Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Br:31][C:32]1[C:40]2[C:39](Cl)=[N:38][CH:37]=[N:36][C:35]=2[NH:34][CH:33]=1>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:39]2[C:40]3[C:32]([Br:31])=[CH:33][NH:34][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:13][CH2:12]1
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
DIPEA (0.670 mL, 3.85 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (400 mg, 1.28 mmol) and 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 50) (298 mg, 1.28 mmol) in butan-1-ol (6 mL). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and triturated with diethyl ether to afford (S)-4-amino-1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (70.0 mg, 10.8%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][S:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCSc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCSc2ccc3ccccc3c2)cc1
Yield: 84 %

Procedure:
A mixture of 4-[[2-(2-naphthalenylthio)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.495 g) in methanol and 0.5N sodium hydroxide (5 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.4 g of colorless 4-[[2-(2-naphthalenylthio)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 121°-123° C.
Reaction SMILES: C(O[CH:4]([O:23]CC)[C:5](=O)[C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[NH2:26][C:27]([CH2:34][F:35])=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)(=O)C>[F:35][CH2:34][C:27]1[NH:26][C:5]([CH:4]=[O:23])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(OCC)OCC
Reactant: CCOC(=O)C=C(N)CF
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 18.3 %

Procedure:
Ethyl 4,4-diethoxy-2-(3-nitrophenylmethylene)-3-oxobutanoate (21.75 g, 62 mmoles) and ethyl 3-amino-4-fluoro-2-butenoate (9.17 g, 68 mmoles) were heated at 125° for 1.5 hours. The reaction mixture was dissolved in ethyl acetate (150 ml), washed with water and saturated brine, dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (195 ml) and 50% aqueous hydrochloric acid (292 ml) was added slowly. After 30 minutes the reaction mixture was extracted with ethyl acetate and the organic extract washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4) and the solvent was removed in vacuo. The residue was chromatographed on silica eluting with ethyl acetate/petroleum ether (60°-80°) mixtures. Crystallisation from 2-propanol gave the title compound (4.6 g), mp 88°-90°.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:13]12([CH2:23][C:24]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[CH:3]3)=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: Nn1cnc2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.8 %

Procedure:
3-Amino-4(3H)-quinazolinone (158.7 mg, 0.99 mmol) was dissolved in chloroform (5 mL). 1-Adamantaneacetyl chloride (204.1 mg, 0.96 mmol) and pyridine (100 μL, 1.24 mmol) were added, and the reaction was allowed to stir at ambient temperature for 22 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white solid (264.9 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.69 (m, 12H), 1.96 (br s, 3H), 7.58-7.63 (m, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.87-7.93 (m, 1H), 8.18-8.20 (m, 2H), 11.12 (s, 1H) ppm; MS (DCI/NH3) m/z 338 (M+H)+; Elemental Analysis: Calculated for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.11; H, 6.85; N, 12.43.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=1[CH:20]=O)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=1[CH:20]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:14])([O-:17])=[O:16]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Product: COc1cc(C=C2C(=O)CCc3ccc([N+](=O)[O-])cc32)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 7-nitro-2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 125° C.; IR (Nujol): 1724, 1540, 1545; 1H NMR: δ2.69 (2H, t), 3.16 (2H t), 3.59 (3H, s), 4.01 (3H, s), 6.45 (1H, s), 7.41 (1H, d, J=8.1), 7.68 (1H, d, J=2.2), 7.72 (1H, s), 7.94-7.99 (1H, dd, J=8.4, 2.2), 8.08 (1H, s); 13C NMR: δ28.4, 36.9, 56.9, 57.0, 108.7, 111.6, 123.2, 124.2, 126.1, 129.7, 132.5, 133.9, 135.8, 141.4, 145.8, 146.8, 150.1, 154.1, 198.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(Cc2ccccc2O)cc1
Reaction time: 5 h
Yield: 66.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzoic acid methyl ester (2.39 g, 7.19 mmol) in methanol (70 mL), a 20% palladium hydroxide catalyst (239 mg) was added. The mixture was stirred under a hydrogen atmosphere for five hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure to obtain the title compound (1.16 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 48 was prepared from bis(4-fluorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31]C)=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([OH:31])=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Temperature: 100 °C
Yield: 69.4 %

