Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[CH3:39])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[C:42]([CH:49]=[CH:50][CH:51]=2)[CH2:43][O:44]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[CH2:59]1C[O:62]CC1>C(Cl)Cl>[CH:43]([OH:44])=[O:62].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[CH3:39])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][CH:49]=[C:50]([CH2:52][N:53]3[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]3)[CH:51]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: C1CCOC1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc([C@@H]6CCCN6C)n5c4)c4ccccc43)c2)CC1
Product: O=CO
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A mixture of Intermediate 149b (87 mg, 0.12 mmol) and 1-methylpiperazine (68 μL, 0.61 mmol) in THF (2 mL) was stirred at 60° C. for 18 h. The reaction mixture was cooled to RT, diluted with DCM (5 mL) and washed with water (5 mL). The aqueous layer was extracted with DCM (5 mL). The combined organic extracts were washed with water (2×5 mL) and passed through a phase separator. The filtrate was concentrated in vacuo and the resultant residue was purified by MDAP (Method 7) to afford the title compound (23 mg, 27%). LCMS (Method 5): Rt 2.69 min, m/z 717.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.84-2.11 (6H, m), 2.13 (6H, br s), 2.15-2.26 (2H, m), 2.26-2.46 (8H, m), 3.13 (1H, m, obscured by water), 3.50 (2H, s, obscured by water), 3.99 (1H, t, J=8.4 Hz), 4.82 (1H, m), 5.39 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.06 (1H, d, J=8.8 Hz), 7.24-7.48 (9H, m), 7.75 (1H, d, J=9.7 Hz), 8.10 (1H, s), 8.19 (1.9H, br s), 8.24 (1H, d, J=1.7 Hz).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[O:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:9].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:6][O:7][C:8]([C:10]1[O:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][C:14]=1[CH3:15])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1occc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1oc(C(C)=O)cc1C

Procedure:
Tin (IV) chloride (2.5 ml) is added to a solution of 3-methyl-furan-2-carboxylic acid methyl ester (1.0 g) and acetic anhydride (3.2 ml) in dichloromethane (8 ml) at 0° C. After 1 hour 30 minutes at 0° C. the reaction mixture is poured into a cold 10% Na2CO3 aqueous solution. The reaction mixture is filtered through a plug of Celite and the filtration cake is washed with dichloromethane. The aqueous phase is extracted two times with dichloromethane. The combined organic phases are washed once with water and with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-Acetyl-3-methyl-furan-2-carboxylic acid methyl ester (0.5 g) as a white solid. MS (HPLC/MS): 183 (MH+). Retention time: 1.09 min.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[K].C(O[C:29]([CH3:32])([CH3:31])C)(C)(C)C>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:14][CH2:2][CH2:3][CH2:4][CH2:32][CH2:29][CH3:31])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1
Reactant: CCCCCCCBr
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)OC(C)(C)C
Agent: [K]
Product: CCCCCCCC1(CCCCCCC)c2ccccc2-c2ccc(Br)cc21

Procedure:
2-bromo-9,9-diheptylfluorene (mp: 32° C.) is synthesized in this manner, for example, from 2-bromofluorene and heptylbromide in the presence of potassium-tert.-butyl oxide.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14](OCC)=N)[CH3:10]>C(O)(=O)C>[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH3:10]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2ccccc2[nH]1
Yield: 81.3 %

