Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:15]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:14]=2[F:13])[CH2:22][CH2:21]1
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a mixture of 2,3-dichloropyrido[3,4-b]pyrazine (8 g, 40.0 mmol) and 1-(2,4-difluorobenzyl)piperazine (8.49 g, 40.0 mmol) in DCM (100 mL) was added triethylamine (16.72 mL, 120 mmol) at room temperature. Then the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with 30 mL of DCM, washed with brine twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 50:1 to 5:1 PE:EtOAc to give the title compound (12 g, 80%). ESI-MS m/z [M+H]+ 376.0.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH-].[Li+].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Yield: 96.7 %

Procedure:
Ethyl 2-[(3S)-7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate (Intermediate 28a, 173 mg, 0.37 mmol) was dissolved in THF (1.5 mL). Lithium hydroxide (52.5 mg, 2.19 mmol) dissolved in water (1.50 mL) was added. The reaction was stirred at rt for 2 h before addition of EtOAc (50 mL). The organic layer was washed with HCl (1M, 30 mL) and brine (30 mL). Dried through a phase separator and evaporated under reduced pressure. The title compound (160 mg, 98%) was obtained crude and used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][C:20]=1[NH:27][S:28]([C:31]1[C:32]2[N:33]=[CH:34][CH:35]=[N:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1, Part C. HPLC: RT=10.09 min. MS (ESI−): mass calcd. for C25H19BrClFN4O5S, 621.86; m/z found, 619/621 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.24 (s, 1H), 8.98 (d, J=1.6, 1H), 8.92 (d, J=1.6, 1H), 8.58 (dd, J=7.3, 1.1, 1H), 8.33 (dd, J=8.5, 1.1, 1H), 7.92-7.86 (m, 1H), 7.76 (d, J=1.9, 1H), 7.28-7.25 (m, 1H), 7.19 (d, J=8.4, 1H), 7.06-6.94 (m, 2H), 6.92 (dd, J=8.4, 1.9, 1H), 6.48 (d, J=7.2, 1H), 4.92 (q, J=5.7, 1H), 3.81 (s, 3H), 3.22-3.09 (m, 2H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[K+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][C:20]2=[O:35])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@H:16]1[CH2:18][O:17]1>C1COCC1.CCOC(C)=O>[CH2:1]([S:3][CH2:18][C@@H:16]([OH:17])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=3)=[CH:21][C:20]2=[O:35])=[CH:9][C:8]=1[O:7][CH3:6])[CH3:2]
Reactant: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1OC[C@H]1CO1
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSC[C@@H](O)COc1ccc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Ethanethiol (47.6 mg, 0.76 mmol) and 25% aq. potassium hydroxide (172 mg, 0.77 mmol) were added to a solution of (R)-1-(3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (32 mg, 0.08 mmol) Part A in THF (1.5 mL). The mixture was stirred overnight at RT. Diluted with EtOAc, washed with sat. NaHCO3, dried (Na2SO4), and concentrated. The residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient) to afford the desired product (S)-1-(4-(3-(ethylthio)-2-hydroxypropoxy)-3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one 15B (28 mg, 0.06 mmol, 76% yield) as a light yellow solid. LC/MS 480 (M+H)+, tR 0.97 min (method 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([CH3:39])(=[O:38])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccccc1F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2S(C)(=O)=O)cc1
Temperature: 90 °C
Yield: 48.8 %

Procedure:
To a solution of INTERMEDIate M (300 mg, 0.717 mmol) and 1-fluoro-2-(methylsulfonyl)benzene (149.0 mg, 0.861 mmol, Apollo) in DMF was added cesium carbonate (467.0 mg, 1.43 mmol). The reaction mixture was heated at 90° C. for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to provide N-(4-methoxybenzyl)-4-(2-(methylsulfonyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (200 mg, 48.8%) as yellow solid. MS (ESI, positive ion) m/z: 572.02 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N+:15]#[C-:16].[CH:17](=O)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>Cl(O)(=O)(=O)=O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:17]=1[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: [C-]#[N+]c1c(C)cccc1C
Reactant: Nc1nc[nH]n1
Reactant: O=Cc1ccco1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1cccc(C)c1Nc1c(-c2ccco2)nc2nc[nH]n12

