Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=O.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[N:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1cccc(Br)c1
Product: O=C(Cc1cccc(Cl)n1)c1cccc(Br)c1
Yield: 86.9 %

Procedure:
In a similar manner as described in Example 1 from ethyl 3-bromobenzoate (50.6 g, 220 mmol) and 6-chloro-2-picoline (24 mL, 220 mmol), 1-(3-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (59.4 g, 87%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.96 (broad s, 1H), 7.71 (d, 1H), 7.35–7.25 (m, 3H), 6.98 (t, 1H), 6.81 (d, 1H), 6.58 (d, 1H), 5.84 (s, 1H); MS m/z 310 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)=[C:15]=[O:16]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:15]([NH:14][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[CH:22]4)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorophenyl)piperazine (206 mg, 1.05 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.84 (s, 1H), 8.49 (d, 1H, J=7.1 Hz), 7.92 (d, 1H, J=7.8 Hz), 7.78 (d, 1H, 6.8 Hz), 7.61-7.72 (m, 2H), 7.25 (t, 1H, J=8.1 Hz), 6.96-7.04 (m, 2H), 6.81-6.84 (m, 1H), 3.68 (m, 4H), 3.29 (m, 4H); MS (ESI+) m/z 367 (M+H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].C1C=CC=CC=1.[OH-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27]>O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]([N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8])=[O:27]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCCC1=NC(=O)Nc1c(Cl)cccc1Cl

Procedure:
To a slurry of 6.73 g (0.05 mole) of 2-imino-1-methylpyrrolidine hydrochloride in 75 ml. of dry benzene is added, with stirring, 2 ml. of water, followed by 6 ml. of 50% NaOH. The benzene is decanted onto anhydrous K2CO3 and the aqueous layer washed twice with 50 ml. portions of benzene, the benzene being collected by decanting onto the K2CO3. The benzene extracts are put under nitrogen and dried for 15 minutes, then filtered rapidly through diatomaceous earth (nitrogen blanket) and washed with 100 ml. of benzene. To the filtrate is added 9.4 g. (0.05 mole) of 2,6-dichlorophenylisocyanate, put under nitrogen, stoppered and stirred at room temperature for 2 hours. The mixture is filtered and the solvent removed under reduced pressure. Trituration of the oily residue results in crystallization, 1-(2,6-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea, and the white crystals are filtered and collected. After recrystallization from benzene-ether-petroleum ether, the m.p. is 134°-136° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O[CH2:34][CH3:35])(=O)C>COCCOC>[NH2:3][C:2]1[CH:10]=[C:9]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:8]=[CH:34][CH:35]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1

Procedure:
The title compound was prepared as described in example 161 using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.7 g, 5.55 mmol), in ethylene glycol dimethyl ether (60 mL), 3-amino boronic acid (1.72 g, 11.10 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.641 g, 0.555 mmol), and potassium phosphate (5.89 g, 27.75 mmol). A second batch was prepared using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.0 g, 6.53 mmol), in ethylene glycol dimethyl ether (70 mL), 3-amino boronic acid (2.025 g, 13.06 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.755 g, 0.653 mmol), and potassium phosphate (6.92 g, 32.65 mmol). The crude compounds were combined and purified by column chromatography using 30% ethyl acetate in hexanes (3.2 g, 82% yield): ES-MS (m/z) 319 [M+H]+.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:32][C:33]1[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=1>O>[C:8]1([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[N:23]([CH2:32][C:33]4[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=4)[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 470 parts of N,N-dimethylformamide were added portionwise 17.3 parts of a dispersion of sodium hydride in mineral oil (50%) and 91.6 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole (as prepared in Example 16 of U.S. Pat. No. 4,695,575) while stirring under a nitrogen atmosphere. After stirring for 1 hour, 67.9 parts of ethyl 5-chloromethyl-2-furancarboxylate were added dropwise while cooling. Stirring was continued for 1 hour and then water was added to the reaction mixture. The product was extracted with methylbenzene and the extract was washed with water, dried, filtered and evaporated. The residue was dried azeotropically with methylbenzene (2x), yielding 119 parts (86.7%) of ethyl 5-[[2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazol-1-yl]methyl]-2-furancarboxylate (interm. 4). Following the same procedure and starting from the appropriate starting materials, there were also prepared:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cccc(F)c1
Temperature: 25 °C