Procedure:
54 g o-phenylenediamine (0.5 mol), 300 mL glacial acetic acid and 98 g 3-ethoxy-3-imino propionic acid ethyl ester (0.5 mol) were stirred at refluxing for 2 hours. After concentration under reduced pressure, the residual solution was poured into ice water and a solid was isolated. After sucking filtration, washing with water and a little amount of ethanol, and drying, 83 g off-white solid was obtained. Yield: 82%, MS: 205 (M+1).
Reaction SMILES: N1([C:7]2[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=2)CCOCC1.[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:18]=1[NH2:19])([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:17]([CH:14]([CH3:16])[CH3:15])[C:18]=1[NH:19][C:7]1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1CCCC=C1N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC1=CCCCC1=O
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A 250-mL three-necked round-bottomed flask equipped with a condenser, gas inlet and septas is placed under N2 atmosphere. The flask is charged with 2-(morpholin-4-yl)-2-cyclohexen-1-one (7.0046 g, 38.65 mmol; Preparation 2), toluene (74.0 mL) and 2,6-diisopropylaniline (6.8521 g, 38.65 mmol). To the yellow solution is added p-toluenesulfonic acid monohydrate (7.3520 g, 38.65 mmol; p-TsOH.H2O). The reaction mixture became very thick with a lot of precipitate. The mixture is heated to 80° C. (oil bath temperature) and allowed to stir. Another 5.0 mL of toluene are added to facilitate stirring. The mixture is stirred for 2 hours. Reaction mixture is allowed to reach room temperature. The mixture is filtered. The filtrate is concentrated under high vacuum to afford 10.09 g of a yellow solid. The solid is dissolved in hot hexanes (about 30 mL) and filtered. The solution is allowed to cool to room temperature, seeded and place on the freezer. The solution is filtered while most of the solid is left behind on the flask. The flask is placed on an ice bath. The solid is rinsed with two about 6 mL portions of cold hexanes. The yellow solid is allowed to dry, transfer to a vial and left to dry overnight under vacuum (first crop: 4.0550 g). Mother liquor is concentrated and recrystallization is repeated two more times. The second crop is left in the freezer for 5 hours (second crop: 1.0785 g) and third crop is left overnight (third crop: 0.6919 g). The combined yield of title compound of Preparation 3 is 5.8254 g (55.54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.C1COCC1.CN1CCCC1=O.[CH2:34]([Mg]Br)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CCOCC>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A flame-dried two-necked flask is charged under argon with 4-(4-methylbenzenesulfonyloxy)benzoic acid methyl ester (0.50 g, 1.63 mmol), Fe(acac)3 (29 mg, 0.08 mmol), THF (10 mL) and N-methylpyrrolidone (NMP, 0.95 mL). A solution of n-hexylmagnesium bromide (2M in Et2O, 1 mL, 2 mmol) is added via syringe to the resulting red solution, causing an immediate color change to dark brown and finally to violet. The resulting mixture is stirred for 5 min, the reaction is diluted with Et2O and is carefully quenched upon addition of aq. HCl (1M, ca. 10 mL). Work-up followed by flash chromatography of the crude product as described above provides 4-hexylbenzoic acid methyl ester as a colorless syrup (298 mg, 83%). The spectroscopic and analytical data are identical to those compiled above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:17][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc(Cl)nn2)cc1

Procedure:
A suspension of 20 g. of 6-(p-fluorophenyl)-1,2,4-triazin-3(2H)-one in 158 ml. of chloroform is cooled in an ice bath and 178.5 ml. of phosphorus oxychloride is added followed by 1.2 g. of N,N-dimethylformamide. The mixture is refluxed for 4.5 hours and then the excess phosphorus oxychloride is removed in vacuo. The residue is redissolved in chloroform and poured into ice-water. When the ice melts the mixture is filtered. The organic layer of the filtrate is washed with water and saturated sodium bicarbonate solution and then dried giving a brown semi-solid. This semi-solid is taken up in chloroform and filtered through a short silica gel column giving 3-chloro-6-(p-fluorophenyl)-1,2,4-triazine as a tan solid.
Reaction SMILES: Br.[F:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:7]2.C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29]([Cl:31])=[O:30].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[ClH:31].[CH3:27][N:28]([CH3:32])[C:29](=[O:30])[O:12][C:11]1[C:3]([F:2])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:5]2
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc2c(c1F)CN(Nc1ccncc1)C2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1ccc2c(c1F)CN(Nc1ccncc1)C2
Product: Cl
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a mixture of 2,3-dihydro-4-fluoro-2-(4-pyridinylamino)-1H-isoindol-5-ol hydrobromide (600 mg), triethylamine (614 mg), and chloroform (10 ml), dimethylcarbamyl chloride (237 mg) in chloroform (5 ml) was added dropwise, with stirring at ambient temperature, under nitrogen. The reaction mixture was stirred under reflux for 5 hrs, at ambient temperature overnight and poured into dilute sodium bicarbonate solution (100 ml). The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was flash chromatographed (silica), eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and excess ethereal hydrogen chloride was added. Ether was added and the solution was cooled. The precipitate was collected to give 450 mg (69%) of product, mp 250-252° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(CCCO)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCBr)cc1C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Compound 37-2 (1.95 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.46 g) and N-bromosuccinimide (2.33 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.20 g) as a colorless oil.
Reaction SMILES: C([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1)C.Cl[CH2:28][C:29]1N(CC)C2C=NC(C(F)(F)F)=CC=2N=1.N1C=CN=C1C1SC=CN=1>>[CH2:28]([N:5]1[C:6]2[CH:7]=[N:8][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:10][C:11]=2[N:3]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:29]
Reactant: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(F)(F)F)cc21
Reactant: CCn1c(CCl)nc2cc(C(F)(F)F)ncc21
Agent: c1c[nH]c(-c2nccs2)n1
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(F)(F)F)ncc21

