Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=2[C:11]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24](O)=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[O:12])=[N:7][CH:8]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([NH2:42])[CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([NH:42][C:24]([C:19]1[CH:20]=[N:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]1[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][N:7]=1)[CH:23]=2)=[O:25])[CH2:40][CH3:41]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Reactant: CC[C@@H](N)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-[2-(5-Trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (25 mg, 0.06 mmol), [R]-1-pyridin-2-yl-propylamine (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), and triethylamine (69 mg, 0.69 mmol) were combined in 5 ml of dichloromethane. After stirring 5 h at room temperature, the mixture was diluted with dichloromethane and washed with 10 ml of 1N HCl, the organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography eluting with 5% methanol in ethyl acetate afforded the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH:12]=O)[CH:7]=1)[CH2:2][CH2:3][CH3:4].N[C:15]1[NH:19][CH:18]=[N:17][C:16]=1[C:20]([NH2:22])=[O:21].C(O)(=O)C.C([BH3-])#[N:28].[Na+]>C(OCC)(=O)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][NH:28][N:17]2[C:16]([C:20]([NH2:22])=[O:21])=[CH:15][N:19]=[CH:18]2)[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [BH3-]C#N
Reactant: CCCCOc1ccnc(C=O)c1
Reactant: NC(=O)c1nc[nH]c1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1ccnc(CNn2cncc2C(N)=O)c1
Yield: 92.2 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 17(e) using 4-butoxypyridine-2-carbaldehyde (0.67 g, 5.0 mmol, obtained from Example 18(d)), 5-aminoimidazole-4-carboxamide (0.81 g, 4.5 mmol), acetic acid (0.58 mL, 9.0 mmol) and sodium cyanoborohydride (0.57 g, 9.0 mmol) with the exception for the following change in work-up. The crude product was dissolved in ethyl acetate/water (1:1, 60 mL). The pH was adjusted to 8. The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.20 g, 90% yield). MS (ESI) m/z 290 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:22])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)n1
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (1.4 g, 6.5 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (1.4 g, 6.5 mmol), and TEA (1.3 mL, 9.7 mmol) in DMF (32.0 mL) was added HATU (2.7 g, 7.1 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (1×). The combined organic phases were dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using silica gel chromatography (0-5% MeOH in EtOAc) to yield pure title compound (1.2 g, 44%). MS (ESI) mass calcd. For C23H23FN6O, 418.48; m/z found 419.2 [M+H]+. 1H NMR (CDCl3): 8.91-8.56 (m, 2H), 7.47-7.42 (m, 1H), 7.24-7.14 (m, 3H), 6.30 (s, 1H), 3.81 (dd, J=11.6, 7.2 Hz, 1H), 3.72 (ddd, J=9.0, 7.2, 2.2 Hz, 2H), 3.68-3.47 (m, 4H), 3.31 (dd, J=11.0, 4.8 Hz, 1H), 3.05-2.89 (m, 2H), 2.31 (s, 6H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24][CH3:25])=[O:23].O>CO.[OH-].[Na+]>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Yield: 83.7 %

Procedure:
0.227 g of sodium borohydride was added portionwise over approximately 30 minutes at a temperature of less than 30° C., with stirring and under an inert atmosphere, to a mixture of 2.5 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate in 40 cm3 of methanol to which had been added one drop of 5N aqueous sodium hydroxide solution. After stirring the reaction mixture for 3 hours at a temperature in the region of 20° C., 100 cm3 of water were added and then the mixture was extracted with 4 times 50 cm3 of ethyl acetate. The combined extracts were washed with 3 times 50 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residual oil obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 3.2 cm; silica volume 100 cm3), elution was carried out with pure ethyl acetate, and 25-cm3 fractions were collected. The fractions comprising the expected product were combined and then concentrated as above. 2.1 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate were obtained in the form of an oil with a pale yellow color. The hydrochloride was prepared in the following way: a solution of 0.5 g of the oil obtained above, dissolved in 15 cm3 of dichloromethane, was poured with stirring into 4 cm3 of a 1N solution of hydrochloric acid in diethyl ether. A product precipitated and then crystallized by addition of 25 cm3 of diethyl ether. The solid was filtered off, washed with 2 times 10 cm3 of ether, and dried under vacuum over potassium hydroxide (5 kPa) and then, to constant weight, in an oven under reduced pressure (10 Pa) at a temperature in the region of 40° C. 0.35 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate dihydrochloride was obtained in the form of a solid with an off-white color.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:26]Br.[C:28]([O-:31])(=[O:30])[CH3:29].[Na+]>CN(C)C=O>[C:28]([O:31][CH2:26][C:3]1[CH:4]=[C:5]([N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:30])[CH3:29]
Reactant: CC(=O)[O-]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(CBr)c2)ccc1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(COC(C)=O)c2)ccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution of tert-butyl 4-bromo-3-(bromomethyl)phenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (4.46 g, 8.98 mmol) in N,N-dimethylformamide (60 mL) was added sodium acetate (3.68 g, 44.9 mmol). The reaction was stirred at 50° C. for two hours. The mixture was cooled to room temperature and extracted with ethyl acetate and water in portions. The organic layer of each portion was washed three times with water and brine, and dried over sodium sulfate, and filtered. The portions were combined and the solvent was removed under reduced pressure. The residue was purified by Combiflash to give 2-bromo-5-(tert-butoxycarbonyl(5-cyano-6-methoxypyridin-2-yl)amino)benzyl acetate (1.99 g, 2 steps 46%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:27])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>CCO.[Pd]>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:27])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Agent: [Pd]
Solvent: CCO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F