Procedure:
(3-Fluorophenyl)magnesium bromide (1 M in THF, 9.3 mL, 9.3 mmol) was added dropwise by syringe to a solution of nicotinaldehyde (0.88 mL, 9.3 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was stirred while warming to room temperature for 30 minutes, then quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate once and the organic layer was washed with water three times. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-60% EtOAc-hexanes) to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: Nc1ccc(O)cc1
Reactant: NC(=O)c1cc(Cl)ccn1
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A1, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.Cl[C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.N1C=CC=CC=1>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]([NH:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=1)=[O:30]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.56 g, 1.4 mmoles) in dichloromethane (40 ml) and pyridine (4 ml) was slowly added methyl 4-chloro-4-oxobutyrate (1.3 ml, 7.5 mmoles). The mixture was stirred at room temperature for 60 hours, and then solvent was removed under reduced pressure. The residue was washed twice with water, dissolved in a mixture of concentrated aqueous ammonium hydroxide and methanol (10 ml/40 ml), and stirred at room temperature for one hour. Solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1% methanol in dichloromethane) to give crude N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid methyl ester (0.54 g, not shown) as a foam, MS (M+H)=515.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C@@:2]1([C:18]([F:21])([F:19])[F:20])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:9]=[C:4]2[N:3]1[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCOc1ccccc1

Procedure:
The product is prepared according to the procedure described in Example 1, using 100 mg of (S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (Example 1j) and 143 mg of (2-bromoethyl)phenyl ether, replacing the sodium hydride with caesium carbonate. After purification by silica column chromatography (eluent: dichloromethane/methanol 97/03), 124 mg of (S)-2-methyl-7-morpholin-4-yl-1-(2-phenoxyethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13](F)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 2-chloroaniline (20.13 g, 157.80 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120 mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 25.63 g, 89.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 14.10 (s, 1H), 9.30 (s, 1H), 8.03 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 7.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH2:21][CH3:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH2:21][CH3:22])[CH3:19])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCNC
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Solvent: CO
Product: CCN(C)c1nc(Cl)nc2c1COCC2c1ccccc1
Yield: 100.2 %

Procedure:
A solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (135 mg, 0.480 mmol) and excess N-methylethanamine (284 mg, 4.80 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford 2-chloro-N-ethyl-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (146 mg, 0.481 mmol, 100% yield). LC-MS (M+H)+=304.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([OH:16])[C:7]1=2)[CH3:2].[C:25]([O:29][C:30](=[O:36])[NH:31][CH2:32][CH2:33]CBr)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([O:16][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:36])[C:7]1=2)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCCNC(=O)OC(C)(C)C)c21
Yield: 41.5 %

Procedure:
A solution of [1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (from Step 7.9, 90 mg, 0.27 mmol) in DMF (10 mL) was treated with (3-bromo-propyl)-carbamic acid tert-butyl ester (92 mg, 0.41 mmol) and potassium carbonate (187 mg, 1.35 mmol) at 50° C. overnight. The reaction was concentrated to dryness. The residue was diluted with MeOH/H2O and the mixture was adjusted pH to 3. The solution was purified by preparative HPLC to afford the title compound as a white solid (53 mg). MS calcd for (C22H28BN3O8+H-Boc)+: 374.2. MS found: (M+H-Boc)+=374.2.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[F:9][C:10]([F:20])([C:17](O)=O)[C:11]([F:16])([F:15])[C:12](O)=O>>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:12]=1[C:11]([F:16])([F:15])[C:10]([C:17]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)([F:20])[F:9]
Reactant: O=C(O)C(F)(F)C(F)(F)C(=O)O
Reactant: Nc1ccccc1N
Product: FC(F)(c1nc2ccccc2[nH]1)C(F)(F)c1nc2ccccc2[nH]1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
In a 250 mL 35/25 ball joint flask, 1,2-phenylenediamine (5.92 g, 54.7 mmol) was combined with tetrafluorosuccinic acid (5.2 g, 27.36 mmol). Polyphosphoric acid (83 g) was added directly to the solid mixture. The flask was fitted with an air-driven mechanical stirring shaft and heated to 160° C. under a nitrogen purge maintained with a septum and needle. The molten mixture was stirred for 7 hours and subsequently poured slowly into a large (1 L) excess of cold water. A Waring™ blender was used to grind the solid product/water slurry. The water was then neutralized to a pH of ˜8 with ammonium hydroxide. The brown particulate product, 1,2-bis(benzimidazol-2-yl)-1,1,2,2-tetrafluoroethane, was isolated by filtration, dried in a vacuum oven, ground to a fine powder with a mortar and pestle, and once again slurried in ca. 1 L water which was then neutralized to pH 8 with ammonium hydroxide. The solid was again collected by filtration and dried under diffusion pump vacuum at 110° C. for several days (7.96 g, 87%; C16H10F4N4, FW=334.27). A small amount of water was still present by 1H NMR (br s, 3.35 ppm). 1H NMR (d6-DMSO): δ 13.66 (br s, 2 H, NH), 7.67 and 7.34 (each br s, 4 H, aryl C—H. 13C{1H} NMR (solid state): δ 142.2, 135.5 (C—N), 124.2, 120.2, 114.4 (aryl) (C═N and CF2 not observed). 19F NMR (d6-DMSO, vs. CFCl3): δ-110.61. IR (KBr pellet, cm−1): 3063 (m), 3011 (m), 2947 (m), 2864 (s), 2749 (s), 2699 (sh), 2647 (s), 2546 (m), 2527 (m), 1942 (w), 1903 (w), 1778 (w), 1622 (w), 1591 (m), 1537 (w), 1492 (m), 1456 (s), 1441 (s), 1389 (w), 1317 (m), 1279 (m), 1231 (m), 1202 (w), 1161 (vs), 1140 (vs), 1030 (m), 1014 (m), 999 (m), 941 (m), 909 (m), 887 (m), 789 (w), 766 (w), 739 (s), 675 (w), 619 (w), 590 (m), 545 (w), 434 (m). Elemental analysis calculated for C16H10F4N4: C, 57.49; H, 3.02; F, 22.73; N, 16.76. Found: C, 56.74; H, 2.82; F, 21.95; N, 16.70. FD-MS m/z (%): 334 (M+, 100), 167 (C8H5F2N2, 6). Melting point (DSC, maximum): 383° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12](O)[CH3:13]>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH2:12][CH3:13]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCO
Agent: [Ni]
Product: CCC1C(=O)Nc2ccc(Cl)cc21

