Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH2:20][CH2:19][C:18]=3[CH:22]=2)=[O:13])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[O:13]=[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1)[CH2:11][CH2:10][CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(CCC1CCNCC1)c1ccc2c(c1)CCO2
Yield: 100.2 %

Procedure:
To 30 ml of concentrated hydrochloric acid was added 5.00 g of 5-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydrobenzofuran, and the mixture was refluxed for 14 hours. The reaction mixture was left standing for cooling and then made basic with a dilute aqueous solution of sodium hydroxide, followed by extraction with methylene chloride. Organic layers were combined and dried over anhydrous sodium sulfate, then the solvent was distilled off to leave 4.31 g (100%) of 2,3-dihydro-5-[1-oxo-3-(piperidin-4-yl)propyl]benzofuran (4). The solid matter thus obtained was dissolved in methanol, treated with hydrogen chloride and recrystallized from methanol--ethyl acetate to give colorless needles, m.p. 203°-205° C. (decomp.)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]([CH2:16][OH:17])=[O:15]>COC(OC)(C)C>[CH3:11][C:1]1([CH3:6])[O:17][CH2:16][C:14](=[O:15])[CH2:13][O:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(CO)CO
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(=O)CO1
Temperature: 25 °C

Procedure:
p-Toluenesulfonic acid (0.18 g) was added to a solution of 1,3-dihydroxyacetone (2.75 g, 30.5 mmol) in 2,2-dimethoxypropane (25 ml). The reaction was heated to reflux for 1.5 hs. The reaction was allowed to cool to room temperature and was concentrated to give the 2,2-dimethyl-1,3-dioxan-5-one as a crude oil.
Reaction SMILES: [F:1][C:2]1(F)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[NH:4][C:3]1=O.BF.Cl.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:9]=2)[NH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)C(F)(F)C(=O)N2
Agent: BF
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2[nH]cc(F)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a stirring solution of 3,3-difluoro-5-(methylsulfonyl)indolin-2-one (1.0 g, 4.0 mmol) in anhydrous THF (25 mL), a solution of “BH2F.THF” (nominal concentration 1.3 M, 13 ml) was added at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was brought to 0° C., aqueous HCl (3 M, 13 mL) was added dropwise. The reaction mixture was subsequently neutralized with aqueous NaOH (2.5M). The mixture was extracted with ethyl acetate, separated and concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound (0.450 g, 52.3%); MS: 213.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:9])[C:5]([CH3:20])=[CH:4][N:3]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:27]=[CH:26][NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][C:5]1[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:9])=[N:7][C:2]([N:25]2[CH:26]=[CH:27][C:23]([C:22]([F:29])([F:28])[F:21])=[N:24]2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(-n2ccc(C(F)(F)F)n2)nc1C(=O)c1cccc(C(F)(F)F)c1
Yield: 16.3 %

Procedure:
The title compound of Step A (0.6 g, 2 mmol), 3-trifluoromethylpyrazole (0.25 g), and potassium carbonate (0.8 g, 6 mmol) were suspended in acetonitrile (15 mL) and heated at reflux for 3 h. The cooled reaction mixture was filtered and the cake washed with acetonitrile. After evaporation of the solvent under reduced pressure, the residue was subjected to silica gel chromatography using hexanes/ethyl acetate (85:15) to give 0.12 g of the title compound of Step B, a compound of the invention, as a white solid. 1H NMR (CDCl3/200 MHz) 2.45 (s, 3H), 6.75 (d, 1H), 7.67 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.27 (s, 1H), 8.54 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][CH2:6][S:7][CH3:8])=[O:2].[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@H:25]([CH3:37])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][SH:29])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH:15]=[CH:16][C:17](=[O:38])[CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@H:25]([CH3:37])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][S:29][C:9](=[O:11])[CH:4]([NH:3][CH:1]=[O:2])[CH2:5][CH2:6][S:7][CH3:8])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH:15]=[CH:16][C:17](=[O:38])[CH:18]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of of N-formyl-L-methionine (7.8 gm) in dry ethyl acetate (120 ml) were added 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (6.0 gm) in dry ethyl acetate (100 ml) and dicyclohexylcarbodiimide (18.2 gm) in dry ethyl acetate (100 ml) at room temperature. The reaction mixture was stirred at room temperature for for 4 hours.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(C[CH:15]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(O)=O.[C:36](O)(=[O:38])C.O>ClCCl>[OH:38][CH2:36][CH:22]1[C:27]2[C:26]3[CH:25]=[CH:31][CH:30]=[CH:29][C:28]=3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[C:35]2[C:23]1=[CH:24][CH:32]=[CH:33][CH:34]=2
Reactant: CC(=O)O
Reactant: O=C(O)CC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reaction time: 3 h
Yield: 10 %

