Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10]Br)C.[OH:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[S:20][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=2)[C:15](=[O:30])[CH:14]=1>>[F:9][C:7]1[CH:8]=[CH:3][C:4]([CH2:10][O:12][C:13]2[CH:18]=[CH:17][N:16]([C:19]3[S:20][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=3)[C:15](=[O:30])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCc1cc(F)ccc1CBr
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Product: CCOC(=O)c1sc(-n2ccc(OCc3ccc(F)cc3)cc2=O)nc1C
Yield: 70 %

Procedure:
Following the procedure as described in Example 17, making variations only as required to use ethyl 1-(bromomethyl)-4-fluorobenzene in place of 2-(bromomethyl)-5-(trifluoromethyl)furan to react with ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 70% yield: mp 214-217° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H), 7.12-7.04 (m, 2H), 6.20 (dd, J=8.1, 2.7 Hz, 1H), 6.07 (d, J=2.7 Hz, 1H), 5.01 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.1, 164.5, 162.8, 161.2, 156.5, 155.6, 131.5, 130.4, 129.8, 119.8, 115.9, 103.9, 97.4, 70.1, 61.9, 17.3, 14.3; MS (ES+) m/z 389.2 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Yield: 94.4 %

Procedure:
A solution of N-morpholinocarbonyl-L-phenylalanine benzyl ester (1.43 g) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (150 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give N-morpholinocarbonyl-L-phenylalanine (1.02 g) as an amorphous powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:5](=[O:6])[CH2:4][CH:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:16][Li]>C1COCC1>[OH:6][C:5]1([CH3:16])[CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1([CH3:15])[CH3:1]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1(C)C
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(C)(O)C1(C)C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of tert-butyl (2,2-dimethyl-3-oxocyclobutyl)carbamate (1.0 equiv.) in anhydrous THF (0.15 M) under nitrogen was added methyllithium (1.6 M in ether, 4.0 equiv.) drop-wise, keeping the temperature below −70° C. The mixture was stirred at this temperature for 1 h. The mixture was quenched with aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate, washed with aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography (5% to 25% ethyl acetate in petroleum ether) to afford the title product (30% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.65-4.52 (m, 1H), 3.60-3.49 (m, 1H), 2.37-2.28 (m, 1H), 1.84-1.76 (m, 1H), 1.66 (s, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H); MS (ESI) m/z 230.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][B-](F)(F)F)=[O:30])([CH3:27])([CH3:26])[CH3:25].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:33][CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCC[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 95 °C
Yield: 66.2 %

Procedure:
To a solution of 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52) (0.13 g, 0.32 mmol) in toluene (4 mL) and water (1 mL) was added potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.082 g, 0.33 mmol), palladium(II) acetate (0.027 g, 0.027 mmol), cesium carbonate (0.33 g, 1.0 mmol), and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (0.016 g, 0.034 mmol), and the solution was stirred under nitrogen and heated to 95° C. for 8 hours. The solution was then cooled and diluted with diethyl ether (5 mL) and adsorbed onto a silica gel pre-column. Flash column chromatography using 0-50% ethyl acetate/hexanes as eluent furnished the title compound as a light tan solid (0.095 g, 63%): mp 149-153° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.18-8.10 (m, 2H), 7.84-7.77 (m, 2H), 7.43-7.35 (m, 2H), 7.31 (d, J=8.2 Hz, 2H), 4.58 (d, J=8.1 Hz, 1H), 3.49-3.34 (m, 1H), 2.87 (t, J=7.0 Hz, 1H), 1.44 (s, 9H); ESIMS m/z 449 ([M+H]+).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].CC(O)=O>CO>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:8])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reaction time: 1.25 h
Yield: 79.2 %

Procedure:
To a stirred solution of 240 g (0.85 mol) of qinghaosu (I) in 12 l MeOH was added 240 g (6.34 mol) NaBH4 over a period of 1.75 h, keeping the reaction mixture at 0°-5° C. After an additional stirring for 1.25 h under the same conditions, the mixture was neutralized with 375 ml AcOH maintaining the temperature in the 0°-5° C. range, concentrated by distilling off 8.5 l of solvent (45° C./400 mm), and diluted with 7.5 l cold H2O--MeOH (2:1, 0°-5° C.). The filtrate was stored for 14 h at 4° C. The small amount of precipitate formed was collected and washed with 2×30 ml H2O--MeOH (2:1, 0°-5° C.). The wet crops were pooled and dissolved in 7 l CH2Cl2. After drying (120 g MgSO4) and evaporation of the solvent, 191.4 g (79%) of (II) was obtained: mp 149°-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[F:21][C:22]([F:44])([F:43])[C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[N:40]=[C:41]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[F:21][C:22]([F:44])([F:43])[C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[NH:40][C:41]1[N:9]([CH3:10])[C:5]2[CH:4]=[C:3]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12]3)[C:2]([Cl:1])=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Reactant: O=C(NCc1ccc(C(F)(F)F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to Example 76 using 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (185 mg, 0.60 mmol), N-(4-trifluoromethyl-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (221 mg, 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (4 mL).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])(=[O:8])=[O:7].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])(=[O:8])=[O:7]
Reactant: O=S(=O)(CCCCCl)c1ccccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccccc1S(=O)(=O)CCCCCl
Yield: 88.2 %

