Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]Cl)[CH3:3].[Mg].[CH2:9]1[CH2:19][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH:4]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:19][CH:9]=1)[CH2:5][CH3:6]
Reactant: O=C1CCCc2ccccc21
Reactant: CN(C)CCCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(C1=CCCc2ccccc21)N(C)C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
The Grignard reagent from 300 g (2.5 moles) of dimethylaminopropyl chloride and 60 g (2.5 moles) of magnesium turnings is prepared in 2 l. of tetrahydrofuran. To this is added 300 g (2.0 moles) of α-tetralone in 1 l. of tetrahydrofuran, at a rate to maintain reflux. After the addition the reflux is continued for 1.5 hours, then the mixture is cooled in ice and quenched with 500 ml of saturated ammonium chloride. The layers are separated, and the aqueous diluted with water and reextracted with ether. The organics are evaporated, then treated with a mixture of 350 ml of concentrated HCl and 1400 ml of glacial acetic acid at reflux for 1/2 hour. The solvents are removed in vacuo, and the residue taken up in water, and the aqueous extracted with benzene. Basification liberates the product which is extracted with benzene, dried over carbonate, the solvent evaporated, and the product distilled at 129° C, 0.3 mmHg to give 250 g (58%) of a light yellow liquid, 1-dimethylaminopropyl-3,4-dihydronaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:3]=1[NH:4][N+:5]([O-:7])=[O:6].[OH-].[Na+].CO.Br[CH2:19][C:20]#[CH:21]>O>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:3]=1[N:4]([N+:5]([O-:7])=[O:6])[CH2:21][C:20]#[CH:19]
Reactant: C#CCBr
Reactant: O=[N+]([O-])Nc1c(Br)cc(Br)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCN(c1c(Br)cc(Br)cc1Br)[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2,4,6-tribromo-N-nitroaniline (5.0 g; 0.01334 mol) is reacted with a methanolic solution of sodium hydroxide (0.53 g; 0.01324 mol) in the presence of methanol (60 ml). The solvent is then removed, and the residue dried. The thus obtained sodium salt is dissolved in dimethyl sulfoxide (DMSO) and reacted with 3-bromopropyne (1.52 g; 0.0147 mol) at 25° C. The reaction mixture is stirred 16 hours and then poured into water. The title product is extracted with ether (3×125 ml), the combined extract washed with water, dilute sodium hydroxide, water and brine. The ethereal solution is then dried over magnesium sulfate and the solution concentrated to afford the product, mp. 58°-58.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:5][CH:4]=1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2cccn2)cc1
Yield: 40 %

Procedure:
The title compound was prepared from 4-methoxyphenylboronic acid (0.45 g, 2.94 mmol), pyrazole (0.4 g, 1.47 mmol) using the general procedure A with a yield of 40% (0.4 g); MS (APCI) m/z: 203 (M+1, 100).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:42][CH:43]([S:45]([NH2:48])(=[O:47])=[O:46])[CH3:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](=[O:41])[NH:48][S:45]([CH:43]([CH3:44])[CH3:42])(=[O:47])=[O:46])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)S(N)(=O)=O
Reactant: CCOC(=O)c1cnn(CC)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(CC)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In a 100 ml round bottom flask dissolve 13-cyclohexyl-6-(4-(ethoxycarbonyl)-1-ethyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (950 mg, 1.680 mmol), propane-2-sulfonamide (652 mg, 5.29 mmol) and DMAP (655 mg, 5.36 mmol) in dichloromethane (16.8 mL). To the reaction add EDC (508 mg, 2.65 mmol). Place the reaction under a nitrogen atmosphere and stir a room temperature for 64 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([N:9]=[N+:10]=[N-:11])=[O:8])([O-:3])=[O:2].[C:15](#[N:17])[CH3:16]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([N:9]1[CH:4]=[C:5]([C:6]23[CH2:7][N:17]([CH2:13][CH2:12]2)[CH2:15][CH2:16]3)[N:11]=[N:10]1)=[O:8])([O-:3])=[O:2]
Reactant: [N-]=[N+]=NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC#N
Product: O=C(c1cccc([N+](=O)[O-])c1)n1cc(C23CCN(CC2)C3)nn1
Reaction time: 8 h

Procedure:
A solution of 4-(triphenylphosphinemethylenecarbonyl)-1-azabicyclo [2.2.1]heptane (D24) (4 g, 0.01 mole) in dry acetonitrile (80 ml) was treated with m-nitrobenzoylazide* (3.8 g, 0.020 mole) under nitrogen and the solution heated to reflux for 2 h. The solution was then concentrated in vacuo to a gum which was dissolved in ethyl acetate (30 ml) and allowed to stand at 0° C. overnight when the title compound (D25) (1.35 g, 0.0043 mole, 43%) crystallised out.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][CH:6]=1.C(O)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][CH3:20]>>[CH3:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11](=[O:13])[CH:19]([CH3:20])[C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OC)nn1
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)C(=O)c1ccc(OC)nn1
Yield: 52.5 %