Procedure:
As described previously for the preparation of 1-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine, nucleophilic displacement of the 2-chloromethyl-3-ethyl-6-trifluoromethyl-3H-imidazo[4,5-c]pyridine with the same 2-(1H-imidazol-2-yl)-thiazole followed by usual work provides 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine. 1H NMR (CD3OD) δ 9.02 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=3 Hz, 1H), 7.52 (d, J=3.3 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 6.29 (s, 2H), 4.56 (q, J=7.5 Hz, 2H), 1.52 (t, J=7.5 Hz, 3H) m/z 379 [M+1]
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.II.CON(C)[C:18](=[O:29])[C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20]>O1CCCC1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:18](=[O:29])[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH3:20])[CH:8]=[CH:7][C:6]=1[S:9][CH3:10]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: COc1cc(Br)ccc1SC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(C(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1SC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Magnesium (17 μg, 0.69 mmol) was placed in a screwcap reaction tube, and a solution of (4-bromo-2-methoxyphenyl)(methyl)sulfane (308e, 100 μg, 0.43 mmol) in tetrahydrofuran (1 mL) was added, followed by a small crystal of iodine. The tube was sealed and flushed with argon. The mixture was stirred at 60° C. overnight. After cooling (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (35 μg, 150 μmol) was added as a solid, and the mixture was stirred at r.t. for 1 h. Then the solvent was evaporated, the mixture was partitioned between aq. HCl (1N) and ethyl acetate. The organic layer was separated and dried. The product was isolated by HPLC to afford 10 mg (10%).
Reaction SMILES: CN([CH2:4][CH2:5][CH2:6]N1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH2:25]([N:29]=[C:30]=[O:31])[CH2:26][CH2:27][CH3:28].[N-]=C=[O:34]>C(O)(C)C>[CH2:25]([NH:29][C:30](=[O:34])[O:31][CH:5]([CH3:6])[CH3:4])[CH2:26][CH2:27][CH3:28]
Reactant: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Reactant: CCCCN=C=O
Reactant: [N-]=C=O
Solvent: CC(C)O
Product: CCCCNC(=O)OC(C)C
Temperature: 60 °C

Procedure:
In a 250 ml round-bottomed flask, 0.02 g of Desmorapid Z, 31.1 g of n-butyl isocyanate were initially introduced and heated to 60° C. Thereafter, 18.9 g of isopropanol were added dropwise and the mixture was further kept at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, cooling was effected and the product was obtained as a clear liquid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Br:23])[N:10]=[C:9]([C:24](=O)[NH2:25])[C:8]=1[S:27]([CH3:30])(=[O:29])=[O:28]>O>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Br:23])[N:10]=[C:9]([C:24]#[N:25])[C:8]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1c(C(N)=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (20 ml) was added to 5-amino-1-(2-bromo-6-chloro-4-trifluoromethylphenyl)-3-carbamoyl-4-methanesulphonylpyrazole (4.0 g) and the solution heated at 50°-60° C. for 3.25 hours, and left at room temperature overnight. The mixture was cautiously added to vigorously stirred water (200 ml), and the precipitated solid collected and dried in vacuo. Recrystallisation from toluene/ethanol gave 5-amino-1-(2-bromo-6-chloro-4-trifluoromethylphenyl)-3-cyano-4-methanesulphonylpyrazole as buff crystals, m.p. 235°-238° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([S:15][CH3:16])[C:4]=1[O:17][CH2:18][O:19][CH3:20].CN(C)CCN(C)C.C([Li])CCC.I[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[C:45]([O:46][CH2:47][O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=[C:42]([O:52][CH2:53][O:54][CH3:55])[C:41]=1[O:56][CH3:57]>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[CH3:57][O:56][C:41]1[C:42]([O:52][CH2:53][O:54][CH3:55])=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:46][CH2:47][O:48][CH3:49])[C:40]=1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:8]1[C:7]([O:9][CH2:10][O:11][CH3:12])=[C:6]([O:13][CH3:14])[C:5]([S:15][CH3:16])=[C:4]([O:17][CH2:18][O:19][CH3:20])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCI)c1OC
Reactant: COCOc1cc(OC)c(OCOC)c(SC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(SC)c(OCOC)c2OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
150 Milligrams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(methylthio)benzene was dissolved in a mixed solvent of 4 ml of toluene with 1 ml of hexamethylphosphoric triamide, to this solution was added 0.104 ml of N,N,N',N'-tetramethylethylenediamine was added, then the whole mixture was cooled to -78° C. on a dry ice-acetone bath. 0.466 Milliliter of n-butyllithium (1.6 M, n-hexane solution) was added dropwise thereto and stirred for 30 minutes. Next, 8 ml of toluene solution containing 269 mg of 1-(5-iodopent-1-yl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was added dropwise and the reaction mixture was stirred overnight. The reaction mixture was warmed to room temperature, then 30 ml of diethyl ether was added thereto, the organic layer was washed three times with 20 ml of water then washed twice with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck Art 5717 silica gel, developing solvent: 40% ethyl acetate-n-hexane). There was obtained 120 mg of 1-[2,5-dimethoxy3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(methylthio)phenyl]pentane as in the form of colorless oily substance.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][NH+:7]=1.[C:16](=[C:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)([CH3:18])[CH3:17]>CN(C)C=O.CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[C:23]([CH:22]=[CH:21][CH:20]=2)=[N+:7]2[C:6]([CH:17]=1)=[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[CH:9][CH2:8]2
Reactant: CC(C)=C1CCCC1=O
Reactant: c1ccc2c[nH+]ccc2c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2[n+](c3c1=CC=C3)CC=c1ccccc1=2

