Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[OH-].[Li+]>C1COCC1.O>[CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(C(=O)O)cc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl (4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-5′-carboxylate (1.40 g, 5.10 mmol) in THF (30 mL) and H2O (15 mL) was added 1.0 N aqueous lithium hydroxide (20.4 mL, 20.4 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The THF was removed in vacuo and the resulting mixture was adjusted to pH=1 by addition of 1.0 N HCl. The precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=260.9 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 12.85 (br s, 1H), 10.98 (br s, 1H), 7.82 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.37 (d, 1H, J=8.4 Hz), 3.38-3.28 (m, 4H), 2.56 (2, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)=[CH:24][C:25](=[O:26])[NH:14][C:5]=23)=[CH:12][CH:11]=1
Reactant: Cc1n[nH]c(N)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=O)[nH]c3c(-c4ccc(Cl)cc4)c(C)nn23)cc1
Yield: 48.2 %

Procedure:
3-Methyl-4-(4-chlorophenyl)-1H-pyrazol-5-amine (166 mg) and ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (266 mg) are stirred overnight at 95° C. in a pyridine (10 mL) solvent. After lowering reaction temperature to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and 141 mg of the target compound is obtained by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 11.40 (br, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.44 (m, 4H), 6.97 (d, J=8.7 Hz, 2H), 4.06 (br, 1H), 3.89 (s, 3H), 2.17 (s, 3H), 2.25 (s, 1H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.[F:54][C:55]([F:81])([F:80])[C:56]1[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=[CH:58][C:57]=1[C:66]1[C:75]([CH3:76])=[C:74](Cl)[C:73]2[C:68](=[CH:69][C:70]([F:79])=[CH:71][C:72]=2[F:78])[N:67]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:81][C:55]([F:54])([F:80])[C:56]1[CH:61]=[C:60]([C:62]([F:64])([F:65])[F:63])[CH:59]=[CH:58][C:57]=1[C:66]1[C:75]([CH3:76])=[C:74]([NH:47][C:46]2[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[N:42][CH:43]=[C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[CH:45]=2)[C:73]2[C:68](=[CH:69][C:70]([F:79])=[CH:71][C:72]=2[F:78])[N:67]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.016 g, 0.034 mmol), 2,5-dimorpholinopyridin-3-amine (0.067 g, 0.25 mmol), 2-(2,4-bis(trifluoromethyl)phenyl)-4-chloro-5,7-difluoro-3-methylquinoline (0.090 g, 0.21 mmol), Pd2dba3 (7.74 mg, 8.46 μmol) and sodium tert-butoxide (0.051 g, 0.53 mmol) in toluene (2.1 mL) at 120° C. for 75 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (1H, s), 7.98 (1H, d, J=8.0 Hz), 7.81 (1H, br. s), 7.62 (1H, J=2.4 Hz), 7.59-7.54 (2H, m), 7.10 (1H, ddd, J=13.3, 8.4, 2.5 Hz), 6.24 (1H, br. s.), 3.93 (4H, m), 3.79 (4H, app t, J=4.7 Hz), 3.40 (4H, br. s.), 3.01 (4H, app t, J=4.9 Hz), 1.92 (3H, s). Mass Spectrum (ESI) m/e=654.3 (M+1).
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([CH2:15][O:16][CH2:17][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][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12].C(O)C.[CH2:38]=[C:39]1[O:43][C:41](=[O:42])[CH2:40]1>N1C=CC=CC=1>[Cl-:1].[C:41]([O:2][CH:3]([CH2:15][O:16][CH2:17][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][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])(=[O:42])[CH2:40][C:39]([CH3:38])=[O:43]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCC[N+](C)(C)C
Reactant: C=C1CC(=O)O1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCC[N+](C)(C)C)OC(=O)CC(C)=O
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
1.5 g (2.94 millimole) of 2-[2-[2-hydroxy-3-(octadecyloxy)propyloxy]ethoxy]ethyltrimethylammonium chloride was dissolved in 80 ml of pyridine, to which 2 ml of diketene was added, and the mixture was stirred at 45° C. for 5 minutes. 10 ml of ethanol was added thereto, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (Merck Co., Art.7734, 38 g, Eluant; chloroform-methanol=4:1-2:1), to give 1.5 g (86%) of the above-captioned compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:26])[CH2:10][N:11]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:25][C@H:23]([CH3:24])[CH2:22][N:11]([C:12]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21])[CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:26])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of benzyl {(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]carbamate (1.95 g, 5.32 mmol) and diisopropylethylamine (1.85 mL, 10.64 mmol) in anhydrous dichloromethane (110 mL) was added dimethylaminopyridine (135 mg) and methane sulfonyl chloride (0.535 mL, 6.92 mmol). The mixture was stirred at room temperature for 1 hour. Reaction was complete as determined by TLC. The reaction mixture was concentrated and purified using flash column chromatography. (1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-1-methylethyl methanesulfonate was obtained in 97.0% yield (2.29 g) as light yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]#[N:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](Cl)(C)C.[N-:33]=[N+:34]=[N-:35].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]2[NH:35][N:34]=[N:33][N:20]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C[Sn](C)(C)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(c1cccc(OCc2ccccc2)c1)C(CCc1nnn[nH]1)c1ccccc1
Temperature: 115 °C
Reaction time: 30 h