Procedure:
Diisobutylaluminum hydride (4.6 ml, 4.62 mmol; 1 M in CH2Cl2) was added at −65° C. to a solution of 13-carboxymethyl-dibenzo(a,c)fluorene (0.5 g, 1.54 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 3 h and the temperature maintained between −50° C. and −40° C. A white precipitate was obtained. The reaction mixture was treated with a mixture of acetic acid and water (1:1; 30 ml) and extracted with dichloromethane (3×60 ml). The organic layer was washed with saturated bicarbonate (50 ml), water (30 ml) and dried over MgSO4. The solvent was removed in vacuo to afford a crude solid. This crude solid was purified by flash chromatography using chloroform as the eluent. Compound (21) was obtained as a white solid which was washed with petrol (0.217 g, 48%); m.p. 167-168° C.; (Found: C, 89.0; H, 5.39; C22H16O requires: C, 89.2; H, 5.41%); t.l.c. Rf(D) 0.26; Rf(E) 0.64; νmax (CH2Cl2) 3610 (free OH), 3490 (H bonded OH), 3060 (CH stretching), 2940, 2890 (CH stretching, alkyl), 1610, 1600, 1580 (aromatic rings) cm−1; λmax 366 (888), 338 (12728), 322 (14504), 266 (27232), 246 (31968) nm; δH (CDCl3, 200 MHz), 8.88-8.68 (3H, m, aromatic), 8.38 (1H, d, 3J=7.9 Hz, aromatic), 8.14-8.08 (1H, m, aromatic), 7.81-7.33 (7H, m, aromatic), 4.45 (2H, m, Ha CH2 and Hc), 3.85 (1H, m, Hb, CH2), 1.64 (1H, s, OH), δC (CDCl3, 50 MHz), 146.7, 142.5, 139.4, 134.9, 130.9, 130.1, 128.7 (quaternary aromatic C's), 127.5, 126.8, 126.1, 125.9, 125.8, 124.7, 124.2, 124.1, 123.8, 123.4, 122.9 (aromatic CH's), 65.7 (CH), 50.0 (CH); m/z (EI) 296, 265.
Reaction SMILES: ClC1C(=O)C2C(C(=[O:13])C=1Cl)=CC=CC=2.[N+]([O-])([O-])=O.[Na+].[N+:20]([C:23]1[C:24](=[O:34])[C:25]2[C:30]([C:31](=[O:33])[CH:32]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)([O-:22])=[O:21]>CO.O>[OH:13][C:32]1[C:31](=[O:33])[C:30]2[C:25]([C:24](=[O:34])[C:23]=1[N+:20]([O-:22])=[O:21])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: O=C1C=C([N+](=O)[O-])C(=O)c2ccccc21
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([N+](=O)[O-])C(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of 2,3-dichloro-1,4naphthoquinone (6,83g; 0.03 mole) in methanol (40ml) was stirred during the addition of a solution of sodium nitrate (6.9g; 0.1 mole) in water (50ml) and the mixture stirred at 80° C for 3 hrs. Solution was attained after about 1 hr and the nitro naphthoquinone began to separate after 2 hrs. After cooling in ice and the yellow crystalline solid was filtered off, taken up in water (200ml), charcoalised and precipitated the product by addition of one-third the volume of concentrated hydrochloric acid, filtered off, washed well with 5N HCl and dried in vacuo over P2O5 /NaOH to give 5.30 g (81%) of material of m.p. 162°-163° C (d) which was identical to that prepared above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH2:11][Br:14])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(Cl)nc1Cl
Yield: 72.2 %

