Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(C(C)C)CC)(C)C.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)c1ccsc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1ccsc1NC(=O)OCc1ccccc1
Reaction time: 60 h

Procedure:
To a stirred solution of 2-aminothiophene-3-carboxamide (5 g, 35.2 mmol) in tetrahydrofuran (200 mL) under argon was added diisopropylethylamine (9.52 ml, 54.5 mmol) and benzyloxycarbonyl chloride (7.53 mL, 52.8 mmol). After stirring for 60 hours, more diisopropylethylamine (9.52 mL, 54.5 mmol) and benzyloxycarbonyl chloride (7.53 mL, 52.8 mmol) were added. After an additional 24 hours, the suspension was filtered and the resulting solution was concentrated to ˜30 mL and diluted with ethyl acetate (100 mL) The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (3×40 mL), a 3:1 mixture of saturated aqueous sodium bicarbonate and water (40 mL), and brine (40 mL), dried with sodium sulfate, filtered, and concentrated. The resulting mixture of white solid and brown oil was triturated with a mixture of ethyl acetate (10 mL) and hexanes (10 mL), and then the solid was collected by filtration. Drying under vacuum afforded the title compound as a solid.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:12]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][C:15]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[O:10])=[CH:14][CH:13]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, 3-anisoyl chloride (195 g) and biphenyl (190 g) were stirred in dichloromethane (1.4 L). The flask was placed in an ice bath and to it was added anhydrous aluminum chloride (172 g) in portions, each spaced 10 minutes apart. After the aluminum chloride addition was complete the reaction mixture was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was slowly poured into a beaker containing a 10% aqueous solution of hydrochloric acid (1.5 L) and ice while stirring vigorously. A separatory funnel was used to separate the organic and aqueous layers. The recovered organic layer was then washed with deionized water three times with 1 liter each time, hereinafter designated as (3×1 L), dried over sodium sulfate and concentrated by rotary evaporation. Crystals formed while sitting overnight and were collected by vacuum filtration. A recrystallization was then performed by dissolving the crystals in a solution of 10% methanol/90% dichloromethane and subsequently removing nearly all of the solvent by rotary evaporation. Crystals formed while sitting overnight and were collected by vacuum filtration yielding 153 g of [1,1′-biphenyl]-4-yl(3-methoxyphenyl)methanone.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[N:15]1([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:25][C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:27][CH:26]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCCCC4)cc3)cc21
Reaction time: 8 h
Yield: 44 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(1-piperidinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified that purified by silica gel chromatography eluting with EtOAc. The product fractions were pooled and concentrated to a foam that was crystallized to give ethyl-7-(4-(piperidin-1-yl)phenylamino)-1H -[1,6]naphthyridin-2-one (79 mg, 44%): mp (CH2Cl2 /hexanes) 137-139° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]C2(S([O-])(=O)=O)C=CC(C)=CC2)[CH2:34][C:33]1=[O:50]>CN(C=O)C.CC(C)=O>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:38][CH:35]1[CH2:36][CH2:37][N:32]([CH3:31])[C:33](=[O:50])[CH2:34]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: CC1=CCC(CC2CCN(C)C(=O)C2)(S(=O)(=O)[O-])C=C1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)C(=O)C1
Temperature: 95 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 0.87 mmol), (prepared as described in Example 49), potassium carbonate (370 mg, 2.68 mmol) and 4-(1-methyl-2-oxopiperidin-4-yl)methyl-4-toluene sulphonate (260 mg, 0.87 mmol) in DMF (8 ml) was stirred at 95° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture was diluted with acetone, filtered and the filtrate evaporated ‘in vacuo’ to give a residue which was purified by column chromatography, eluting with dichloromethane/methanol/0.88 ammonia (100/8/1). The relevant fractions were combined and evaporated ‘in vacuo’ to give an oil which crystallised on trituration with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methyl-2-oxopiperidin-4-ylmethoxy)quinazoline (66 mg, 17%).
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:39])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:38])[C@H:16]([CH2:34][CH2:35][S:36][CH3:37])[NH:17][P:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].[OH-].[Na+].O>CC(C)=O>[CH2:20]([P:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:40])=[O:2])=[O:39])=[O:38])[CH2:34][CH2:35][S:36][CH3:37])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)NP(=O)(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CSCC[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester (1.87 g, 3.0 m mole) was dissolved in acetone (18 ml), and 1N sodium hydroxide (4.5 ml) was added thereto under cooling and the mixture was stirred for 4 hours. To the solution, water (100 ml) was added, and the solution was washed with diethyl ether. Ethyl acetate (200 ml) was added thereto and the mixture was adjusted to pH 2 with 1N hydrochloric acid while stirring strongly. The ethyl acetate phase was separated and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain an oily dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline (1.81 g, yield: 99.1%). All of the thus obtained product (3.0 m mole) was dissolved in ethanol (15 ml) and a L-arginine (0.58 g, 3.0 m mole) water (5 ml) solution was added thereto. The solvent was evaporated, water was added thereto, and the thus obtained solution was freeze-dried to obtain dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline L-arginine salt (2.27 g, yield: 98.7% from dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester). This product gave a single spot respectively having a Rf =0.8 for peptides in the free form and an Rf =0.25 for arginine by thin layer chromatography (developing solvent, n-butanol:acetic acid:water=2:1:1, Colour forming method, spraying of 25% hydrobromic acid and 0.1 ninhydrin, and heating). After hydrolysis of the product with 6N hydrochloric acid, the amino acids were analyzed. Methionine:Proline:Arginine=1.00:2.03:0.95.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([OH:13])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.Cl>C1COCC1>[OH:13][C:3]1([C:2]([F:1])([F:14])[F:15])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: OC1(C(F)(F)F)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(O)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decane-8-ol (2.0 g, 8.84 mmol) was dissolved in THF (30 ml), followed by addition of 1N aqueous HCl solution (15 ml), and then the resulting mixture was stirred at room temperature for 24 hours. The resulting reaction liquid was concentrated under reduced pressure, and then extracted with 10% MeOH/MC (15 ml×6). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 1.24 g of white solid (77%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:33][NH:34][CH:35]([CH2:37][CH3:38])[CH3:36]>C(Cl)(Cl)Cl>[CH3:33][N:34]([CH:35]([CH3:36])[CH2:37][CH3:38])[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:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Reactant: CCC(C)NC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 63.5 %