Procedure:
A mixture of 1-(3-benzyloxyphenyl)-4-cyano-2-phenylbutan-1-one (2.2 g), toluene (80 mL), trimethyltin chloride (6.17 g) and sodium azide is stirred at 115° C. for 30 hours. The cooled reaction mixture is filtered and the insoluble material is washed with a little ethyl acetate. The combined filtrate plus washings are evaporated and the resulting orange oily solid (3 g) is subjected to flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (29:1 v/v), followed by crystallisation from a mixture of ethyl acetate and cyclohexane, to give 5-[4-(3-benzyloxyphenyl)-4-oxo-3-phenylbutyl]-1H-tetrazole (0.86 g), in the form of a white solid, m.p. 136-138° C. [Elemental analysis:- C,72.5;H,5.63; N,14.0%; Calculated:- C,72.3;H,5.56; N,14.1%].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: OC1CCN(c2ccc(Br)cn2)CC1
Reaction time: 3 h

Procedure:
In 100 ml of 1-methyl-2-pyrrolidone was dissolved 10 g of 2,5-dibromopyridine which was then added with 5.2 g of 4-hydroxypiperidine, along with 17.5 g of potassium carbonate at room temperature. Reaction was conducted at 100° C. for 3 hours with stirring. After completion of the reaction, the same post-treatment as in Preparation Example 13 was carried out to obtain the title compound. 9 g.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:27]1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.C1COCC1>[C:39]1([CH:28]2[CH2:27][CH:26]([NH:2][C@@H:3]3[CH2:5][C@H:4]3[C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=4)=[CH:10][CH:11]=3)[CH2:31][CH2:30][N:29]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N[C@@H]2C[C@H]2c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)CC1c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (60 mg) in methanol (1.5 mL)/THF (1.5 mL) were added tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (60.2 mg) and sodium hydrogen carbonate (28.3 mg). The mixture was stirred at 60° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (12.7 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0° C. and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (62 mg).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>C1(C)C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:19]
Reactant: CCC(C)NC
Reactant: O=C(O)c1nc(-c2ccccc2)c2ccccc2n1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(C)N(C)C(=O)c1nc(-c2ccccc2)c2ccccc2n1