Procedure:
Compound 18 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) 2,6-dimethylphenylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) furfural solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2ccc(CCCC#N)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
To a stirring solution of ethyl 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylate (24w) (375 mg, 1.46 mmol) in THF:MeOH (4:1, 5 mL) was added 2N LiOH (500 μL). The reaction was heated at 50° C. for 45 minutes then cooled to room temperature and the pH was adjusted between 3-4 with 1N HCl. The solvent was partially concentrated and the remaining aqueous was lyophilized to yield 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (25). 1H NMR (400 MHz, d6-DMSO) δ 9.21-9.19 (m, 1 H), 8.45 (s, 1 H), 7.85 (dd, J=0.8, 9.2 Hz, 1 H), 7.70 (dd, J=1.6, 9.2 Hz, 1 H), 2.82 (t, J=7.2 Hz, 2 H), 2.55 (t, J=7.2 Hz, 2 H), 1.97-1.90 (m, 2 H). MS m/z 230.3 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(SSN(C)C(=O)ON=C2SCOC2C)cc1

Procedure:
4-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 4.0 g (0.03 m) of 5-methyl-4-oximino-1,3-oxathiolane, 6.95 g (0.03 m) of N-methyl-N-(4-methylphenylthiosulfenyl) carbamoyl fluoride and 3.07 g (0.03 m) of triethylamine in 50 ml of dioxane. The crude residual oil (7.3 g) was purified by dry column chromatography using silica gel.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:16][C:17]([CH3:19])=[CH2:18].O>C1COCC1.C(OCC)C>[CH3:18][C:17](=[CH2:16])[CH2:19][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=C(C)COc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Suspend 40 g (0.25 mol) of 4-(1H-imidazol-1-yl)phenol in 280 mL of THF and treat with 15 9 (0.375 mol) of a 60% dispersion of sodium hydride in mineral oil. Stir this suspension for 20 min and then add 27.1 mL (0.25 mol) of 3-chloro-2-methylpropene. Heat this mixture to 100° C. for 3 h. After this time, add 250 mL of water and 250 mL of diethyl ether and separate the layers. Re-extract the aqueous layer with 2×250 mL of diethyl ether. Evaporate the combined ether extracts on a rotary evaporator. Triturate with 300 mL of hexanes and filter off the resulting solid to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)CCCC>[ClH:16].[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[C:6]([CH2:8][OH:9])[CH:7]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(N2CCOCC2)c(CO)c1
Solvent: CCCCCO
Product: Cl
Product: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
[5-Amino-2-(morpholin-4-yl)phenyl]methanol (1.21 g, 5.80 mmol) and 4,7-dichloroquinoline (1.38 g, 6.98 mmol) were refluxed in 10 mL of n-pentanol for 3 h. The reaction mixture was then cooled to room temperature and the hydrochloride precipitate was removed by filtration to yield expected compound as a yellow powder (1.90 g, 80% yield). LC-MS: m/z (ESI) 370.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH3:2].[CH2:28]([NH:32][C:33]1[CH:39]=[C:38]([O:40][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH:37]=[CH:36][C:34]=1[NH2:35])[CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:28]([N:32]1[C:33]2[CH:39]=[C:38]([O:40][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH:37]=[CH:36][C:34]=2[N:35]=[C:10]1[C:9]1[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:15][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:26][CH3:27])[CH2:1][CH3:2])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCNc1cc(OCCCN(CC)CC)ccc1N
Reactant: CCN(CC)CCCOc1cc(OCCc2ccc(Cl)cc2)ccc1C=O
Solvent: CCO
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2OCCCN(CC)CC)nc2ccc(OCCCN(CC)CC)cc21
Yield: 64.8 %

