Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[N:14]([CH3:13])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[C:10]([O:11][CH3:12])[C:2]=5[N:1]=4)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CN
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: COc1nccc(C(=O)O)c1N
Product: COc1nccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-2-methoxyisonicotinic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde. The obtained compound was recrystallized from ethyl acetate-heptane to give a colorless tabular crystal (m.p. 178.0-180.2° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].O[N:39]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:39])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 65 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (09.13 g, 65.0%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[N:18]1([C:24]2[C:25](=[O:30])[NH:26][CH2:27][CH2:28][CH:29]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:29]2[C:24]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)([C:25](=[O:30])[NH:26][CH2:27][CH2:28]2)[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Reactant: O=C1NCCC=C1N1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NN(c2ccc(OC)cc2)C2(N3CCOCC3)C(=O)NCCC12
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 582 mg, 2.0 mmol) in ethyl acetate (EtOAc, 10 mL) was treated with 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 364 mg, 2.0 mmol, 1.0 equiv) at 0-5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 505 mg, 0.70 mL, 5.0 mmol, 2.5 equiv) at 0-5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (10 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridin-3-carboxylic acid ethyl ester (51, 523 mg, 805 mg theoretical, 65%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 51, CIMS m/z 401 (M+−H, C20H26N4O5).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:33][C:34]1[S:38][CH:37]=[N:36][CH:35]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:33][C:34]1[S:38][CH:37]=[N+:36]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:32])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=3)[CH:4]=2)[CH:35]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CBr)c2)cc1
Reactant: Cc1cncs1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Yield: 91.9 %

Procedure:
A mixture of 4 g of N-[3-(bromomethyl) phenyl]-4-(tetradecyloxy)benzamide and 3.95 g of 5-methylthiazole in 50 ml of toluene is refluxed under argon for 4 hours. The solvent is removed and ether added to the residue. The solid is collected by centrifugation and washed several times with ether then vacuum dried to give 4.4 g of the desired product as a white powder, m.p. 188°-192° C.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=O)[N:13]=1)=[O:6].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]([CH3:28])[CH:26]=[O:27])C=CC=CC=1>C1C=CC=CC=1>[CH3:28][C:25](=[CH:14][C:12]1[N:13]=[C:9]([CH2:8][O:7][C:5]([O:4][CH2:3][C:2]([Cl:17])([Cl:16])[Cl:1])=[O:6])[S:10][CH:11]=1)[CH:26]=[O:27]
Reactant: O=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C=O)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C

Procedure:
A mixture of 2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazole-4-carboxaldehyde (21.0 g) and 2-(triphenylphosphoranylidene)propionaldehyde (20.6 g) in 300 mL of benzene is heated at reflux for 3 hours, then cooled to ambient temperature and concentrated. Purification by flash column chromatography on SiO2 (hexanes/ethyl acetate, 4:1) yields the product as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH2:5][C:6](OC)=[O:7].[NH3:12]>CO>[O:7]=[C:6]1[NH:12][CH2:10][CH:4]([C:3]([O:2][CH3:1])=[O:11])[CH2:5]1
Reactant: N
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CO
Product: COC(=O)C1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-methylene-succinic acid dimethyl ester (158 g, 1 mol, 1 eq) in MeOH (150-160 mL) was added dropwise anhydrous liquid ammonia (17 g, 1 mol, 1 eq). The mixture was stirred at room temperature for 1.5-2 h, keeping the outlet of the flask connected with a small mercury trap (1-2 cm Hg), and left to stand overnight. Most part of MeOH was evaporated on a water bath and then residual MeOH was evaporated in vacuo until the mixture transformed into a semisolid mass. This mass was distilled in vacuo. Starting compound was distilled (bp 60-70° C. at 1 mm Hg) followed by distillation of title compound (bp 140-150° C. at 1 mm Hg) as colorless liquid, which crystallized very fast (72 g, 0.5 mol, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=2[CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccc(F)cc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.047 g, 59%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 188-191° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])[CH:3]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a solution of 81 (318 mg; 0.85 mmol) in toluene (8.5 mL) was added a solution of phenylboronic acid (152 mg; 1.12 mmol) in ethanol (5.6 mL). Bis(triphenylphosphine)palladium(II) dichloride (32 mg; 0.05 mmol) was then added, followed by the addition of aqueous saturated sodium bicarbonate (3.3 mL). The reaction was placed under a nitrogen atmosphere and then heated at 80° C. for 17 hours. After cooling to room temperature, the reaction was extracted with dichloromethane (70 mL) and washed with aqueous hydrochloric acid (40 mL; 2N), water (40 mL), and aqueous saturated sodium chloride (40 mL). The dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by a silica gel chromatography (9% to 16% ethyl acetate in hexanes gradient) to yield the title compound as a white solid (217 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate (0.23 g, 0.70 mmol) in a mixture of tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide (0.15 g, 3.51 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and acidified to pH=6 with acetic acid. The white solid precipitated was collected by filtration, washed with water and dried in air to afford the title compound as a white solid (0.20 g, 95%): MS (ES+) m/z 301.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(C2CCNCC2)c1
