Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][NH:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2
Yield: 84.8 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (400 mg) and 4-benzyloxyphenylacetyl chloride (700 mg) according to an analogous synthetic method to Example 152, the title compound (591 mg) was obtained.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]=[CH:5]1)(=O)C.[CH:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH:13]([N:6]1[C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][N:4]=[CH:5]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cn(C(C)=O)cn1
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1cncn1C(c1ccccc1)c1ccccc1

Procedure:
1.7 g (0.01 mol) of 1-acetyl-4-methoxycarbonyl-imidazole in 5 cc of acetonitrile and 2 g of benzhydryl-chloride were refluxed for 4 hours, the solvent was removed under reduced pressure and the residue was stirred with 15 cc of 0.5 N sodium acetate solution to split off the acetyl group. The 1-benzhydryl-5-methoxycarbonyl-imidazole, m.p. 129° C., was recrystallized from chloroform.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH:12]1(C(C2CC2)(O)C#C)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:13]1[C:1]2[C:10]3[C:5]([CH:4]=[CH:3][C:2]=2[O:11][CH2:14][CH:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: C#CC(O)(C1CC1)C1CC1
Reactant: Oc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: C1=Cc2c(ccc3ccccc23)OC1

Procedure:
Acidic alumina (20 grams) was added to a solution of 2-naphthol (4.2 grams, 0.03 moles) and 1,1-Dicyclopropylpropyn-1-o1 (3.08 grams, 0.0226 moles) in toluene (30 cc). The mixture was boiled under reflux for three hours and the alumina removed by filtration. The filtrate was washed sequentially with a dilute (10 percent) sodium hydroxide solution and water. The organic layer was extracted with diethyl ether (2×50 cc), dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure leaving a brown oil which was chromatographed on silica gel using petroleum (b.p. 60°-80° C.) as the eluant. The fraction which exhibited a reversible change from colorless to yellow on exposure to the flash from the flash gun of Example 2 was collected. Petroleum solvent was removed under reduced pressure leaving as a colorless oil 0.3 grams of 2,2-Dicyclopropyl- [2-H-2,1b] naphthopyran (i.e., graphic formula III).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].O>O1CCCC1>[I:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (19, 323.6 mg, 1.25 mmol) in 8 mL of tetrahydrofuran under nitrogen, sodium hydride (57.41 mg, 60% in mineral oil, 1.44 mmol) was added. The reaction was stirred at room temperature for 10 minutes, then triisopropysilyl chloride (3, 0.304 mL, 1.44 mmol) was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:4]2[CH:3]=1>CCOC(C)=O.CO.[OH-].[Pd+2].[OH-]>[O:13]([CH2:12][C:10]1[N:11]=[C:4]2[CH:3]=[CH:2][NH:7][C:6](=[O:8])[N:5]2[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]c(Cl)cc2nc(COc3ccccc3)cn12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2nc(COc3ccccc3)cn12
Reaction time: 16 h
Yield: 92.7 %

Procedure:
10% Palladium hydroxide (0.43 g, 3 mmol) was added to a solution of 7-chloro-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.24 g, 0.85 mmol) and TEA (0.6 mL, 4.32 mmol) in a mixture of AcOEt and MeOH (60 mL). The mixture was hydrogenated in a Parr reactor (45 psi) at 50° C. for 16 hours. Then 10% palladium hydroxide (0.18 g, 0.43 mmol) was added and the mixture hydrogenated again in a Parr reactor (45 psi) at 50° C. for 16 hours. The mixture was hydrogenated over 5 cycles with addition of 10% palladium hydroxide (0.18 g, 0.43 mmol) every cycle. The mixture was filtered through a pad of diatomaceous earth and washed with MeOH. The solvents were evaporated in vacuo and the crude product purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM with a gradient of 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.19 g, 92% yield) as a white solid.
Reaction SMILES: B(OC(C)C)(OC(C)C)OC(C)C.I[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.[CH2:24]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:24]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1