Procedure:
Operations are carried out as for Example 19, starting from 2.5 g of 4-phenyl quinazoline 2-carboxylic acid, 10 ml of thionyl chloride, 25 ml of toluene and 10 ml of N-methyl 2-butanamine. 2.2 g of N-methyl N-(1-methyl propyl) 4-phenyl quinazoline 2-carboxamide, melting at 128° C., are obtained.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[NH:20]1[CH:24]=[N:23][C:22]([C:25]([OH:29])([C:27]#[CH:28])[CH3:26])=[N:21]1>>[F:19][C:3]1[C:2]([C:28]#[C:27][C:25]([OH:29])([C:22]2[N:23]=[CH:24][NH:20][N:21]=2)[CH3:26])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1nc[nH]n1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1nc[nH]n1
Yield: 20 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (40 mg, 20%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6](O)[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[S:10][C:8]=2[N:9]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:6]1[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[S:10][C:8]=2[N:9]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc(O)c2c3c(sc2n1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Product: COCc1nc(Cl)c2c3c(sc2n1)CCCC3
Temperature: 92.5 °C

Procedure:
A stirring suspension of 2-Methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol (2.0 g, 0.008 mol) in POCl3 (20 ml) was heated to 90-95° C. for 4 h and progress was monitored by TLC. After completion of reaction, excess of POCl3 was distilled off to get oily mass which was poured onto ice-water solution (200 ml) and basified with saturated solution of NaHCO3 to pH ˜8. The aqueous phase was extracted well with ethyl acetate (2×250 ml). Combined organic layers were washed with brine solution (100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to get brown colored crude compound 4-Chloro-2-methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine which was forwarded as such for the next step reaction. Yield: (2 g, 93%); 1H NMR (400 MHz, CDCl3) δ ppm=4.60 (s, 2H), 3.37 (s, 3H), 3.00-2.99 (m, 2H), 2.88 (m, 2H), 1.85-1.83 (m, 4H); LCMS: [M+H]=269.1.
Reaction SMILES: ClC1C=C(Cl)C=CC=1[C:4](Cl)=[O:5].Cl[C:13]1[CH:28]=[CH:27][C:16]([C:17]([NH:19][C:20]2[CH:21]=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[O:18])=[CH:15][CH:14]=1>>[OH:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:27]=[CH:28][C:13]([O:5][CH3:4])=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(O)nc2)cc1

Procedure:
Starting from 2,4-dichlorobenzoyl chloride (2.10 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.O.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)[CH2:12][CH:14]1[O:16][CH2:15]1
Reactant: CNc1ccc(CC#N)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CC1CO1)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of 4-methylaminobenzylcyanide (3.05 g, 20.9 mmol), epichlorohydrine (2.4 ml, 2.87 g, 31 mmol), ethanol (25 ml) and water (20 ml) was heated under reflux for 3 hours. After cooling the mixture was diluted with ethanol (10 ml) followed by addition of aqueous 10N NaOH (6 ml). The obtained clear solution was stirred at room temperature for one hour and the ethanol was distilled off. The residue was diluted with 100 ml of water and extracted with ether (3×50 ml). The organic extracts were washed with brine until neutral, dried over MgSO4 and concentrated. The residue was chromatographed over a silica gel column eluting with a 3:1 mixture of benzene and ethyl acetate to give 2.21 g of the oily title compound, yield: 52.2%.
Reaction SMILES: [Na].[CH2:2]([OH:8])[CH:3]1[O:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][Si:11]([CH3:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>[I-].[K+].C1(C)C=CC=CC=1>[CH2:2]([O:8][CH2:10][Si:11]([CH3:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:3]1[O:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCC1CCCO1
Reactant: CCO[Si](C)(CCl)OCC
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCO[Si](C)(COCC1CCCO1)OCC

Procedure:
Under conditions similar to Example 3, the reaction product of sodium metal and tetrahydrofurfuryl alcohol was reacted with chloromethylmethyldiethoxysilane in the presence of potassium iodide catalyst in toluene. The reaction proceeded to the desired product only to the extent of 20% with the formation of significant amounts of byproducts.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]([CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C=O)c(OCCCN2CCOCC2)c1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCCc2ccccc2)c(OCCCN2CCOCC2)c1
Yield: 81.4 %