Procedure:
A solution of 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (synthesized via General Procedures D1 and D2) (429 mg; 1.1 mmol) and 2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized via General Procedures G1 and G2 and I) (293 mg; 1 mmol) in ethanol (5 mL) was heated to reflux following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford of (3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine (430 mg).
Reaction SMILES: O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2:11].[NH2:12][C@H:13]([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[NH2:12][C@H:13]([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].[Cu:11]
Reactant: [Cu+2]
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: [Cu]
Temperature: 70 °C
Reaction time: 8 h

Procedure:
One mole of copper sulfate pentahydrate powder, two moles of L-lysine powder, 10% by weight of corn starch (90% starch content), and 10% rice flour (90% starch content) were dry blended and placed in a bomb calorimeter. The calorimeter was submersed in a water bath maintained at about 70° C. for about 90 minutes. The calorimeter was removed from the water bath and allowed to cool to room temperature. The calorimeter was then opened and the product was allowed to stand overnight. A copper lysine chelate complex was formed having ligand to metal molar ratio of about 2:1 and a copper content of about 9.5% by weight. The particle size of the product was then analyzed on a Ro-Tap screen shaker fitted with 16, 20, 40, 60, 80, and 100 mesh screens. About 16% of the product did not pass through a 20 mesh screen, 49% of the product was between 20-60 mesh, and 35% of the product passed through a 60 mesh screen. The bulk density of a 20-80 mesh cut of the product measured about 0.95 gm/cc.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][CH2:8][C:9]1[NH:10][C:11](=[O:19])[C:12]2[CH2:18][O:17][CH2:16][CH2:15][C:13]=2[N:14]=1.[F:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:7]([CH2:8][C:9]3[NH:10][C:11](=[O:19])[C:12]4[CH2:18][O:17][CH2:16][CH2:15][C:13]=4[N:14]=3)[CH2:6][C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:35])[CH2:31][CH2:32]2)=[O:26])=[CH:37][CH:38]=1
Reactant: O=c1[nH]c(CNC[C@H]2CCCO2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)C[C@H]2CCCO2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (20.2 mg) from (R)-2-(((tetrahydrofuran-2-yl)methylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H33FN4O4 512.6. found 513.7 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.89 (dd, J=8.84, 5.31 Hz, 2H) 7.11 (t, J=8.59 Hz, 2H) 4.52-4.69 (m, 1H) 4.28-4.52 (m, 4H) 4.09-4.28 (m, 3H) 3.77-3.95 (m, 5H) 3.62-3.74 (m, 2H) 3.28-3.45 (m, 4H) 2.54-2.62 (m, 1H) 2.19 (d, J=7.07 Hz, 1H) 2.12 (br. s., 3H) 1.84-2.02 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:15]>CCO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:14](=[O:15])[C:13]3[C:12](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=[C:6]2[C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH3:10])[CH:4]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C=O)ccc1O
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1O
Yield: 57.6 %

Procedure:
Anhydrous CuCl2 (0.306 g, 2.20 mmol) and 4-hydroxy-3-methylbenzaldehyde (0.155 g, 1.10 mmol) were added to a solution of 2-amino-N-(4-chlorophenyl)benzamide (0.280 g, 1.10 mmol) in anhydrous EtOH (10 mL). The mixture was heated at reflux temperature for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 50% EtOAc in heptane, afforded 3-(4-chlorophenyl)-2-(4-hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.230 g, 57%).
Reaction SMILES: [F:1][CH:2]([C:8](=O)C1C=CC=CC=1)[C:3](OCC)=[O:4].[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].C(O)(=O)C>C(O)C>[F:1][C:2]1[C:3](=[O:4])[N:23]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[N:22][CH:8]=1
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(F)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1nc2ccccc2ncc1F