Procedure:
Sodium hydroxide (0.2 mL of 1 N, 0.2 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-hydroxymethyl-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (15.0 mg, 0.037 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 100° C. for 10 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (10.0 mg, 69%). ESI-MS m/z 390 (MH+); 1H NMR (500 MHz, MeOD) δ 1.19-1.34 (m, 1H) 1.36-1.56 (m, 2H) 1.63 (m, 1H) 1.74-1.87 (m, 2H) 1.91-2.21 (m, 5H) 2.37-2.60 (m, 1H) 2.74 (m, 1H) 2.97 (m, 1H) 3.36 (m, 1H) 3.47-3.67 (m, 2H) 4.59 (m, 1H) 7.38-7.50 (m, 4H) 7.72 (m, 1H) 7.88 (m, 1H) 8.18 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CC2
Yield: 46 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxyindan-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide (0.53 g) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C>CN(C=O)C.O.ClCCl>[C:25]([O:29][C:30](=[O:33])[CH2:31][NH:32][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:23][CH:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (8.7 mL, 99.7 mmol) and several drops of N,N-dimethylformaldehyde (hereinafter DMF) were added to a solution of dichloromethane (40 mL) containing 4-benzyloxybenzoic acid (11.1 g, 48.6 mmol) under ice-cooling. The mixture was stirred at room temperature for 2 hours, and then the solvent was evaporated. The resulting residue was dissolved in dichloromethane (100 mL), and then glycine tert-butyl ester hydrochloride (8.20 g, 48.9 mmol) and N-ethyl-N,N-diisopropylamine (21 mL, 120 mmol) were added thereto under ice-cooling. The mixture was stirred at room temperature for 19 hours, and then water was added thereto to terminate the reaction. The mixture was extracted with dichloromethane twice, and the organic layers were combined and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1 to 2:1, v/v) to give N-[4-(benzyloxy)benzoyl]glycine tert-butyl ester. All the given ester was dissolved in methanol (165 mL), and 20% palladium hydroxide-carbon (926 mg) was added thereto. The mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 3.5 hours. The reaction mixture was filtered through Celite and then concentrated to give 12.2 g of the title compound (colorless crystalline solid, yield: quantitative).
Reaction SMILES: [OH2:1].[C:2]([C:24](F)=[O:25])([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3].F>>[C:2]([C:24]([OH:25])=[O:1])([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:22])([F:21])[F:23])([F:19])[F:18])([F:15])[F:16])([F:12])[F:13])([F:10])[F:9])([F:6])[F:7])([F:3])[F:4]
Reactant: O
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 500 ml PFA vessel equipped with a stirrer was used. Water (250 g, 13.9 mol) was temperature conditioned to 15° C. within the vessel, following which C7F15COF (125 g, 0.3 mol) having a purity of 99.9 wt % was added dropwise under stirring. The resulting mixture was a solid-liquid dispersed system composed of an aqueous phase containing the hydrogen fluoride that formed in hydrolysis, and a solid phase of the C7F15COOH that formed in hydrolysis.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:14]1(C(O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH:14]1([C:11]2[C:10](=[O:12])[C:9]3[C:4]([C:3](=[O:13])[C:2]=2[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: O=C(O)C1CCCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1C(O)=C(C2CCCCC2)C(=O)c2ccccc21
Yield: 24.7 %

Procedure:
To a stirred solution of 2-hydroxynaphthalene-1,4-dione (1.00 g, 5.74 mmol), cyclohexane carboxylic acid (1.10 g, 8.61 rnmol) and silver nitrate (520 mg) in acetonitrile (15 ml) and water (20 ml) heated at 65-70° C. was added an aqueous solution of ammonium persulphate (1.77 g, 7.77 mmol) in water (10 ml). After heating for 1 hour the mixture was cooled, diluted with water (50 ml) and extracted with ether (3×40 ml). The combined ether fractions were washed with water (3×25ml), saturated sodium chloride solution (25 ml) and dried over magnesium sulphate. Filtration and evaporation of solvents under reduced pressure and silica gel chromatography yielded the title compound (364 mg, m.p. 133° C.). This compound is listed as compound 12 in the Tables below.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19]>C(#N)C>[N:23]1[CH:24]=[CH:25][C:20]([CH2:18][CH2:19][N:3]2[CH2:2][CH2:1][C:6]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]3)[CH2:5][CH2:4]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC1CCC2(CCNCC2)CC1
Reactant: C=Cc1ccncc1
Solvent: CC#N
Product: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2

Procedure:
A solution of 0.48 g (2.0 mmol) of the intermediate from Example 1, Step C and 0.21 g (2.0 mmol) 4-vinylpyridine in 6 ml acetonitrile were heated at 80° C. over night. The solvent was removed under reduced pressure, and the remaining solid title compound was purified by stirring several times with tert.-butylmethylether, filtered with suction, and dried in vacuo.
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][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH:37]([O:39][CH3:40])[CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:41].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH:37]([O:39][CH3:40])[CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:41][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][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COC(C)CC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCC(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 64.3 %