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: COc1cccc(C2CCN(CCC(c3ccc(Cl)c(Cl)c3)C3c4ccccc4C(=O)N3C)CC2)c1
Product: Cl
Yield: 38.3 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.52 g) was coupled to 4-(3-methoxyphenyl)piperidine (0.41 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in Example 8 to afford the title compound (0.16 g); mp 210°-220° C.; MS: m/z=523(M+1); NMR(CD3 SOCD3): 1.98-2.1 (m,4), 2.79 (m,2), 3.06 (s,3), 3.7 (s,3), 4.87 (d,1, J=3.2), 6.8 (m,4), 6.98 (s,1), 7.23-7.35 (m,2), 7.5 (s,2), 7.65 (m,1), 7.95 (d,1, J=7.5). Analysis for C30H32Cl2N2 O2.1.5 HCl: Calculated: C, 62.32; H, 5.84; N, 4.85; Found: C, 62.51; H, 5.77; N, 4.76.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]2[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ncccc1C1=CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 3-bromo-2-fluoropyridine (5.2201 g, 29.7 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.79 g, 37.1 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (1.666 g, 2.373 mmol), and sodium carbonate (15.72 g, 148 mmol) in DME (47.5 mL) and Water (11.86 mL) to stir at 80° C. overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine. MS (ESI, pos. ion) m/z: 180.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([NH2:23])=[O:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]([NH2:23])=[O:22])[CH2:18][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: NC(=O)c1ccccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Product: NC(=O)c1ccccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 41.9 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.306 g) and 2-(piperazin-1-yl)benzamide (0.336 g) are converted to 0.236 g of the title compound after chromatography on silica gel using methanol/dichloromethane (8/92) and crystallization from ethyl acetate/dichloromethane. A portion of this material was recrystallized from ethyl acetate/methanol/hexane; mp 178-179° C.; ms m/z 369; IR (mineral oil) 1663, 3289, 1325, 1448, 796 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.08, 3.78, 5.76, 7.13, 7.23, 7.46, 7.52, 7.53, 8.14, 8.17, 9.57.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].Cl>ClCCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][C:14]=1[CH3:19]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In a mixed solution of 2.0 g of succinic anhydride and 50 ml of 1,2-dichloroethane, 6.7 g of aluminum chloride were added, followed by stirring at room temperature for 40 minutes. To the resulting mixture, 20 ml of 2 -fluorotoluene were added dropwise at room temperature and they were stirred for 20 minutes, followed by further stirring for 20 minutes at an external temperature of 50° C. The reaction mixture was cooled and then poured into ice water to which 5% hydrochloric acid had been added. The resulting mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated. The residue so obtained was recrystallized from chloroform, whereby 3.2 g of the title compound was obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]([O:8][CH3:9])=[O:7]>CO>[CH3:1][O:2][CH:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[O-]
Reactant: COC(=O)CCCC(Br)C(=O)OC
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC(OC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
12.2 g of sodium methoxide were added to a solution of 38.0 g of dimethyl α-bromoadipate (prepared as described in the following Preparation) in 100 ml of methanol, and the mixture was stirred overnight at room temperature. After this, methanol was evaporated from the reaction mixture under reduced pressure, and diethyl ether was added to the resulting residue. The solution thus obtained was washed with water and dried over anhydrous sodium sulfate. The diethyl ether was evaporated off under reduced pressure, and the residue was distilled, to give 11.4 g of the title compound, boiling at 74°-79° C./1 mm Hg (133 Pa).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[N:5]=[C:4]([CH3:18])[CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:26])=O.O>C(Cl)(Cl)Cl>[Cl:26][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[N:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(O)nc(Nc2ccccc2[N+](=O)[O-])n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(Nc2ccccc2[N+](=O)[O-])n1

Procedure:
A mixture of 160 g (0.65 mol) of N-(6-hydroxy-4-methylpyrimidin-2-yl)-o-nitroaniline, 2 ml of N,N-dimethylformamide and 120 ml of phosphorus oxychloride are heated at reflux for 3 hours. After having been cooled, and black slurry is dissolved in chloroform and this solution is added dropwise to 1 l of water. The temperature is maintained at 35° by the addition of ice. After 1 hour the organic phase is separated off and the aqueous phase is washed with chloroform. The two chloroform solutions are together dried and concentrated by evaporation. The black residue is dissolved in hot toluene, filtered and crystallised by the addition of hexane. 104.9 g (61%) of the title compound of formula ##STR16## (compound No. 2.007) are obtained in the form of crystals having a melting point of 175° C.