Procedure:
Ethyl 3-(6-methoxypyridazin-3-yl)-2-methyl-3-oxopropionate is prepared by the fractional addition, over a period of 20 minutes, of sodium hydride (19.2 g) (50% in mineral oil) to a solution of methyl 6-methoxypyridazine-3-carboxylate (50 g) in ethyl propionate (220 g) at a temperature of about 98° C. The reaction mixture is maintained under reflux for a further 30 minutes. It is subsequently cooled to a temperature of about 20° C, and ethanol (10 cc) is added with care, followed by distilled water (800 cc). The aqueous phase is removed, washed by decantation with diisopropyl ether (3 × 250 cc), pure acetic acid (250 cc) is added (pH = 5-6) and the aqueous phase is washed again with ethyl acetate (3 × 150 cc). The organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (30 mm Hg) to give ethyl 3-(6-methoxypyridazin-3-yl)-2-methyl-3-oxopropionate (37.2 g) in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30]>O>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 86.6 %

Procedure:
To a mixture of methyl 4-hydroxybenzoate (4.84 g), potassium carbonate (4.80 g), and N,N-dimethylformamide (50 mL) was added 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (6.00 g) with stirring, and the mixture was stirred at 80° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate (8.09 g, yield 87%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). White crystals were obtained by recrystallization from ethyl acetate-diisopropyl ether. melting point: 104-105° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 92.3 %

Procedure:
A mixture of (4-hydroxy-phenyl)-acetic acid methyl ester (5.0 g, 30.0 mmol) and potassium carbonate (5.0 g, 36.1 mmol) in acetone (10 mL) was treated with benzyl bromide (4.29 mL, 36.1 mmol). The reaction mixture was then heated at 90° C. for 6 h. At this time, the potassium carbonate was removed by filtration. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded (4-benzyloxy-phenyl)-acetic acid methyl ester (7.1 g, 92.1%) as a clear oil: EI-HRMS m/e calcd for C16H16O3 (M+) 256.1099 found 256.1103.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]>COCCOC.CC(=O)OCC>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][S:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:23])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCc2ccccc2)nc(-c2ccncc2)nc1OCCO
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (644 mg, 60% in mineral oil) in DME (15 ml) was added ethylene glycol (15 ml). After evolution of gas had ceased, 2-phenyl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (800 mg) was added and the resulting solution was stirred at 90° C. for 16 h. A further portion of NaH (322 mg) was added and stirring was continued at 90° C. for 4 d. The mixture was diluted with EA (200 ml) and washed once with 10% aq. citric acid and 3 times with water. The organic phase was evaporated and the residue was suspended in diethyl ether. The solid material was collected, washed with diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (513 mg) as a beige solid. LC-MS: tR=4.05 min, [M+1]+=523.10, [M−1]−=521.24.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:31][OH:32])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1>>[CH:11]1([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:15])[N:3]=[C:2]([O:32][CH2:31][C:19]4[CH:20]=[CH:21][C:22]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)=[C:17]([F:16])[CH:18]=4)[CH:14]=[C:6]23)[CH2:13][CH2:12]1
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Product: O=c1nc(OCc2ccc(Oc3cccc(F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-(3-fluorophenoxy)phenyl) methanol.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.Cl.[F:30][C:31]([F:39])([F:38])[C:32]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33]1.CN1CCCC1>C1COCC1.CCOC(C)=O>[F:27][C:8]1[CH:9]=[C:10]([CH3:26])[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:12][C:7]=1[NH:6][C:5]([NH:37][CH2:36][CH2:35][C:32]1([C:31]([F:39])([F:38])[F:30])[CH2:34][CH2:33]1)=[O:4]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)nc3nc2C)c(C)cc1F
Reactant: NCCC1(C(F)(F)F)CC1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC4(C(F)(F)F)CC4)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 41.8 %

Procedure:
Treat a mixture of prop-1-en-2-yl(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (1.09 g, 2.86 mmol) and 2-(1-(trifluoromethyl)cyclopropyl)ethanamine hydrochloride (0.542 g, 2.86 mmol) in THF (30 mL) with 1-methylpyrrolidine (1.52 mL, 14.3 mmol) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (MeOH/EtOAc). Treat the resulting material with acetonitrile, cool to −20° C. for 2 h, collect the solids via filtration, rinse with acetonittrile (−20° C.) and dry to afford the title compound as a pale yellow solid (570 mg, 42% yield). MS (m/z): 477.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.O>O1CCCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:16])=[CH:13][CH:12]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether) was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81 mmol) in tetrahydrofuran (25 ml) at 0° C., under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred for 17 hours. Water (3 ml) was then added and the solvent was removed under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl solution. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:9), to yield the title compound (2.30 g). LC/MS: (PS-B3) Rt 3.49 [M−H]+ 297.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:9].[Cl-:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:1]([Cl:10])([Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: O=Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClC(Cl)c1ccccc1
Yield: 45 %