Procedure:
To a solution of 5.3 g (24.1 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester in CCl4 (92 ml) were added 3.1 g (26.5 mmol) N-Bromosuccinimide, 395 mg (2.4 mmol) AlBN and 1.45 ml (25.3 mmol) acetic acid. The mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 97:3) provided 5.2 g of a mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester and 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester which was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]([NH2:30])[C:28]#[CH:29]>>[CH2:27]([NH:30][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)[C:28]#[CH:29]
Reactant: C#CCN
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: C#CCNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (400 mg) and propargylamine (80 mg) were reacted in the same manner as described in Preparation Example 25 to give the title compound.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].C([N:15](CC)CC)C>C(Cl)Cl>[NH2:15][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: O=C(NCCO)c1ccccn1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NCCNC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
3.0 g of N-(2-hydroxyethyl)pyridine-2-carboxamide were placed in a round flask with 20 ml of methylene chloride and 2.5 ml of triethylamine and the mixture was cooled to 0°-5°. A solution of 1.4 ml of methanesulfochloride in 30 ml of methylene chloride was added dropwise thereto while cooling well at 0°-5°. The reaction mixture was stirred at 0°-5° for a further 2 hours and thereafter added dropwise at 0°-5° to 30 ml of concentrated (25%) ammonia. The reaction mixture was stirred at room temperature overnight and thereafter concentrated under reduced pressure. The residue was dissolved in methylene chloride, extracted with 2N hydrochloric acid and washed with water. The aqueous extracts were combined, made basic with concentrated (28%) sodium hydroxide solution and extracted 3 times with methylene chloride. The organic extracts were dried over magnesium sulfate, filtered and evaporated. There was obtained a yellow oil which was chromatographed on silica gel for further purification. As the elution agent there was used firstly ethyl acetate, thereafter an ethyl acetate/alcohol mixture and finally alcohol. There was obtained N-(2-aminoethyl)pyridine-2-carboxamide which, in accordance with thin-layer chromatography, was identical with the compound described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[C:5]([C:13](O)(O)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26].C(=O)=O.S(Cl)(C)(=O)=O.C(NCC)C>CC(C)=O.C(Cl)(Cl)Cl.C(OCC)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[C:5]([CH:13]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc2cccc(C(O)(O)CO[Si](C)(C)C(C)(C)C)c2nc1C
Agent: CS(=O)(=O)Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(CO[Si](C)(C)C(C)(C)C)c1cccc2cc(C)c(C)nc12
Temperature: 25 °C
Yield: 52.5 %

Procedure:
1.04 g (3.15 mmol) of 2,3-dimethyl-8-(1-hydroxy-2-[tert-butyldimethylsilyloxy]-1-hydroxy-ethyl)quinoline, 20 ml of ethyl ether and 0.53 ml (3.77 mmol) of triethylamine are introduced into a 100 ml round-bottomed flask. The mixture is cooled to −30° C. by a bath of cardice in acetone and 0.30 ml (3.9 mmol) of mesyl chloride are added. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature over 30 minutes. 100 ml of water are added and the resulting mixture is extracted with ethyl ether (3×100 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is transferred, without further purification, into a 25 ml three-necked flask fitted with a condenser. 6.5 ml (63 mmol) of diethylamine and 5 ml of chloroform are added and this mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature and concentrated under vacuum, 50 ml of water are added and the resulting mixture is extracted with ethyl acetate (3×50 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a column of silica (elution solvent: 10% methanol in dichloromethane). 0.64 g (yield: 53%) of 2,3-dimethyl-8-(1-diethylamino-2-[tert-butyldimethylsilyloxy]ethyl)quinoline is obtained in the form of an oil.
Reaction SMILES: [Li].[CH3:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.O.N#N>N.C(O)C.C1COCC1>[CH3:16][O:15][C:12]1[CH2:13][CH:14]=[C:9]([CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH3:2])[CH2:10][CH:11]=1
Reactant: CCCNCCCc1ccc(OC)cc1
Agent: N
Agent: N#N
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNCCCC1=CCC(OC)=CC1
Reaction time: 0.75 h
Yield: 93.5 %