Procedure:
Operations are carried out as for Example 7, starting with 2.96 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.33 g of triethylamine, 1.49 g of ethyl chloroformate and 1.34 g of N-methyl 2-butanamine in 120 ml of chloroform. 2.4 g of N-methyl N(1-methyl propyl) 1-phenyl isoquinoline 3-carboxamide melting at 95°-96° C., are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:10][N:11]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1)[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CNC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)C1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIPEA (642 μl, 3.67 mmol) was added to a mixture of N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D13 (177 mg), benzoic acid (93 mg, 0.765 mmol), HATU (349 mg, 0.918 mmol), aza-HOBt (62.5 mg, 0.459 mmol) in N,N-Dimethylformamide (DMF) (2551 μl). The mixture was stirred at room temperature during 2 h. Then the solvents were evaporated. The crude was finally purified via MDAP using a high pH method. Because of the NMR the solid was purified again using the High pH MDAP method. Fractions of each MDAP were combined and evaporated together to give a white solid of E30 in 51 mg. LCMS [M+H]+336.19@0.62 min (2 min run)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[CH2:17]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 70 °C
Yield: 94895.6 %

Procedure:
To a stirred solution of 4-(4-bromophenyl)phenol (25.5 g, 0.102 mmol) in 400 mL of dimethylsulfoxide was added 2.5N NaOH (40.9 ml, 0.102 mol) followed by n-pentyl bromide (12.7 mL, 0.102 mol). The resulting mixture was heated at 70° C. for a period of 18 h. After cooling, the solution was partitioned between ethyl acetate (1000 ml) and water (500 ml). The organic phase was washed with water (3×) and brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 30.9 g of 4-(4-n-pentoxyphenyl)-bromobenzene: 1H NMR (400MHz, DMSO-d6) δ0.93 (t, 3H, J=7.2 Hz), 1.41 (m, 4H), 1.79 (m, 2H), 3.97 (t, 2H, J=6.6 Hz), 6.94 (d, 2H, J=8.8 Hz), 7.39 (d, 2H, J=8.6 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.51 (d, 2H, J=8.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH2:11].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:15]1[C:16]([Cl:20])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: COc1ccc(Br)c(CN)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CNc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 1-(2-bromo-5-methoxyphenyl)methanamine (3.6 g, 13 mmol) and 2,4,5-trichloropyrimidine (1.60 mL, 14 mmol) in N,N-dimethylformamide (41.3 mL) was added potassium carbonate (5.53 g, 40 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a light yellow gel (4.65 g, 96%). LCMS for C12H10BrCl2N3O (M+H)+: m/z=361.9, 363.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](O)=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:15]1[C:16]2[C:11](=[CH:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][CH:17]=2)[CH:12]=[N:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2cc(Nc3ccc(F)cc3)ccc12
Product: Fc1ccc(Nc2ccc3c(Cl)nncc3c2)cc1
Temperature: 105 °C