Procedure:
2.8 g of 2-[(4-chlorobutyl)sulfonyl]benzyl alcohol was treated with 1.4 ml of oxalyl chloride, 2.4 ml of dimethylsulfoxide, and 7.8 ml of triethylamine in the same manner as described for Example 1, Part B. Purification of the crude product via column chromatography on silica gel, eluting with 60:10:30 toluene:ethyl acetate:hexane provided 2.45 g of the product. 1H-NMR (CDCl3) δ 1.91-1.97(m,4H); 3.35(t,2H,J=7 Hz); 3.54(t,2H,J=6 Hz); 7.80-7.85(m,2H); 8.07-8.14(m,2H); 10.75(s,1H). Mass spectrum: 261 (M+H).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C:4]([OH:17])([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:3]1>CCOC(C)=O.[Pd]>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C:4]([OH:17])([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)C1(O)CCC(F)(F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1(O)CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (+)-benzyl 3,3-difluoro-1-hydroxycyclopentanecarboxylate (1.8 g, 7.0 mmol) in 45 ml of EtOAc was added a suspension of 10% Palladium on Carbon (720 mg) in 5 ml of EtOAc. The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour (balloon). The reaction mixture was filtered through a glass micropore filter to remove the catalyst and the filtrate was concentrated under vacuum to give (+)-3,3-difluoro-1-hydroxycyclopentanecarboxylic acid.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH3:37])[N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH3:37])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OC
Agent: Br
Product: COc1cc2nc(C)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 10 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7-dimethoxy-2-methylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 53.1 mg (yield: 10%) of Compound 80 was obtained as white crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14].[C:16](O)(=O)C.C(N)=N.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CCO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][CH:12]1[CH2:13][NH:14][CH:16]=[N:15]1
Reactant: CC(=O)O
Reactant: NCC(N)CC1=Cc2ccccc2CC1
Agent: N=CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: C1=NC(CC2=Cc3ccccc3CC2)CN1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture composed of 0.505 g (2.5 mmol) of the compound obtained in Step 4 and 0.286 g (2.75 mmol) of formamidine acetate in 20 ml of EtOH is stirred at 20° C. for 16 hours. After evaporating off the solvent, the residue is taken up in 10 ml of CH2Cl2 ; the mixture is treated with 5 ml of 2N NaOH and extracted with CH2Cl2 (3×20 ml). The combined organic phases are dried and concentrated; the residual oil is dissolved in 10 ml of EtOH and the mixture is treated with a solution of 0.29 g (2.5 mmol) of fumaric acid in 5 ml of EtOH. The title compound is isolated after recrystallisation.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:13][C:14](=O)[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](=O)[CH3:17])C>>[OH:13][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:16]([CH3:17])[C:15]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: Cc1nn(-c2cc(C#N)ccn2)c(O)c1-c1ccccc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and 3-oxo-2-phenyl-butyric acid ethyl ester according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277; Found, 277.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of 2-carboxybenzaldehyde (15.00 g, 0.100 moles), benzyl bromide (20.52 g, 0.120 moles) and potassium carbonate (41.46 g, 0.300 moles) in 250 ml of acetone under nitrogen in a 500 ml round-bottom flask equipped with a magnetic stirrer was refluxed for 6 hours and then stirred at room temperature overnight. The mixture was then filtered through Celite and the filtrate concentrated in vacuo to remove the acetone. The remaining yellow oil was dissolved in ether (200 ml) and this solution washed with saturated sodium bicarbonate solution (1×50 ml), saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 20.4 g of the product as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(Cc4ccccc4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O2, 433.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][N:15](CC4C=CC=CC=4)[CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139 %

Procedure:
2-[4-(4-Chlorophenyl)-1H-imidazol-2-yl]-4-(phenylmethyl)morpholine (2.8 g, 7.91 mmol) was hydrogenated in ethanol (30 mL) over of Pd/C (10 wt %, 0.842 g, 0.791 mmol). To the mixture 0.2 mL of concentrated hydrochloric acid was added. After stirred at room temperature overnight, the catalyst was filtered off. The filtrate was concentrated to get 2.9 g of residue, which was purified by preparative HPLC to afford the title compound (200 mg) as a pale solid. LC-MS (ES) m/z=264 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(CC)CC>>[N:20]1([S:16]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])(=[O:18])=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Solvent: CCN(CC)CC
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)N3CCCCC3)ccc2[nH]1
Yield: 43.4 %