Procedure:
The product of Example 10, Step D, 3,4-Difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)-benzamide was hydrogenated in absolute EtOH in the presence of 5% Pd/C by the procedure of Example 1, Step D. An off-white solid was isolated which was purified by filtration through a plug of silica gel (EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a crystalline cream solid (52 mg, 73%); m.p. (EtOAc/Et2O) 115-116° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.83 (br s, 1 H), 7.44-7.37 (m, 1 H), 7.13-7.05 (m, 1 H), 7.03 (dd, J=12.6, 1.6 Hz, 1 H), 6.88 (dd, J=8.2, 1.6 Hz, 1 H), 6.81 (ddd, J=8.7, 8.7, 4.5 Hz, 1 H), 4.76 (br s, 1 H), 4.46 (t, J=5.1 Hz, 1 H), 3.86 (t, J=4.8 Hz, 2 H), 3.57 (t, J=5.0 Hz, 2 H), 3.43-3.35 (m, 2 H), 2.58-2.52 (m, 2 H), 1.72-1.64 (m, 2 H). Anal. calcd. for C18H19F3N2O4.0.5Et2O: C, 57.0; H, 5.7; N, 6.7. Found C, 56.6; H, 5.5; N, 6.8.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][S:10][C:2]1[NH:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2cnccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cnccc2[nH]1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 1H-imidazo[4,5-c]pyridine-2-thiol (4 g) in acetone (50 ml) were added potassium carbonate (11 g) and MeI (1.8 ml). After stirring for 3 h, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-70% EtOAc in hexane) to give 2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine (4.07 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21](Cl)=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]3=[O:33])[CH2:10][CH2:9]2)=[C:4]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:3]=1.[CH3:40][NH:41][CH3:42]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]([N:41]([CH3:42])[CH3:40])=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]3=[O:33])[CH2:10][CH2:9]2)=[C:4]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cn(COCC[Si](C)(C)C)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O
Temperature: 130 °C

Procedure:
A mixture of 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-chloro-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (0.5 g, 0.84 mmol), prepared as in Example 25, aqueous dimethylamine (40%, 3 mL) and ethanol (3 mL) was heated in a sealed tube 3 hours at 130° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5+3% ammonium hydroxide) to give 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-dimethylamino-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (0.26 g, 0.44 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C)CNc1ccnc(Cl)n1
Reactant: BrCc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CN(Cc1ccc(CBr)cc1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (2.0 g, 10.0 mmoles) and 1,4-bis-bromomethyl-benzene (4.0 g, 15.0 mmoles) are dissolved in 50 ml of DMF and NaH (0.8 g, 21.0 mmoles, 60% oil suspenstion) is added at 0° C. The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 0.9 g of desired (4-bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 24% yield.
Reaction SMILES: [C:1]1([N:7]([CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=2)[N:30]=1.C(O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[ClH:24].[ClH:24].[ClH:24].[C:1]1([N:7]([CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=4)[N:30]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(N(Cc2cccs2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(N(Cc4cccs4)c4ccccc4)CC3)ccc2n1
Product: Cl
Temperature: 170 °C
Reaction time: 4 h
Yield: 124.8 %

Procedure:
1.44 g of 4-[phenyl(2-thienyl)methylamino]-1-piperidinepropanamine and 585 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were dissolved in 3 ml of 1-methyl-2-pyrrolidone, followed by stirring in an oil bath (170° C.) for 4 hours. After cooling, ethanol and saturated aqueous sodium bicarbonate were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, dissolved in 5 ml of ethyl acetate; 0.86 ml of 4N-hydrogenchloride in ethyl acetate was added, followed by concentration. Ethanol-ethyl acetate (1:4) was added to the residue; the crystal precipitated was collected by filtration and dried to yield 609 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[NH:35][CH:32]1[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(NC3CC3)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C24H23N5O3, 429.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[C:21](OC(=O)C)(=[O:23])[CH3:22]>[Cl-].[Cl-].[Zn+2]>[C:21]([O:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1/[CH:12]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2)(=[O:23])[CH3:22]
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)Oc1ccccc1/C=C1\CCCc2cc(C)cnc21

