O=Cc1cccc(F)c1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(F)c1O
Temperature: 0 °C

Procedure:
To a round-bottomed flask containing a stir-bar were added, methyltriphenylphosphonium bromide (5.6 g, 16 mmol) and anhydrous THF (50 mL). The mixture was stirred until homogeneous and then cooled to 0° Celsius. The flask was then charged drop-wise with n-BuLi (6.85 mL, 2.5 M in hexanes). The resultant solution was stirred for 30 minutes and then transferred via cannula to a stirred mixture of 3-fluoro-2-hydroxybenzaldehyde (1 g, 7 mmol) and THF (28 mL) at rt under an argon atmosphere. The resultant mixture was stirred for 3 h before quenching with saturated NH4Cl (50 mL), diluting with water, and extracting with ether (3×100 mL). The combined ethereal extracts were dried over magnesium sulfate, filtered through a plug of silica gel, and then concentrated to dryness to provide the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.20 (m, 1H), 7.04-6.92 (m, 2H), 6.80 (m, 1H), 5.81 (dd, J=17.8, 1.3, 1H), 5.69 (s, 1H), 5.35 (dd, J=11.2, 1.3, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([I:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(I)c1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(Cc2cccc(I)c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3-iodobenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.71 (s, 1H), 7.62-7.60 (m, 1H), 7.36-7.26 (m, 5H), 7.09-7.01 (m, 2H), 6.33 (s, 1H), 3.52-3.48 (m, 6H), 2.49-2.46 (m, 4H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][C:13]2=[O:25])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([C:36]([O:38][C:39]4[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=4)=[O:37])[CH2:21][CH2:20]3)=[CH:14][C:13]2=[O:25])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)cc1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(C(=O)Oc4ccc(Br)cc4)CC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a mixture of 1-(4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloric acid (154 mg, 0.40 mmol) and diisopropylethylamine (0.35 mL, 0.20 mmol) in CH2Cl2 (1.5 mL) at room temperature was added 4-bromophenyl chloroformate (prepared according to procedures described at Step B of Example 2 substituting 4-bromophenol for 1,1,1-trifluoro-2-propanol) in CH2Cl2 (1.0 mL). The resulting mixture was stirred at room temperature for 3 hrs, diluted with CH2Cl2 and washed with water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/Hexanes) to give the title compound (159 mg, 73%) as a light yellow solid. MS (ESI) 547, 549 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:16]C)=[C:4]([C@@H:9]2[C@H:14]3[C@@H:10]2[CH2:11]O[C:13]3=[O:15])[C:5]([F:8])=[CH:6][CH:7]=1.[BrH:18].CC(O)=O>O>[Br:18][CH2:11][C@H:10]1[C@@H:9]2[C@H:14]1[C:13](=[O:15])[O:16][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=12
Reactant: COc1c(F)ccc(F)c1[C@H]1[C@H]2COC(=O)[C@H]21
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1Oc2c(F)ccc(F)c2[C@@H]2[C@H](CBr)[C@H]12
Temperature: 90 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one (130 mg, 0.55 mmol) was mixed with 1.2 ml of 30% HBr/AcOH (6 mmol) and heated in a sealed vessel at stirring for about 4 h at 90° C. The reaction mixture was then cooled down, mixed with water and extracted into diethyl ether (3×20 ml). Ether extract was washed with sat. sodium bicarbonate solution and brine. Dried over magnesium sulfate. Concentration gave 160 mg of white solid material. 98% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=2)[CH:24]=[O:25])O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
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: C1COCCO1
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.4-bromo-2-chlorobenzonitrile (1.082 g, 5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), Pd(PPh3)4 (0.144 g, 0.125 mmol), sodium carbonate (2.5 mL, 5.00 mmol) in 1,4-dioxane (20 mL) was heated to reflux for 6 h. After cooling to room temperature, the solid was filtered and washed by ethyl acetate and water. After drying under vacuum, yellow powder was collected (1 g). 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J=1.68, 8 Hz, 1H), 7.79 (d, J=1.68 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.35 (dd, J=2.24 Hz, 2.04 Hz, 1H), 9.07 (d, J=2.36 Hz, 1H), 9.15 (d, J=1.88 Hz, 1H), 10.22 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH-].[Na+].Br[CH2:21][CH2:22][CH:23]=[CH2:24]>CN(C)C=O>[CH2:24]([O:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:23][CH:22]=[CH2:21]
Reactant: C=CCCBr
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCCOc1cc(C(=O)OCC)ccc1C(=O)OCC
Yield: 41.3 %