Procedure:
Condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 50 mg, 160 μmol) with piperidine (17 μL, 168 μmol), employing NEt3 (23 μL, 168 μmol) as base as outlined for Example 1, gave the title compound (25 mg, 42%): δH ((CD3)2SO)=1.30–1.40 (m, 2H), 1.50–1.60 (m, 4H), 2.90 (t, 4H), 7.15 (s, 1H), 7.60 (d, 1H), 7.90–8.00 (m, 2H); m/z (ES+)=361.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (200 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1.0 N aqueous sodium hydroxide solution (40 ml) and allowed to stir at ambient temperature for a few minutes. The reaction mixture was extracted 4 times with ethyl acetate and the organic extracts washed with water and brine. The organic extracts were dried over magnesium sulphate, filtered and the solvent removed by evaporation. The residue was triturated with ether/isohexane, filtered and dried to give 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline (102 mg, 39%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=1>C(O)(=O)C.[Pt]=O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1
Reactant: CCOC(=O)c1cc(CO)ccn1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(CO)CCN1

Procedure:
A mixture of 13.9 g of ethyl 4-(hydroxymethyl)-pyridine-2-carboxylate, 5 g platinum oxide in 250 ml acetic acid is hydrogenated at 50 lbs/in2. Filtration, concentration in vacuo, and neutralization with potassium carbonate in methylene chloride yields an oil that is purified by flash chromatography using methylene chloride/methanol saturated with ammonia (20:1) to yield ethyl 4-(hydroxymethyl)-piperidine-2-carboxylate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18](Cl)([N:20]=[C:21]=[O:22])=[O:19]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[O:15][C:21](=[O:22])[NH:20][C:18](=[O:19])[C:13]=3[CH2:12][O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCOCC1c1ccc(C(F)(F)F)cc1
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(C(F)(F)F)cc1)COC2

Procedure:
3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Z(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Z(3)).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH:19]2[CH2:27]Cl)[C:14](=[CH2:30])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]>CC1C=C(C)N=C(C)C=1>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14](=[CH2:30])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=C1C[C@H]2[C@@H]3CC[C@](OC(C)=O)(C(C)=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)CC2CCl
Solvent: Cc1cc(C)nc(C)c1
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(C)=O)[C@]2(C)C1=CC(=O)[C@@H]1C[C@@H]12

Procedure:
A solution of 7.5 g of 17α-acetoxy-1-chloromethyl-6-methylene-4-pregnene-3,20-dione in 66 ml of γ-collidine is stirred for one hour at a bath temperature of 180° C. and then poured on an ice water-sodium chloride solution. The mixture is filtered off and the residue worked up as usual. The crude product is purified on 700 g of silica gel with a hexane-ethyl acetate gradient. Yield: 4.3 g of 17α-acetoxy-1α,2α-methylene-6-methylene-4 pregnene-3,20-dione, mp 205°-206° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=O>[Ti](Cl)(Cl)(Cl)Cl.CCCCC>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Product: C1=C(N2CCCC2)Cc2ccccc21
Reaction time: 2 h

Procedure:
To a 100 ml reaction tube equipped with a stirrer bar, Suba.Seal™ stopper, and a nitrogen balloon, was added pyrrolidine (1.3 ml) and pentane (8 ml). Titanium tetrachloride (0.2 ml) was added slowly to each tube. 2-Indanone (0.2 g, 1.33 mmol) was added as a solid and the reaction stirred vigorously for 2 h. The reaction mixture was filtered through Celite and the solvent removed in vacuo to give the title compound as a dark solid. m/z (ES+) 186 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[Cl:36][C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([Cl:37])[CH:33]=1)[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(Cl)cc(Cl)c1
Product: CC(C(=O)NCc1cc(Cl)cc(Cl)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=523.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3,5-dichloro-benzyl)-malonamic acid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19]CC)=[O:18])=[CH:5][N:4]=1.[OH-].[K+]>C(O)C>[O:2]=[C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([OH:19])=[O:18])=[CH:5][NH:4]1
Reactant: CCOC(=O)c1cccc(Nc2cnc(OC)c3c2CCCC3)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Nc2c[nH]c(=O)c3c2CCCC3)c1
Reaction time: 2 h

Procedure:
180 mg (0.58 mmol) of ethyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino)benzoate (compound 38) are introduced into 3 ml of ethanol and, at room temperature, 3 ml of 2N KOH are added. After two hours, the solvent is removed in vacuo and the residue is taken up in 5 ml of H2O and acidified with 2N HCl. The resulting precipitate is filtered off with suction and dried. Yield: 123 mg (75%).