Procedure:
In a first step, 4′-bromo-4-hydroxybiphenyl is reacted with an n-pentyl halide to give the corresponding 4′-bromo-4-n-pentoxybiphenyl. The 4′-bromo-4-n-pentoxybiphenyl is reacted in a second step with n-butyllithium at −78° C. to form, by transmetallation, 4′-lithium-4-n-pentoxybiphenyl which, in another step likewise at −78° C., is reacted with triisopropyl borate. Hydrolysis and work-up result in 4′-n-pentoxybiphenyl-4-boronic acid which is reacted in further steps with 4-iodobenzoic acid in a standard Suzuki coupling. The 4″-n-pentoxy[1,1′:4′,1″]-terphenyl-4-carboxylic acid is obtained as crude product which is purified by chromatography on silica gel.
Reaction SMILES: [Br:1]Br.[NH:3]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[N:14][C:4]1=2>C(O)(=O)C.C(Cl)Cl>[Br:1][C:12]1[CH:13]=[N:14][C:4]2[NH:3][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:11]=1
Reactant: c1cnc2c(c1)CNCCCN2
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CNCCCN2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Bromine (33 μL, 0.63 mmol) was added to a solution of 1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocine (69 mg, 0.42 mmol) in 5 mL of acetic acid and stirred at room temperature for 19 h. Dilute with DCM and wash with saturated NaHCO3, wash the organic layer with brine, separate, dry over MgSO4, and concentrate in vacuo to obtain orange solid product. Yield 91 mg (90%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.54 (s, 1H), 4.44 (s, 2H), 3.68 (s, 2H), 3.33 (m, 2H), 2.05 (m, 2H); ESI MS m/z 242, 244 [C9H12N3Br+H]+
Reaction SMILES: [C:1]([N:5]1[C:9](=O)[CH2:8][CH:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:23]=3)=[CH:17][C:16]=2[F:34])=[O:13])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[C:1]([N:5]1[CH2:9][CH2:8][CH:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:23]=3)=[CH:17][C:16]=2[F:34])=[O:13])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC4CC(=O)N(C(C)(C)C)C4)c(F)c3)ccn2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC4CCN(C(C)(C)C)C4)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirring solution of 1-(1-tert-butyl-5-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea from Example 35 (95 mg, 0.20 mmol) in dry THF (3 ml) at RT was added 1.0 M LAH/THF (0.81 ml, 0.82 mmol). The resulting mixture was stirred overnight at RT. It was carefully quenched by the sequential addition of H2O (0.1 ml), 3M NaOH (0.1 ml) and H2O (0.3 ml) and then EtOAc was added. The mixture was stirred at RT for 4 hours. The solution was filtered through a pad of Celite® and washing forward with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified via silica gel column chromatography (CH2Cl2/MeOH), dissolved in CH3CN:H2O (1:1 2 mL) and lyophilized to obtain 1-(1-tert-butylpyrrolidin-3-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (45 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (brs, 1H), 8.34 (d, J=6.0 Hz, 1H), 8.24 (s, 1H), 8.16 (t, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.16 (m, 2H), 6.93 (m, 2H), 6.63 (dd, J=2.4, and 5.6 Hz, 1H), 4.05 (m, 1H), 3.84 (s, 3H), 2.3-2.8 (m, 4H), 2.03 (m, 1H), 1.48 (m, 1H), 1.01 (s, 9H); MS (ESI) m/z: 453.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Reactant: NCCCCCCCCCCCCN
Solvent: Cc1ccccc1
Product: N=C(NCCCCCCCCCCCCN)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol), toluene (3.5 mL) and 1,12-diaminododecane (If) (1.02 g, 5.0 mmol) was stirred at 40° C. for 12 h and at 20° C. for 1 h. The crystalline product was collected by filtration, washed with toluene (3×1 mL), and vacuum dried (35° C., 1.5 h) to afford 0.55 g (73%) of white crystals of N-(12-Aminododecyl)-N'-benzyloxycarbonyl guanidine (IIIf).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](=O)[CH3:8])[CH3:2].S(=O)(=O)(O)O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[C:21]2[C:20](=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)[NH:23][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOC(=O)CCC(C)=O
Reactant: NNc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12

Procedure:
4-Oxo-pentanoic acid ethyl ester (17.6 ml, 0.124 mol.) and conc. sulfuric acid (10 ml) were added to a solution of 4-fluorophenylhydrazine (20.2 g, 0.124 mol.) in abs. ethanol (90 ml), and the mixture was heated at reflux for 4 h. For working up, the mixture was filtered over silica gel and washed with ethanol (3×20 ml). The solution was poured into 500 ml of ice-water and extracted with ether (3×100 ml). The combined extracts were washed with 2M sodium hydrogen carbonate solution (50 ml), dried, filtered and concentrated. By recrystallisation from EE/cyclohexane (1:1) it was possible to obtain (5-fluoro-2-methyl-1H-indol-3-yl)acetic acid ethyl ester in a yield of 4.5 g (yellow solid, m.p. 61–62° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:31]=[CH:30][C:15]3[N:16]=[C:17]([NH:19][CH2:20][C:21]4([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].C[CH2:33][N:34](C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.CN.C1COCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:31]=[CH:30][C:15]3[N:16]=[C:17]([NH:19][CH2:20][C:21]4([C:27](=[O:28])[NH:34][CH3:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(NCC4(C(=O)O)CCCCC4)oc3c2)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4(C(=O)NC)CCCCC4)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-{[6-(2-methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]-methyl}-cyclohexanecarboxylic acid (1 eq) in DMF was added DIPEA (3 eq) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 eq). This was stirred at room temperature for 2 hours, then a 2 M solution of methylamine in THF (5 eq) was added and allowed to react overnight at 70° C. The mixture was diluted with ethyl acetate and washed twice with a saturated aqueous solution of ammonium chloride and once with brine, then dried with anhydrous sodium sulfate, filtered and concentrated, then purified by preparatory reverse phase HPLC. MH+=438.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH3:8].F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH3:8][CH:3]1[N:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:4]1
Reactant: CC1CNCCN1C
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Temperature: 150 °C
Yield: 36.2 %