Procedure:
4-Methoxy-2-[3-(4-morpholinyl)propoxy]-benzaldehyde (29.7 g) and 13.0 g of phenethylamine are reacted in 110 ml. of toluene following the procedure described in Example 1B, yielding 33.1 g of the title compound, boiling point 240°-245° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[CH:15]3[CH:11]2[CH2:12][N:13]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]3=O)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[OH-].[Na+]>O1CCCC1.O>[C:20]1([CH2:19][CH2:18][CH2:17][N:13]2[CH2:12][CH:11]3[CH:15]([CH:10]3[C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1C2C(CN1CCCc1ccccc1)C2c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(C2C3CN(CCCc4ccccc4)CC32)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a solution of 6-(3-nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 24, 55 mg, 0.16 mmol) in tetrahydrofuran (3 ml) under nitrogen, was added dropwise at room temperature a 1.0 M solution of lithium aluminium hydride in tetrahydrofuran (0.81 ml, 0.81 mmol). The mixture was heated to 60° C. for 4 h. Further lithium aluminium hydride in tetrahydrofuran (1.0M, 0.3 ml, 0.3 mmol) was added, and the mixture was heated at 60° C. for 20 minutes, then cooled to room temperature. Water (30 ml) was carefully added, then the residue was acidified by the addition of 2N hydrochloric acid (5 ml), and then basified with 2N sodium hydroxide solution (6 ml). The mixture was extracted with ethyl acetate (3×50ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in ethanol (5 ml), Raney nickel (50 mg) was added, and the mixture was placed under an atmosphere of hydrogen (2 atm, 203 kPa) and stirred at 60° C. for 16 h. The mixture was filtered through Celite™ and concentrated in vacuo to give the title compound as a pale yellow oil (35 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:10][C:8]1([F:11])[O:9][C:5]2=[CH:4][C:3]3[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:24]([C:23](=[O:28])[C:22]([F:30])([F:29])[F:21])[C:25]([CH3:26])=[N:1][C:2]=3[CH:12]=[C:6]2[O:7]1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OC(F)(F)O2
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc2cc3c(cc2c(-c2ccccc2)c1C(=O)C(F)(F)F)OC(F)(F)O3
Reaction time: 16 h
Yield: 30 %

Procedure:
The title compound was prepared from (6-Amino-2,2-difluoro-benzo[1,3]dioxol-5-yl)-phenyl-methanone [example A10] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 30%; MS: m/z=396 (M+H).
Reaction SMILES: NC1C=CC=CC=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C(N(C(C)C)CC)(C)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: Nc1ccccc1
Product: O=[N+]([O-])c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 402.9 %

Procedure:
0.46 mL (5.0 mmole) of aniline was added to a 10 mL diisopropylethylamine solution of 437 mg (1.0 mmole) of fluoronitrobenzene compound (1B-8) and the mixture was stirred for 16 hours at 120° C. The solvent was removed under reduced pressure, 1N hydrochloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure, yielding 496 mg (97 percent) of nitrobenzene compound (1B-9).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:13]1([NH:19][C:20](=[O:28])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]([NH:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:28])[CH2:23][CH2:24]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(CN1CCNCC1)Nc1ccccc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (10 ml) was added N-phenyl-2-piperazin-1-yl-acetamide×2HCl salt (0.160 g, 0.55 mmol) followed by diisopropylethylamine (0.32 ml, 1.76 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane. The title compound was obtained as a pale yellow solid (0.134 g, 62%); 1H-NMR (500 MHz, DMSO-d6) 2.67 (br s, 4H, piperazine N(CH2)2), 3.12 (br s, 4H, piperazine N(CH2)2), 3.19 (s, 2H, NCH2CO), 7.06 (m, 3H, 2-NH2, p-ArH), 7.31 (t, J=7.44 Hz, 2H, m-ArH), 7.62 (d, J=8.29 Hz, 2H, o-ArH), 8.16 (s, 1H, 6-H), 9.76 (s, 1H, CONH);