Procedure:
A mixture of 6-(4-fluorophenylamino)phthalazin-1-ol (0.650 g, 2.55 mmol) and phosphorus oxychloride (5.00 mL, 53.6 mmol) was heated at 105° C. in an oil bath for 2 h. The volatiles were removed by vacuum distillation. The residue was diluted with CH2Cl2 and treated with saturated aqueous solution of NaHCO3. The organic layer was collected and the aqueous layer was extracted with 25% i-PrOH/CHCl3 (2×). The combined organics were dried over Na2SO4, filtered through a pad of silica gel and eluted with EtOAc. The filtrate was concentrated to yield the title compound as a tan solid. MS (ESI, pos. ion) m/z: 274.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][NH:29][CH2:28][CH2:27][NH:26]2)=[N:21]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:29]4[CH2:28][CH2:27][NH:26][CH:25]([C:22]5[CH:23]=[CH:24][NH:20][N:21]=5)[CH2:30]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cc(C2CNCCN2)n[nH]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4cc[nH]n4)C3)c(F)cc2c1=O
Temperature: 130 °C
Yield: 19.7 %

Procedure:
A mixture of 703 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.14 g of 2-(1H-pyrazol-3-yl)piperazine and 5 ml of pyridine was heated in a pressure bottle at 130° C. for 24 hours. It was allowed to cool at room temperature, then cooled to 0° C., the pyridine removed and the crude product purified by flash chromatography on silica gel, giving 195 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.[CH3:17][N:18]([CH2:20][CH:21]([OH:32])[CH2:22][N:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:24])[CH3:19]>>[CH3:19][N:18]([CH2:20][CH:21]([OH:32])[CH2:22][N:23]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:7]2[N:6]=[C:5]([NH:4][C:3]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)=[CH:30][CH:31]=1)[CH3:24])[CH3:17]
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Reactant: CN(C)CC(O)CN(C)c1ccc(N)cc1
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(N(C)CC(O)CN(C)C)cc3)n2)c1
Yield: 17 %

Procedure:
By a procedure analogous to Example 96, 4-(2-fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropyl(N-methyl)amino]aniline (Reference Example D-2) were reacted to give the title product as a brown oil (60 mg, 17%). M/z: (ES+) 425.3 (MH+). HPLC (Hypersil 10 cm base deactivated) 60% MeCN/H2O/0.2% TFA. Retention time: 2.66 min.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=O.[K+].[C:10]([C:13]1[CH:20]=[CH:19][C:16](C=O)=[CH:15][CH:14]=1)([OH:12])=[O:11].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[CH3:8][O:7][C:1]([CH:2]=[CH:3][C:16]1[CH:19]=[CH:20][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:6]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)C=Cc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
18.74 g (0.12 mol) of potassium monomethyl malonate were suspended in 18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine were added at room temperature with stirring and the mixture was boiled under reflux until the evolution of carbon dioxide had ceased (about 2 h). A further 60 ml of pyridine were added and the mixture was stirred under reflux for a further 1 h. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was stirred for a further 20 min, and the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 12.85 g (62%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc2c(=O)c3ccccc3oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)-4-acetylxanthen-9-one (2.4 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.1 g of product m.p. 116-118° C., 1H-NMR (CDCl3)δ:1.69 (s, 3H); 1.72 (s, 3H); 4.71 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 7.05-7.10 (m, 2H); 7.08 (d, 1H, J=8.8 Hz); 7.10 (d, 1H, J=16 Hz); 7.30-7.48 (m, 6H); 7.50-7.58 (m, 2H); 7.65-7.60 (m, 1 H) 8.30-8.33(m, 1H); 8.42 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20]>>[CH3:23][N:21]([CH3:22])[C:19]([C:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([CH2:24][CH3:25])[CH2:26][CH3:27])=[O:20]
Reactant: CCC(N)(CC)C(=O)N(C)C
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CCC(CC)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-amino-2-ethyl-N,N-dimethyl-butyramide as starting materials, MS (EI): 374.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][NH2:23].C(=O)(O)[O-].[Na+].CO>O>[CH3:21][O:22][N:23]=[CH:16][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]=12
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 8 h

Procedure:
A suspension of 5.51 g (20 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde, 2.23 g (26.6 mmol) of O-methylhydroxylamine hydrochloride and 75 ml of water is treated dropwise at room temperature with a solution of 7.67 g (26.6 mmol) of sodium bicarbonate in 65 ml of water. 40 ml of methanol are added thereto and the mixture is stirred at 70° for 8 hours. The mixture is then poured into 700 ml of water, the suspension is suction filtered and the filter residue is dissolved in methylene chloride. The solution is dried over magnesium sulphate and evaported. By chromatography on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate there is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3carboxaldehyde O-methyl oxime of melting point 173°-174°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(OO[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1)(=O)=O>CN(C=O)C>[O:46]=[S:42]1(=[O:45])[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][CH2:36][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][CH:17]=[C:16]5[CH3:22])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:23][CH3:24])[CH2:40][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)OOCCCN2CCS(=O)(=O)CC2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (600 mg, 1.87 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (773 mg, 5.60 mmol) and 3-(1,1-dioxothiomorphlino)propoxy tosylate (1.296 g, 3.74 mmol) in DMF (30 ml) was stirred at 75° C. overnight and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product recrystallised from ethanol to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (525 mg, 56%).