Reaction SMILES: [CH2:1]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][Br:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[Br-:13].[CH2:1]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A mixture of 7.2 g of 2-nonylbenzyl bromide, 5.77 g of triphenylphosphine and 60 ml of toluene is heated under reflux for 4 hours, cooled and diluted with 80 ml of ether. The 2-nonylbenzyl-triphenylphosphonium bromide that separates out is removed by filtration, washed with ether and dried in vacuo; m.p. 174°-176°.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.OP=O.C(O[C:19]([CH2:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([OH:36])[C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=2)=[O:24])=O)C>O.C(Cl)Cl>[C:1]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[O:22][C:23](=[O:24])[C:25]3[CH:26]=[C:27]([OH:36])[C:28]4[C:33]([C:34]=3[CH:19]=2)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COC(=O)c1cc(O)c2ccc(C)cc2c1
Reactant: Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=PO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(O)cc3c(=O)oc(C(c4ccccc4)c4ccccc4)cc3c2c1

Procedure:
Toluene, 1000 milliliters (mL), heptanes, i.e., a C7 distillate having a boiling range of from 82 to 98° C., (1000 mL), methylene chloride (1000 mL), phosphoric acid, 20.0 grams of an 85 weight percent solution, 5.0 grams of hypophosphorus acid and 625.0 grams of 3-(ethoxycarbonyl)methoxycarbonyl-1-hydroxy-6-methylnaphthalene were added to a reaction flask. The reaction flask was a 5 liter four necked round bottom reactor equipped with an overhead mechanical stirrer, thermometer, electric heating mantle, heavier than water Barrett water trap, Fredrich's condenser and bottom outlet. The mixture was heated to reflux (~55° C.) and about 2 mL of water was removed. 1,1-Diphenyl-2-propyn-1-ol, 903.25 grams of a 61 weight percent solution in methylene chloride, was added to the reactor and the mixture was heated at reflux (~57° C.) for about 8 hours. The hot mixture was filtered to separate the insoluble desired product from the other products of reaction. The crystals were washed with 1 liter of a 1:1:2 mixture of toluene:heptanes:methylene chloride and dried to yield 144 grams of 2-diphenylmethyl-6-hydroxy-9-methyl-4-oxo-4H-naphtho[2,1-c]pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([O:13][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(I)cc(Cl)c2cccnc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1c(I)cc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A flame-dried, 50-mL, three-necked flask is charged with 5-chloro-8-hydroxy-7-iodoquinoline (2.814 g), which is commercially available, t-butyldimethylchlorosilane (1.76 g), and 10 mL of DMF. Imidazole (1.66 g) is added, and the resulting mixture is stirred at room temperature for 18 h. The reaction mixture is then quenched with 10 mL of saturated aqueous NaHCO3 and extracted with hexane three times. The combined organic layers are dried over MgSO4, filtered and concentrated to give 3.898 g of the title compound as a pale green solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[Cl:14][C:15]1[N:20]=[N:19][C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)=[C:17]([OH:32])[CH:16]=1.Cl>O>[Br:1][C:16]1[C:17]([OH:32])=[C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)[N:19]=[N:20][C:15]=1[Cl:14]
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
108 mg (0.607 mmol) of N-bromosuccinimide was added to a N,N-dimethylformamide (2 mL) solution containing 157 mg (0.567 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Water, and then, 4 mol/L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO. 1.05744, developed by hexane:ethyl acetate=2:1) to obtain 123 mg (0.346 mmol, Yield: 61.0%) of 5-bromo-6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3843).