Procedure:
3.55 g of this diethyl hydroxyterephthalate was dissolved in 100 mL dimethylformamide and combined with 640 mg crushed sodium hydroxide. 4.03 g 4-bromo-1-butene dissolved in 20 mL dimethylformamide was added dropwise in while cooling on an ice bath. After stirring the reaction for 16 hours, purification by the usual methods gave 1.8 g diethyl 2-(3-butenyloxy)terephthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[N:3]=1.CCN(S(F)(F)[F:16])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][F:16])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1nccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(4-Chloropyrimidin-2-yl)methanol (Example 548, Step 1) (121 mg, 0.84 mmol) was taken up in DCM (2.5 mL) and cooled to 0° C. DAST (0.122 mL, 0.92 mmol) was added and the resulting mixture stirred at 0° C. for 15 minutes and room temperature for 90 minutes. Saturated NaHCO3 was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (2-40% EtOAc-hexanes) gave the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([OH:52])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:65][CH2:66]I)(=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61].O>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH2:66][O:65][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.2 g) in DMF (10 ml) were added potassium carbonate (0.53 g) and pivaloyloxymethyl iodide (0.94 g), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (30 ml) and 1N-HCl (6 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless crystals (1.13 g. 63%), m.p. 104°-106° C.
Reaction SMILES: [Cl-].[Li+].CS(C)=O.[CH2:7]([C:10]([CH:21]([CH2:23][CH3:24])[CH3:22])(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH2:9]>O>[CH:21]([CH:10]([CH2:7][CH:8]=[CH2:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:23][CH3:24])[CH3:22]
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC(C(=O)OCC)C(C)CC
Temperature: 185 °C
Reaction time: 6 h

Procedure:
Lithium chloride (9.67 g, 228.1 mmol) and water (2.05 mL, 113.9 mmol) were added to a dimethyl sulfoxide (60 mL) solution of diethyl allyl(sec-butyl)malonate (30.90 g, 120.5 mmol), and the mixture was stirred at 185° C. for 6 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a brown oil substance. This compound was used in the next reaction without being purified.
Reaction SMILES: [CH:1]1([CH2:5][S:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>O>[CH:1]1([CH2:5][S:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH:20]3[O:22][CH2:21]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CO1
Reactant: Oc1ccc(CCSCC2CCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(OCC2CO2)ccc1CCSCC1CCC1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
13 g (0.058 mol) of p-(2-cyclobutylmethylthioethyl)-phenol suspended in 80 ml of water are introduced into an Erlenmeyer flask placed under nitrogen. The temperature is kept below 20° C. and 2.72 g (0.068 mol) of sodium hydroxide pellets are added. The solution becomes homogeneous. It is stirred for about 30 minutes and 11.92 g (0.087 mol) of epibromohydrin are then added dropwise at ambient temperature. The batch is stirred at ambient temperature for about 4 hours. The solution becomes cloudy. The oily phase is extracted with ether and the ether phase is washed with 2 N sodium hydroxide solution and then with water. The ether is dried over magnesium sulphate and then evaporated. The residue is distilled on a bulb still at a temperature of 160° C. under a pressure of 0.04 mm Hg. 6.2 g (yield: 38.8%) of 1-[4-(2-cyclobutylmethylthio-ethyl)-phenoxy]-2,3-epoxy-propane are obtained, and this material is used directly.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH2:11][CH:10]1[CH3:24])[CH:7]=[CH2:8]>CO>[CH2:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:11][CH:10]1[CH3:24])[CH:7]=[CH2:8]
Reactant: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: C=CCN1CCN(c2ccc(N)cn2)CC1C
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
4.975 g (22.05 mmol) of tin(II) chloride dihydrate were added to a solution of 707 mg (2.45 mmol) of 1-allyl-2-methyl-4-(5-nitropyridin-2-yl)piperazine from Example 13.2 in 50 ml of methanol and the resulting mixture was stirred at 70° C. for 90 minutes. After the solvent had been evaporated down to dryness, water was added to the resulting residue and the mixture was made alkaline using a dilute aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction and the phases were separated. The aqueous phase was extracted with dichloromethane. After that, the combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness. The resulting title compound was used in the next step without any further purification.
Reaction SMILES: ClC1C=C(C(F)(F)F)C=CC=1O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[Cl:22].[N+:31]([O-:34])(O)=[O:32]>S(=O)(=O)(O)O>[Cl:22][C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:11][C:10]1[CH:5]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[Cl:22])[CH:7]=[CH:8][C:9]=1[N+:31]([O-:34])=[O:32]
Reactant: FC(F)(F)c1ccc(Oc2ccccc2Oc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1Oc1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 47 %