Procedure:
This was prepared by the method described in example 4 but using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxole-4-amine (174 mg, 0.65 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (216 mg, 64%) as an off-white solid; NMR Spectrum:(CDCl3) 1.33 (d, 3H), 2.12 (quintet, 2H), 2.47 (m, 4H), 2.55 (m, 3H), 2.74 (dd, 1H), 3.40 (s, 3H), 3.58 (m, 1H), 3.71 (m, 4H), 3.98 (s, 3H), 4.25 (t, 2H), 6.07 (s, 2H), 6.90 (s, 1H), 7.03 (s, 1H), 7.09 (s, 1H), 7.30 (s, 1H ), 8.62 (s, 1H); Mass Spectrum: M+H+ 569/571.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(c1ccccc1)c1ccccc1
Yield: 21.3 %

Procedure:
Methyltriphenylphosphonium bromide (4 g, 11.12 mmol) was added over a 15-min period to a mixture of butyllithium (7.3 ml of 1.6 M solution in THF, 11.76 mmol) and dry THF (50 ml) with stirring and under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature and the mixture was then recooled to −78° C. A solution of diphenylacetaldehyde (2.2 g, 11.12 mmol) in dry THF (10 ml) was added to the above mixture over a 15-min period. The reaction mixture was stirred for 24 h at room temperature, followed by addition of ethyl ether (200 ml), and the reaction mixture was then filtered. The ether extracts were washed with water (3×50 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The crude material was purified by flash chromatography on silical gel (Hexane:Ethyl ether=9:1) to give pure 3,3-diphenylpropene 460 mg (46%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[NH2:19]>>[CH3:26][O:25][C:21]1[CH:20]=[C:18]([NH:19][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:17]=[C:16]([O:15][CH3:14])[C:22]=1[O:23][CH3:24]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(C(=O)O)cc1C#N
Product: COc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1C#N

Procedure:
Compound 68 is synthesized following a similar method as in Example 1 and using 3-cyano-4-methoxybenzoic acid and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:10].C([N-]C(C)C)(C)C.[Li+].[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([C@H:40]([CH3:44])[C:41](Cl)=[O:42])=[CH:36][CH:35]=1)[CH:31]([CH3:33])[CH3:32]>O1CCCC1>[Cl:21][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]=[C:9]([O:10][C:41](=[O:42])[C@H:40]([C:37]1[CH:38]=[CH:39][C:34]([CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:35][CH:36]=1)[CH3:44])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)[C@@H](C)c2ccc(CC(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)-ethanone (2.0 g, 6.2 mmol) in dry tetrahydrofuran (10 ml) was cooled down to −78° C. then a 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (4.1 ml, 7.4 mmol) was added dropwise keeping the temperature below −70° C. The resulting solution was stirred for 30 min., then added with a solution of 2-(S)-(4-isobutyl-phenyl)-propionyl chloride (1.4 g, 6.4 mmol) in dry tetrahydrofuran (10 ml) and left to warm to room temperature. After stirring for further 30 min., the reaction was quenched with brine (20 ml) and water (50 ml) and the mixture was extracted with ethyl acetate (2×40 ml). The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give an oil as mixture of Z and E isomers. These were separated by preparative HPLC water (water/acetonitrile=70/30 to 20/80).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[Mg].[CH:15]1[N:16]=[CH:17][N:18]2[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:19]=12>O1CCCC1>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:24])[CH2:21][CH2:22][CH2:23][N:18]3[CH:17]=[N:16][CH:15]=[C:19]23)=[CH:3][CH:4]=1)([O:12][CH3:13])[CH3:9]
Reactant: O=C1CCCn2cncc21
Reactant: COC(C)(OC)c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(C)(OC)c1ccc(C2(O)CCCn3cncc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The Grignard reagent, prepared from 3.68 mmol of 1-bromo-4-(1,1-dimethoxyethyl)benzene [53578-00-0] and 14.72 mmol of magnesium in 5.5 ml of tetrahydrofuran is added slowly dropwise to a solution of 1.84 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in 10 ml of tetrahydrofuran under argon. The reaction mixture is stirred at room temperature for 12 hours and then quenched with 0.5N HCl. It is extracted with dichloromethane and the phases are separated. The aqueous phase is rendered basic with sodium hydrogen carbonate and the precipitated solid is isolated by filtration and dried at 40° C. The title compound is obtained as a greyish solid. Rt=3.42 (Gradient I). By the process described in Example 3 the following compounds are prepared analogously: