Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:32])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]2=[N:10]1
Reactant: COc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-methoxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 5.693 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-methoxybenzotriazole was 6.3 g (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>CN(C)C=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[N:10]=[CH:11][N:12]=[C:13]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=2)[CH:14]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 4-chloro-2-(6-chloropyrimidin-4-yl)benzenamine (1.5 g, 6.25 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), potassium carbonate (2.7 g, 19.54 mmol, 3.00 equiv), 3-(trifluoromethyl)benzylamine (1.7 g, 9.70 mmol, 1.50 equiv). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 1 g (42%) of N-(3-(trifluoromethyl)benzyl)-6-(2-amino-5-chlorophenyl)pyrimidin-4-amine as yellow oil
Reaction SMILES: CN(/C=[C:5]1\[C:6](=O)[CH2:7][CH2:8][C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:11][C:10]\1=2)C.C(O[C:36]([NH:38][NH:39][CH2:40][CH2:41][OH:42])=O)(C)(C)C>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[C:17]=2[C:9]2[CH2:8][CH2:7][C:6]4[N:39]([CH2:40][CH2:41][OH:42])[N:38]=[CH:36][C:5]=4[C:10]=2[S:11]3)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CN(C)/C=C1\C(=O)CCc2c1sc1ncnc(OCCc3ccc([N+](=O)[O-])cc3)c21
Reactant: CC(C)(C)OC(=O)NNCCO
Product: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCO)cc1

Procedure:
This compound was prepared in a similar fashion as described in Example 80 starting from (8E)-8-[(dimethylamino)methylene]-4-[2-(4-nitrophenyl)ethoxy]-5,8-dihydro[1]benzothieno[2,3-d]pyrimidin-7(6H)-one (7.05 g, 16.61 mmol) and 2-tert-butyloxycarbonyl-2-hydroxyethylhydrazine (4.39 g, 24.91 mmol). The desired product was obtained as a yellow solid (3.82 g, 53%). 1H-NMR (DMSO-d6) δ 8.50 (s, 1H), 8.18 (m, 2H), 7.64 (m, 3H), 4.88 (m, 1H), 4.77 (t, 2H, J=6.1 Hz), 4.10 (t, 2H, J=5.5 Hz), 3.68 (m, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 2.96 (m, 2H); LCMS RT=2.92 min; [M+H]+=438.1
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1(O)[C:13]#[C:14][CH:15](O)[CH3:16]>O>[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13](=[O:2])[CH:14]=[CH:15][CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CC(O)C#CC1(O)CCCCC1C
Solvent: O
Product: CC=CC(=O)C1=C(C)CCCC1
Reaction time: 0.75 h

Procedure:
20 g of 50 % aqueous sulphuric acid (parts by weight) were added to 20.2 g (0.11 mole) of 2-methyl-1-hydroxy-1-[3-hydroxy-but-1-ynyl]-cyclohexane and the thus obtained mixture was stirred for 45 minutes at 50°. After having added water to the said mixture, it was extracted three times with pentane, and the combined organic extracts were washed, dried (MgSO4) and concentrated. The resulting residue gave, by fractional distillation, a product of b.p. 118°-120°/12 Torr; 10.9 g (60 %). By purification by means of vapour phase chromatography there was obtained 2-methyl-1-[but-2-enoyl]-cyclohex-1-ene.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCCCBr)c1ccccc1
Yield: 97.7 %

Procedure:
According to the procedure given for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reduced with LiBH4 (5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) in anhydrous CH2Cl2 (390 mL). After the typical workup, crude 206h (51.0 g, 98%) was obtained as a yellowish oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ 7.25-7.08 (m, 5H), 3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz), 1.92-0.95 (m, 9H), 1.28 (s, 3H). 13C NMR (CDCl3): δ 144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59. HRMS (EI): Calcd for C14H21BrO (M+): 284.0776, found: 284.0787.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][F:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([C:3]1[C:11]([N:12]([CH2:13][CH2:14][CH2:15][F:16])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1nn2ccccc2c1NCCCF
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1nn2ccccc2c1N(C)CCCF
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.4 %