Procedure:
In 100 ml of dimethyl sulfoxide, there were dissolved 129 g. (0.60 mole) of 3,4-dichlorobenzotrifluoride and 27.5 g. (0.25 mole) of resorcin. Then, a solution of 34 g. (0.60 mole) of potassium hydroxide dissolved in 15 ml of water was added to the resultant solution and the mixture was heated with stirring at 150° to 160° C. for 50 hours. After the reaction mixture was left to cool, water was added thereto and the oily product precipitated was subjected to extraction with benzene. The extract was washed with a dilute aqueous sodium hydroxide and with water to remove unaltered resorcin, followed by drying over sodium sulfate and evaporation of benzene under reduced pressure, to give crude bis(2-chloro-4-trifluoromethylphenoxy)benzene. Subsequently, said crude bis(2-chloro-4-trifluoromethylphenoxy)benzene was added dropwise into a mixed acid comprising 60 ml of conc. nitric acid (d=1.38) and 60 ml of conc. sulfuric acid under stirring at 10° to 15° C. After completion of the dropwise addition, the mixture was further stirred at 20° to 27° C. for additional one hour to complete the reaction. Then, ice-water was added to the reaction mixture and the resultant precipitate of an oily product was extracted with benzene. The extract was washed with a dilute aqueous sodium hydroxide, and then with water, followed by drying over sodium sulfate and evaporation of benzene. Recrystallization of the residue from isopropyl alcohol gave 2,4-bis(2-chloro-4-trifluoromethylphenoxy)nitrobenzene as pale yellow powders, melting at 111° to 113° C. (yield: 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[I:26]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][I:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: II
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCI)ccc1Cl
Yield: 88.4 %

Procedure:
2-Chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.1 3,7]dec-1-ylmethyl)-benzamide (5.9 g, Example 6d), iodine (6.2 g, 24.4 mmol), triphenylphosphine (6.4 g, 24.4 mmol) and imidazole (1.66 g, 24.4 mmol) were stirred in dichloromethane (100 ml) at room temperature for 1 h. The reaction was quenched with sat. aq. Na2S2O3 and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography on silica (eluting with EtOAc: isohexane/1:3) to afford the subtitled compound as a pale yellow solid (6.8 g)
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>C(#N)C>[C:1]([O:5][C:6](=[O:10])[CH2:7][N:8]([CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CC(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In acetonitrile (80 mL) was stirred sarcosine t-butyl ester•hydrochloride (10.1 g, 55.5 mmol) and triethylamine (6.57 g, 65 mmol). To this was added 2-fluoronitrobenzene (5.66 g, 40 mmol) and the mixture was stirred overnight at 50° C. The solution was evaporated at a reduced pressure until free of acetonitrile. The residue was partitioned between ether (100 m]L) and water (100 mL). The ether layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated at reduced pressure to give an oil which was dried at 60° C. in vacuo to remove all traces of fluoronitrobenzene. MS: M++1=267.1 Da.
Reaction SMILES: Cl[CH:2]1[N:7]=[C:6](C2CC2)[N:5]=[C:4](C2CC2)[N:3]1N.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([NH:18][C:2]2[N:3]=[C:4]([NH:18][CH:15]3[CH2:17][CH2:16]3)[N:5]=[C:6]([NH:18][CH:15]3[CH2:17][CH2:16]3)[N:7]=2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: NN1C(C2CC2)=NC(C2CC2)=NC1Cl
Solvent: C1COCCO1
Product: C1CC1Nc1nc(NC2CC2)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 20 g of 2-chloro-4,6-bis-cyclopropyl-amino-s-triazine, 10.1 g of cyclopropylamine and 80 ml of dioxan is heated at 140° C. in an autoclave for 22 hours. The reaction mixture is concentrated in vacuo to half its volume and 300 ml of water are added. The mixture is extracted with ethyl acetate, the product phase is dried over sodium sulfate and the solvents are removed in vacuo. The residue is recrystallised from dioxan/petroleum ether; melting point 75°-77° C.