Procedure:
Furthermore, it is known from Liebig's Annalen der Chemie, Volume 626, pages 26 to 34 (1959) to react benzaldehyde with triphenylphosphine dichloride to give benzal chloride, but the yield is only 59%. When cyclohexanone is reacted with triphenylphosphine dichloride in the presence of an equimolar amount of triethylamine it is not the corresponding geminal dihalide which is obtained but 1-chlorocyclohex-1-ene in 45% yield (loc. cit., page 33).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH2:1]([NH:8][C:9]1[S:10][CH:13]=[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=S)NCc1ccccc1
Product: COC(=O)Cc1csc(NCc2ccccc2)n1
Yield: 105.1 %

Procedure:
1.87 g of N-benzylthiourea and 1.82 g of methyl 4-chloroacetoacetate were subjected to a cyclization reaction to obtain 3.10 g of methyl (2-benzylaminothiazol-4-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[CH2:11][CH2:10]1)=[O:5].[C:28](OC(=O)C)(=[O:30])[CH3:29].[OH-].[NH4+]>O>[C:28]([NH:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[CH2:11][CH2:10]1)=[O:5])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of 5.8 parts of 2-amino-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-4-fluorobenzamide, 5.5 parts of acetic acid anhydride and 55 parts of water is stirred and heated for 30 minutes in a water-bath at about 80° C. The reaction mixture is cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane. The combined organic phases are washed three times with water, dired, filtered and evaporated. The oily residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4.5 parts of 2-(acetylamino)-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-4-fluorobenzamide; mp. 175.1° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=O.C(OCC)(=O)C>[Pd].CO>[NH2:1][C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(cc1N)OCO2
Reaction time: 3 h

Procedure:
A mixture of the methyl 6-nitro-1,3-benzodioxole-5-carboxylate, 5% palladium on carbon (1.5 g), ethyl acetate (180 mL) and methanol (80 mL) was stirred 3 hours under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated and the residue was recrystallized from cyclohexane (200 mL) to give methyl 6-amino-1,3-benzodioxole-5-carboxylate (6.3 g, 32 mmol), m.p. 107°-108° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C(O)C>CN(C)C=O>[CH2:19]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:18][CH2:17][CH2:16][C:15]#[CH:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CCCCCCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCO
Product: C#CCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 40.1 %

Procedure:
To potassium phthalimide (37.5 g) in dimethylformamide (400 ml) at 100° C,. was added dropwise 1-chloro-5-hexyne (23.67 g) in dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for a further hour, cooled and stirred at room temperature overnight. The mixture was poured on to ice/water to give an oil, which on trituration gave as a white solid N-5-hexynyl phthalimide (18.35 g), m.p. 74°-6° C. (recrystallisation from ethanol).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>O>[CH:1]([NH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)=[O:2]
Reactant: O=CO
Reactant: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1N
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1NC=O
Temperature: 50 °C

Procedure:
1 g of powdered iron was added in portions to a mixture comprising 1 g of 4-(3-nitro-4-methoxybenzyl)amino-6-chloroquinazoline, 4 ml of acetic acid, 4 ml of water and 40 ml of ethanol, while heating the mixture under mild reflux. The obtained mixture was heated under reflux for 2 hours and filtered to remove insolubles. Concentrated hydrochloric acid was added in portions to the brown filtrate obtained above to give a yellow transparent solution. This solution was cooled with ice to precipitate crystals. The crystals were recovered by filtration and dried to give 1.1 g of 4-(3-amino-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride. This hydrochloride was dissolved in ethanol/water and the obtained solution was made alkaline by adding a 15% aqueous solution of sodium hydroxide in portions. Water was added to the resulting alkaline solution in portions to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 770 mg of 4-(3-amino-4-methoxybenzyl)amine-6-chloroquinazoline (an aniline derivative), Separately. 1 ml of formic acid was dropped into 2 ml of acetic anhydride under cooling with ice and the obtained mixture was heated at 50° C. for 15 minutes and immediately cooled with ice, followed by the addition of the above aniline derivative as such (in a crystalline state), The obtained mixture was reacted at that temperature for one hour and at room temperature for one hour, followed by the addition of water. The crystals thus formed were recovered by filtration, washed with water and dried to give 130 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][N:16]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:38]=[CH:39][C:2]([C:45]3[CH:46]=[CH:47][C:42]([C:41]([F:52])([F:51])[F:40])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)=[CH:20][CH:21]=1)#[N:26]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(CN(CCc2ccc(C#N)cc2)CCc2ccccc2OCc2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(CN(CCc2ccc(C#N)cc2)CCc2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Yield: 70.6 %

Procedure:
200 mg (0.34 mmol) of methyl 4-({{2-[2-(4-bromobenzyloxy)phenyl]ethyl}-[2-(4-cyanophenyl)ethyl]amino}methyl)benzoate from Example 9A are dissolved in 2 ml of 1,2-dimethoxyethane and, under argon, 78 mg (0.41 mmol) of 4-trifluoromethylphenylboronic acid, 2.5 mg of bis(triphenylphosphine)palladium(II) chloride and 0.38 ml of a 2 M aqueous sodium carbonate solution are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelut, washed with dichloromethane and concentrated. The resulting crude product is purified by preparative HPLC. 158 mg (0.24 mmol, 71% yield) of a colorless oil are obtained.