Procedure:
Isoquinolinium perchlorate (2.3 g) and 2-isopropylidene cyclopentanone (1.5 g) in dimethylformamide (5 ml) were refluxed for 18 hours. The reaction mixture was cooled, diluted with methanol and filtered. Purification was effected by recrystallization from acetonitrile (norite). Yield 1.5 g, m.p. > 300°,
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH2:26]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:26][CH3:25])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Product: CNC(=O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Yield: 34 %

Procedure:
The compound (97 mg, 0.28 mmol) prepared in Example 42 and methylamine instead of ethylamine were reacted according to the same procedure as Example 89 to give the title compound (34 mg, Yield 34%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H].[Br:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:33]2[N:32]=[C:31]([CH3:34])[N:30]=[C:29](Cl)[C:28]=2[NH:27][C:26](=[O:36])[CH2:25]1>>[Br:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:33]2[N:32]=[C:31]([CH3:34])[N:30]=[C:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:28]=2[NH:27][C:26](=[O:36])[CH2:25]1
Reactant: Cc1nc(Cl)c2c(n1)N(c1ccc(C(C)C)cc1Br)CC(=O)N2
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1nc(C)nc2c1NC(=O)CN2c1ccc(C(C)C)cc1Br
Temperature: 0 °C

Procedure:
Sodium hydride suspension in mineral oil was washed with hexane and dried under vacuum, then taken up in tetrahydrofuran. This mixture is cooled to 0° C., and treated with diethyl malonate (1.1 eq.). After the evolution of hydrogen gas is complete, the resulting solution is treated with 8-(2-bromo-4-isopropylphenyl)-4-chloro-2-methyl-5,6,7,8-tetrahydropteridin-6-one (see Example SF445, Part A, below; 1.0 eq.). The solution is heated to reflux until thin-layer chromatography shows the consumption of the starting material is nearly complete. The mixture is allowed to cool, and poured into saturated aqueous ammonium chloride solution. This is extracted twice with ethyl acetate, and the extracts are washed with brine, combined, dried over sodium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford the title product.
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(O)C=CC=CC=1.[I-].[Na+].[H][H]>O>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
131 parts of a mixture of tetrachloroaniline and pentachloroaniline, corresponding to the composition given in Example 3, 200 parts of phenol and 9 parts of sodium iodide are reacted in the presence of 22 parts of a ruthenium-on-charcoal catalyst (5% strength) which is moist with water and has already been used for 6 similar reaction cycles, corresponding to 15 parts of dry catalyst, with hydrogen at 165° C. under a pressure of 40 to a maximum of 50 bars, during the course of 8 hours. After the usual working up, 91.5 parts of 3,5-dichloroaniline are obtained, with complete conversion of the starting material. Yield: 98% of theory.