Procedure:
A solution of 2-ethyl-N-(3-fluoropropyl)pyrazolo[1,5-a]pyridin-3-amine (0.301 g, 1.36 mmol) in DMF (4 mL) was treated with K2CO3 (0.200 g, 1.45 mmol) and methyl iodide (0.06 mL, 0.96 mmol). The reaction was stirred at room temperature for 22 hours then concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organics was dried over MgSO4, concentrated in vacuo to give 0.190 g (84%) of a brown oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=6.9 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.08–7.05 (m, 1H), 6.73–6.70 (m, 1H), 4.56 (dt, J=47.5, 5.9 Hz, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.78 (s, 3H), 2.71 (q, J=7.6 Hz, 2H), 1.77–1.64 (m, 2H), 1.24 (t, J=7.6, Hz 3H); 13C NMR (100 MHz, DMSO-d6) δ 152.3, 135.2, 128.7, 122.1, 120.9, 116.4, 110.6, 82.6 (d, J=161.4 Hz), 52.4 (d, J=5.2 Hz), 43.6, 29.0 (d, J=19.3 Hz), 19.0, 13.5; 19F NMR (376 MHz, DMSO-d6) −219.0 (m); HRMS (FAB) calcd for C13H18FN3+H 236.1563. found 236.1573.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>O1CCCC1>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH:16][S:33]([C:31]3[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=3)(=[O:35])=[O:34])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:18][CH3:19]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(CN)cc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1CCc2ccc(CNS(=O)(=O)c3cn(C)cn3)cc2C1
Temperature: 15 °C

Procedure:
Using procedure 9, (R)-7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenemethanamine 9 and triethylamine in dry tetrahydrofuran was cooled to 15° C., and 1-methylimidazole-4-sulfonyl chloride was added. After extraction, purification by flash chromatography (tetrahydrofuran/ethyl acetate) gave the title compound as an oil. [α]D =+46° (25° C., CH3OH, c=0.7458).
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH3:41][NH2:42]>>[CH3:41][NH:42][C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: CN
Product: CNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and methylamine were reacted to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[NH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Temperature: 95 °C
Reaction time: 15 h
Yield: 77.7 %

Procedure:
A mixture of ethyl 6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.1 g, 4.0 mmol), tert-butyl 2-aminoacetate hydrochloride (0.99 g, 5.9 mmol) in 10 mL dioxane, was treated with N-ethyl-N-isopropylpropan-2-amine (1.5 g, 12 mmol). The mixture was warmed to 95° C. and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 1.13 g of the title compound as a white solid. MS m/e=364 (M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: OC1CCNCC1
Product: O=c1[nH]c2cc(CN3CCC(O)CC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 4-hydroxypiperidine. To give a yellow solid. MS m/z: 419.0 (M+1).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[O:8][C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=3[N:24]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCCC1Cl
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Product: c1ccc(CN2CCC(c3nc4c(o3)CCCC4)CC2)cc1
Temperature: 160 °C
Yield: 70.9 %

Procedure:
A mixture of 2.43 g 2-chlorocyclohexanone and 1 g 1-benzylpiperidine-4-carboxylic acid amide (see WO2005/61483) is heated to 160° C. in the microwave until there is no further reaction. The product is purified by chromatography. 963 mg of the product are obtained. Analytical HPLC-MS (method B): RT=1.28 min.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:46])[CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:46])[CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(C(c1ccccc1)c1ccccc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
235 mg (0.378 mmol) of (2R*,4S*)-2-benzyl-1-(diphenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 58 mg (1.51 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR43## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.49, FD-MS: M+ =525.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([C:20]#[C:21][C:22]([O:24][CH3:25])=[O:23])=[O:19]>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:19])/[C:20](/[O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)/C=C(\Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OC

Procedure:
A mixture of 5 parts of 2,4-di-t-butylphenol, 3.55 parts of acetylene dicarboxylic acid dimethyl ester and four drops of benzyl-trimethylammonium hyroxide were heated on a steam bath for 20 min. The 2,4-di-t-butylphenoxyfumaric acid dimethyl ester formed was hydrolysed by heating with 2.8 parts of sodium hydroxide in 15 parts by volume of water and 8 parts by volume of methanol. The hydrolysis was complete when one layer was obtained. The methanol was boiled off and the solution was cooled and acidified with concentrated hydrochloric acid. The crude 2,4-di-t-butylphenoxyfumaric acid was liberated as an oil, and was extracted into ether. This acid was purified by extraction with sodium bicarbonate solution which was washed well with ether. Acidification of the sodium bicarbonate solution gave the purified fumaric acid which was extracted again into ether. The dried ether extracts were evaporated to give the fumaric acid as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O>CS(C)=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: Fc1ccccc1CCl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1ccccc1F
Reaction time: 1.8 h
Yield: 86 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 125 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 36.3 g (0.25 mole) of 2-fluorobenzyl chloride. The reaction mixture was heated to 105° over 0.3 hours, held at 105° for 1.8 hours, and poured into 1.51 of water all with rapid stirring. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 42 g (86%) of a light yellow oil. The crude product was washed with 100 ml of ether to give 10 g (20%) of a white solid m.p. 72°-76°.
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@@H:16]([CH3:20])[C:17](Cl)=[O:18])[CH:13]=[CH:14][CH:15]=1.C([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)CC>O>[CH:30]1([C:27]2[CH:26]=[CH:25][C:24]([C:17](=[O:18])[C@@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH3:20])=[CH:29][CH:28]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COc1cccc([C@@H](C)C(=O)Cl)c1
Reactant: CCC[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc([C@@H](C)C(=O)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 0.25 h