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 ml), salicylaldehyde (20 ml) and acetic anhydride (40 ml) was heated at 100° for 48 hours. Further acetic anhydride (50 ml) and ZnCl2 (1 g) was added and the mixture was heated at reflux for 16 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate, neutralised with Na2CO3 solution and extracted with ethyl acetate. The extracts were extracted with 2N HCl and the extract washed with ethyl acetate basified (Na2CO3) and extracted with diethyl ether. The solution was dried (MgSO4) and evaporated to give an oil which was triturated with n-hexane and recrystallised from n-hexane to give the title compound (12 g) m.p. 85°-7° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]=[CH:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[Cl:17])C.C1COCC1.[OH-].[K+]>CO.O>[Cl:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C=CC=Cc1ccc(OC)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC=CC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The crude ester product was taken up in 200 mL each of methanol and THF and then cooled to 0° C. To this mixture was added a solution of KOH (19 g, 0.338 mol, 3 eq.) in 200 mL H2O. The mixture was stirred at room temperature for 1.5 hr and the organic solvent was evaporated. The aqueous layer was diluted with 300 mL H2O and washed with ether to remove the mineral oil. It was then cooled in an ice-bath and acidified with concentrated HCl to ˜pH 2. The thick precipitate was filtered and rinsed with water, then dried in a vacuum oven at 75° C. to provide 26.2 g of 5-(2-chloro-4-methoxy-phenyl)-penta-2,4-dienoic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].Cl[C:10]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[C:11]([C:12]#[N:13])=[CH:14][CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[N:17]=1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOc1nc(C(F)(F)F)ccc1C#N
Temperature: 65 °C
Yield: 92 %

Procedure:
To N,N-dimethylaminoethanol (25 mL) at 0° C. was added in small portion NaH 60% (4 mol eq, 0.465 g, 11.62 mmol) and after 10 min 2-chloro-6-trifluoromethyl-nicotinonitrile (0.6 g, 2.90 mmol) was slowly added. The mixture was heated at 65° C. for 4 h. Then the solvent was removed at reduced pressure, water was added and the aqueous phase was extracted with EtOAc (3×30 mL). The recombined organic phases were washed with brine, anhydrified over Na2SO4 and evaporated at reduced pressure to obtain a pale yellow oil (0.69 g, 2.66 mmol, 92% Yield) used for the next step of reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:23](=[O:43])[CH2:24][CH2:25][C:26](=[O:42])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]1(=[O:50])[O:49][C:47](=[O:48])[CH2:46][CH2:45]1>N1C=CC=CC=1>[CH2:35]([O:34][N:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:42])[CH2:25][CH2:24][C:23](=[O:43])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:44](=[O:50])[CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Temperature: 81 °C
Yield: 81.4 %

Procedure:
A mixture of (9) (2.2 g, 3.48 mmol), succinic anhydride (0.55 g, 5.5 mmol) and pyridine (70 mL) was heated at 81° C. for 2 hours. Solvent was removed in vacuo and cold 1N HCl (100 mL) was added. Extraction was carried out with CHCl3 (6×75 mL), followed by a water wash (100 mL). Solvent removal and flash column chromatography, eluting with 7% MeOH/CH2Cl2, afforded 1.98 g (81%) of (10) as an oil: 300 MHz NMR δ 1.2-1.7 (m+s, 21 H), 2.53 (t, 2 H, J=7), 2.67 (s, 4 H), 2.78-2.86 (m, 2 H), 3.02-3.11 (m, 2 H), 3.22 (q, 2 H, J=6), 3.56-3.77 (m, 4 H), 4.7 (br s, 1 H), 4.83 (s, 2 H), 4.86 (s, 2 H) , 6.73 (br s, 1 H) , 7.38 (s, 10 H) . Anal. calcd. for C37H54N4O9 : C, 63.59; H, 7.79; N, 8.02. Found: C, 63.4 5; H, 7.81; N, 8.07.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH:20]4[CH2:22][CH2:21]4)[CH2:25][CH2:26]3)=[N:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)nc1
Reactant: C1CN(CC2CC2)CCN1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(N2CCN(CC3CC3)CC2)nc1

Procedure:
In analogy to example 1.a 6-chloro-N-[2-(4-chloro-phenyl)-ethyl]-nicotinamide was reacted with 1-(cyclopropylmethyl)piperazine. Off-white solid. MS (ISP): 399.3 ([M+H]+)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (2 g, 5.69 mmol) and potassium carbonate (1.967 g, 14.23 mmol) were suspended in DMF (20 ml) and heated to 50° C., under nitrogen for 30 mins. The mixture was cooled to room temperature, 1-bromo-4-chlorobutane (0.656 ml, 5.69 mmol) was added and stirring continued at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between DCM (40 ml) and water (40 ml). The layers were separated using a hydrophobic frit and the aqueous layer washed with DCM (10 ml). The combined organic extracts were concentrated in vacuo to give crude material that was purified by silica chromatography using the FlashMaster (70 g cartridge) eluting with a cyclohexane:ethyl acetate 0-100% gradient over 30 mins. The product-containing fractions were combined and evaporated to give the title compound as a white solid (1.4 g).