Procedure:
The title compound is prepared from 5-chloro-oxindole according to methods known from the literature [B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595]. 1.68 g (0.01 mole) of 5-chloro-oxindole is dissolved in 20 ml of ethanol and 1.0 g of Raney-nickel is added to the solution. The mixture is allowed to react in an autoclave at 110° C. for 36 hours. The catalyst is then filtered off, the solvent is evaporated, and the residue is recrystallized from a mixture of hexane and ethyl acetate.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:11]>>[C:1]1([S:7]([NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
200 ml of aq. NH3 is cooled to −10° C. and treated with benzenesulfonylchloride (13 g, 73 mmol). The resulting mixture is stirred at this temperature for 3 h. When TLC confirmed the completion of the reaction, the reaction mixture is warmed to rt, and the resulting solid is filtered, washed with water and dried under vacuum to afford the title compound (11.1 g, 96%). LC/MS: (ES+): 158.2, (ES−): 156.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOC(C)=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccccc1C(C)=O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (1.0 g, 7.3 mmol) and methyl bromoacetate (0.70 mL, 7.3 mmol) were combined in acetone (20.0 mL) with potassium carbonate (2.0 g, 15 mmol) and was stirred at room temperature. The reaction mixture was stirred for 18 h, diluted with EtOAc and filtered to remove the solids. The organic layer was concentrated to give the sub-title compound as a clear oil (1.5 g, 100%). LCMS calc. for C11H13O4 (M+H)+: m/z=209.1. found: 209.1.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Br)=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][NH2:29]>C(O)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:29][CH3:28])=[CH:20][CH:19]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Solvent: CCO
Product: CNCCOc1ccc(C(=C(CCO)c2ccccc2)c2ccccc2)cc1
Yield: 73 %

Procedure:
42.3 g of (Z)-1,2-diphenyl-1-[4-(2-bromoethoxy)phenyl]-1-buten-4-ol is stirred over 500 ml of 33% methylamine in ethanol for 10 h at 100° C. in autoclave. The solvent is evaporated and the evaporation residue is dissolved in ethyl acetate in the presence of 2 M sodium carbonate solution. After washing the ethyl acetate layer with water and drying with sodium sulfate the solvent is evaporated. Recrystallization from toluene gives 27.2 g (73%) of the product having m.p. 134°-9° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20](=O)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]([Cl:33])[CH2:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc3ccccc3c(=O)[nH]2)ccc1OCCOCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(C2=Cc3ccccc3CN2Cl)ccc1OCCOCc1ccccc1

Procedure:
The resulting 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]isoquinolin-1-one (3.15 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl)-2-chloroisoquinoline. Then, N-ethylpiperazine (30 ml) and potassium carbonate (1.83 g) were added to the resulting compound as it was. The resulting mixture was reacted at 90° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20](O)=[O:21])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Reactant: Nc1ccccc1O
Product: Clc1ccc(-c2c(Cc3nc4ccccc4o3)cnn2-c2ccccc2)cc1

Procedure:
A mixture of 31.3 g of (5-p-chlorophenyl-1-phenyl-pyrazol-4-yl)-acetic acid, 10.9 g of o-aminophenol and 400 ml of polyphosphoric acid is heated at 175° for 2 hours. After cooling and the customary working up, 5-p-chlorophenyl-1-phenyl-4-(benzoxazol-2-ylmethyl)-pyrazole is obtained; m.p. 137°-139°.