Procedure:
To a methylene chloride suspension of aluminum chloride, a methylene chloride solution of (R)-2-(3-methoxyphenyl)propionic acid chloride was added dropwise under ice cooling. After stirring at the same temperature for 15 minutes, a methylene chloride solution of trans-4-propylcyclohexylbenzene was added dropwise. After the completion of the reaction, the reaction system was added to iced water and the organic layer was separated by adding methylene chloride. The organic layer was washed twice with water and then washed with saturated brine. The aqueous layer was washed with methylene chloride and, after combining the organic layer, the solvent was concentrated to obtain a crude product of (R)-1-(4-cyclohexylphenyl)-2-(3-methoxyphenyl)-propan-1-one. To an ethylene glycol solution of the resulting crude product, hydrazine monohydrate was added and the solution was stirred at 110° C. while removing water as a by-product. After efflux of water has nearly terminated, excess hydrazine was distilled off by stirring at 120° C. The temperature of the reaction system was reduced and potassium hydroxide was added, followed by heating to 160° C. After the completion of the reaction, the temperature of the reaction system was reduced and water and toluene were added, followed by stirring. After separating the organic layer, the aqueous layer was washed with toluene and the organic layer was combined and then washed three times with water. The residue was washed with saturated brine and concentrated to obtain a crude product of a compound represented by the formula (XI-a). The resulting crude product was purified by column chromatography and recrystallized from ethanol to obtain (S)-1-{2-(3-methoxyphenyl)propyl}-4-(trans-4-propylcyclohexyl) benzene (S-isomer of the compound represented by the formula (XI-a)).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[SH:23]>>[N+:10]([C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][C:2]=1[S:23][C:14]1[CH:15]=[N:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)([O-:12])=[O:11]
Reactant: Sc1cnc2ccccc2n1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cnc3ccccc3n2)s1

Procedure:
Prepared according to the procedure described for example 18 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (250 mg, 1.215 mmol) and quinoxaline-2-thiol (197 mg, 1.215 mmol). The title compound was obtained as a solid (200 mg, 50% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.26 (1H, s), 8.63 (1H, s), 8.01 (1H, m), 7.98 (1H, m), 2.61 (3H, s). MS m/z: 331.88 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8])[CH3:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:15]Cl>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:15][CH:6]([C:7](=[O:8])[CH3:9])[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(Cl)cc(Cl)c1)C(C)=O
Yield: 55.3 %

Procedure:
Sodium metal (1.01 g, 44 mmol) was added to ethanol (100 ml) and stirred until all the metal had dissolved. Ethylacetoacetate (15.6 g, 111 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 10 minutes. 3,5-dichlorobenzyl chloride (7.24 g, 40 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the solution was concentrated under reduced pressure. The orange oil was purified by flash chromatography on silica gel eluting with pentane followed by pentane:ethyl acetate (30:1, by volume) to afford the title compound as a colourless oil (6.4 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)=[C:4]([OH:7])[NH:5][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:24]([CH3:35])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25](=[O:26])[CH:24]([O:7][C:4]1[NH:5][N:6]=[C:2]([CH3:1])[C:3]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[N:9]1)[CH3:35]
Reactant: Cc1n[nH]c(O)c1-n1ccc(C(F)(F)F)n1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c(OC(C)C(=O)c2ccc(Cl)cc2Cl)c1-n1ccc(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5′-methyl-3-trifluoromethyl-2′H-[1,4′]bipyrazolyl-3′-ol (Intermediate KA)(270 mg, 1.163 mmol) and cesium carbonate (379 mg, 1.163 mmol) in DMF (2.684 ml) at 50° C. is added 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (328 mg, 1.163 mmol) slowly in DMF (1.789 ml). The reaction is stirred at 50° C. for 1 hour before cooling to RT. 2M Na2CO3 (100 ml) is added and the crude product is extracted with EtOAc (2×100 ml). The organic phases are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 24 g SiO2 column to give the title compound as a light brown oil; MS: m/z 433.24 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:16].CO>ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:16])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c[nH]c2ncccc12
Solvent: ClCCl
Solvent: CO
Product: Cc1c[nH]c2c1ccc[n+]2[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A little at a time, 3.00 g (22.70 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine (Hands, David; Bishop, Brian; Cameron, Mark; Edwards, John S.; Cottrell, Ian F.; Wright, Stanley H. B.; Synthesis 1996, 877-882.) are added to a solution of 10.45 g (45.40 mmol) of meta-chloroperoxybenzoic acid in 250 ml of dichloromethane, and the mixture is stirred at 10° C. for 2 h. Addition of methanol gives a clear solution which is subjected directly to column chromatography on silica gel (mobile phase: dichloromethane/methanol 100:4 to 3:1). A further purification step by preparative HPLC yields the target compound.