Procedure:
Refluxing of ethyl α-fluorobenzoylacetate (2.25 g, 10 mmol) with o-phenylenediamine (10 mmol) in the mixture of acetic acid and ethanol (25%) for 5 h gave 3-fluoro-1,5-benzodiazepin-2-one derivatives in good yields as follows. ##STR17## wherein X=H, 4-Me, 4-Cl or NO2. It is clear that the first step of this reaction is condensation of carbonyl ketone and amine by losing water and second step is cyclization of their ester with another amine by losing ethanol. When used p-CH3 or p-Cl o-phenylenediamine, these were condensed with α-fluorobenzoylacetate,
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][OH:9].[CH3:10][O:11][C:12](=[O:15])[CH2:13]Br>C1COCC1>[CH3:10][O:11][C:12](=[O:15])[CH2:13][O:9][CH2:8][C:4]1[S:3][CH:7]=[CH:6][N:5]=1
Reactant: OCc1nccs1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1nccs1
Temperature: 45 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
NaH (55% dispersion in oil, 1.4 g) was added to a stirred sol. of thiazol-2-ylmethanol (3.55 g, 30.8 mmol) in THF (155 mL). The suspension was then heated to 45° C. for 1 h, and methylbromoacetate (3.40 mL, 37.0 mmol) was added. Stirring was continued at 45° C. for 4 h. The reaction mixture was partitioned between EtOAc and H2O, the phases separated, and the aq. layer extracted with EtOAc (2×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (MeOH/CH2Cl2 1:9) yielded the title compound (5.50 g, 95%) as an orange oil. LC-MS: tR=0.62 min, ES+: 188.14.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([CH2:16][OH:17])[NH:4]1.C(N(CC)CC)C.[C:25](=[S:27])=[S:26].[CH3:28]I>CS(C)=O>[OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([CH2:16][OH:17])[N:4]1[C:25]([S:27][CH3:28])=[S:26]
Reactant: CI
Reactant: S=C=S
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CSC(=S)N1[C@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1CO
Yield: 38 %

Procedure:
In the same manner as described in Example 13 by using (1RS, 3RS)-cis-1,3-dihydroxymethyl-1,2,3,4-tetrahydro-β-carboline (0.70 g), triethylamine (0.84 ml), CS2 (0.36 ml), methyl iodide (0.37 ml) and dimethylsulfoxide (6 ml), there is prepared the title compound (369 mg, 38%) as white powder. NMR (CDCl3, δ): 2.66 (s, 3H, CSSCH3), Mass m/e: 322 (M+), 304 (M+ --H2O), 274 (M+ --CH3SH).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNC(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.3 (aluminium oxide, methylene chloride/methanol=20:1) C29H29N3O5
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([Cl:24])=[O:23]>>[ClH:24].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)nc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc(N3CCN4CCC3CC4)nc2)c1
Product: Cl

Procedure:
Was prepared according to Method G from 6-(1,4-diaza-bicyclo[3.2.2]non-4-yl)pyridin-3-ylamine and 3-methoxybenzoyl chloride. Mp. >265° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)[Cl:28]>C1COCC1.CCCCCC>[ClH:28].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: ClCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cl
Product: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
25 g of 2-bromopyridine are dissolved in 100 ml of THF at −70° C., under nitrogen, and a 1.6M solution of n-butyllithium in hexane is added dropwise followed by a solution of 30 g of 1-benzyl-piperid-4-one in 25 ml of THF. The temperature is allowed to rise to RT, and, after one hour, the solvents are partially evaporated, the residue is poured over a saturated solution of NH4Cl, extracted with ether, washed with water, dried over MgSO4 and evaporated. An oil is obtained which is dissolved in 200 ml of DCM and gaseous HCl is bubbled so as to form the hydrochloride. The expected product (21 g) crystallizes from a methanol/ether mixture, m.p.=185° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3ccccc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, benzoyl chloride.