Procedure:
A solution was prepared by dissolving 9.9 g of lithium in 2 l of anhydrous liquid ammonia. 98.7 g of 4-(3-n-propylamino)propylanisole were dissolved in a mixture of 27.8 ml of anhydrous ethanol and 300 ml of THF. This solution was added slowly in dropwise fashion with stirring to the lithium in liquid ammonia solution. After the addition had been completed. The reaction mixture was stirred for about 45 minutes. Water was then added slowly until the blue color of dissolved Li had been discharged. A stream of N2 was passed over the reaction mixture overnight to evaporate the ammonia. Additional water was then added to dissolve the salts which had formed. The alkaline aqueous solution was extracted three times with equal volumes of diethyl ether. The ethereal extracts were combined and dried. Evaporation of the ether yielded 93.2 g of 1-methoxy-4-(3-n-propylamino)propyl-1,4-cyclohexadiene; yield=93.5%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:8]1[CH:9]=[C:4]([O:3][C:2]([F:1])([F:11])[F:12])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: Nc1ncccc1OC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ncc(Br)cc1OC(F)(F)F
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of 3-(trifluoromethoxy)pyridin-2-amine (300 mg, 1.68 mmol) in dichloromethane (8 mL) was added N-bromosuccinimide (450 mg, 2.53 mmol) at 20° C. The reaction mixture was stirred at the same temperature for another 5 min and subsequently concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 15% ethyl acetate in petroleum ether) affording product (220 mg, 51%): 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J=2.0 Hz, 1H), 7.75-7.74 (m, 1H), 6.68 (brs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:12][C@@:13]([OH:28])([CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(C(C)=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:27][C@@:13]([OH:28])([CH3:12])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=2)=[O:15])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(O)cc1F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCC(C)=O
Product: Cc1cc(NC(=O)[C@@](C)(O)COc2ccc(C#N)c(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
(2S)-3-(4-Cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 3 starting from 2-fluoro-4-hydroxybenzonitrile and (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide according to the following procedure. A solution of 2-fluoro-4-hydroxybenzonitrile (0.2 g, 1.4 mmol), (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (0.37 g, 1.2 mmol), K2CO3 (0.34 g, 2.5 mmol) and benzyltriethylammonium chloride (0.028 g, 0.1 mmol) in methyl ethyl ketone (40 ml) was refluxed for 5 hours. The mixture was cooled to the room temperature and evaporated. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml) and the phases were separated. The organic phase was washed with 1 M Na2CO3 (4×20 ml) and water (1×20 ml), dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (eluent CH2Cl2). 1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J=10.1 Hz), 4.371 (1H, d, J=10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.91 (1H, d, J=2.1 Hz), 8.03 (1H, d, J=9.0 Hz) 10.21 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[C:24]1([CH3:33])[C:25]([N:30]=[C:31]=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:33])=[O:32])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)c(F)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoro-aniline (50 mg) was dissolved in chloroform (3 ml) and o-toluyl isocyanate (30 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 17 mg (yield 24%) of the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:36])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[O:36]=[C:23]1[CH2:22][C:21]([C:17]2[CH:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=3)[CH:20]=[CH:19][CH:18]=2)=[N:27][C:26]2[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:25]=2[NH:24]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc1

Procedure:
The title compound was prepared from 3′-(4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-4-sulfonic acid tert-butylamide (Example 5) (235 mg, 0.5 mmol) and TFA (5 mL) according to the general procedure I step 2. Obtained as a yellow solid (122 mg, 58%). MS (ISP) 460.1 [(M+H)+]; mp 195-210° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=3)[N:10]=[CH:9][N:8]=2)=[CH:23][CH:22]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1-c1ccccc1
Reactant: Clc1ccc2c(c1)NCC2
Product: COc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1-c1ccccc1

Procedure:
The title compound was prepared from 7-Methoxy-6-phenyl-3H-quinazolin-4-one (250 mg, 0.99 mmol) and 6-chloroindoline (152 mg, 0.99 mmol) utilizing the method of Example 45 (163 mg, 39%). One hundred sixty-three milligrams (39%) of product was obtained after column chromatography and precipitation as the HCl salt.
Reaction SMILES: ClCCl.[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCCCC(O)=[O:24]>>[CH:13]1([NH:12][C:11]([NH:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:24])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCC(=O)O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of a 2.5g (7.68 mmol) portion of the product of Example 26 in 40 ml of anhydrous dichloromethane 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmol) of n-valeric acid were added and the reaction mixture was maintained at 25° C. under intermittent stirring for 24 hours. Then the N,N'-dicyclohexylurea formed as by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was mixed with 2×40 ml of distilled water, decanted and the wet product was left to solidify under 50 ml of 50% ethanol. The solid compound was filtered, washed with 2×10 ml of 50% ethanol and dried at 80° C. The raw product obtained was recrystallized from 24 ml of ethanol and the crystals were dried at 100° C. to yield 2.20 g (70%) of the aimed product as a yellow powder, m.p.: 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:3]=1.Cl>CC(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2c(N3CCNCC3)cccc2n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate in 2-propanol (3 vol) was added dropwise hydrochloric acid (37%, 3 vol). The mixture was stirred at 40° C. for 1.5 hours then concentrated. Water (30 vol) was added and the solution was extracted with ethyl acetate (3×20 vol). The aqueous layer was basified with an aqueous sodium carbonate solution then extracted with dichloromethane (5×40 vol). The combined organic extracts were dried and evaporated to give the title compound as an off-white solid (80% th, 2 steps).