Procedure:
1,2-Dimethyl-piperazine (0.914 g, 8.00 mmol) and ethyl 4-fluorobenzoate (0.587 mL, 4 mmol) were dissolved in DMA (6 mL) and sealed into a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction mixture was evaporated and the crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM (containing 0.1% 0.880 ammonia). Pure fractions were evaporated to dryness to afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.380 g, 36.2%) as a colourless waxy solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1)(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO>O1CCOCC1.[Cl-].[Na+].O>[C:1]([C:4]1[N:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1)#[N:2]
Reactant: NC(=O)c1c[nH]c(=O)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: N#Cc1c[nH]c(=O)cn1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 5-carbamoylpyrazin-2-one (Chem. Pharm. Bull., 1980, 28, 3057; 0.28 g) in dry 1,4-dioxane (5 ml) was cooled to 5° C. prior to adding dry pyridine (0.65 ml). Trifluoroacetic anhydride (0.3 ml) was added dropwise and the reaction mixture allowed to warm to 10° C. After stirring at room temperature for 1 hour the reaction mixture became a slurry and additional trifluoroacetic anhydride (0.25 ml) and pyridine (0.5 ml) was added to give a brown solution. After an additional 1 hour at 10° C. the reaction mixture was added dropwise to methanol and the reaction mixture evaporated under reduced pressure to give a brown gum. The gum was treated with brine and extracted with ethylacetate. The organic phase was washed with dilute hydrochloric acid, brine and dried with sodium sulphate and evaporated under reduce pressure to give an oil that solidified upon scratching to give 5-cyanopyrazin-2-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](I)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:65][C:66]1[CH:71]=[CH:70][N:69]=[CH:68][C:67]=1[CH3:72].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10]([NH:65][C:66]3[CH:71]=[CH:70][N:69]=[CH:68][C:67]=3[CH3:72])[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: Cc1cnccc1N
Reactant: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)COC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 80 °C
Yield: 26.7 %

Procedure:
To a solution of 2-(5-chloro-2-fluorophenyl)-4-iodo-5,7-dihydrofuro[3,4-d]pyrimidine (80 mg, 0.21 mmol, 1 eq) in anhydrous dioxane (5 ml) was added Pd(OAc)2 (2 mg, 0.01 mmol, 0.05 eq) followed by BINAP (10 mg, 0.02 mmol, 0.075 eq), 4-amino-3-picoline (25 mg, 0.23 mmol, 1.2 eq) and Cs2CO3 (100 mg, 0.32 mmol, 1.5 eq). The reaction mixture was heated to 80° C. for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite® and the crude material was purified by flash column chromatography (9:1/ethyl acetate:hexane) to afford [2-(5-Chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine, compound of formula (33) (20 mg, 26%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].Br[C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][N:44]=1>>[NH:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43]([C:18]2[N:19]=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:21]3[S:22][C:14]([CH2:13][N:10]4[CH2:9][CH2:8][N:7]([C:2]([CH3:1])([CH3:6])[C:3]([NH2:5])=[O:4])[CH2:12][CH2:11]4)=[CH:15][C:16]=3[N:17]=2)=[N:44]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Brc1n[nH]c2ccccc12
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4n[nH]c5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure G for Stille coupling, 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide and 3-bromo-1H-indazole were reacted to give 215. LCMS m/z: 521.6 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:19]1([N:25]([CH2:29][CH2:30][OH:31])[CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])=[CH:17][CH:18]=1.[CH3:16][C:13]([Si:10]([CH3:11])([CH3:12])[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCN(CCO)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A procedure analogous to that used for 1a was used with the following materials: 2,2'-(phenylimino)diethanol (9.0 g, 50 mmol), t-butyldimethylsilyl chloride (18.1 g, 0.12 mol), imidazole (17.0 g, 0.25 mol), and dimethylformamide (50 mL). The reaction was stirred overnight for convenience. Workup as in 1a gave 3a as a pale oil (21.6 g, >100%). 1H NMR (CDCl3) δ7.21 (2H, d, J=8.4), 6.68 (3H, overlapping d, t), 3.77 (4H, d, J=6.6), 3.52 (4H, d, J=6.6), 0.92 (18H, s), 0.06 (12H, s). 13C NMR (CDCl3) δ147.8, 129.2, 115.7, 111.4, 60.3, 53.5, 25.9, 18.3, -5.3. FDMS (m/e) 409 (M+). It was used as 100% without purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1.ClCCl>[O:1]=[C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCI
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN1C(=O)CN=C(c2ccccc2)c2ccccc21
Temperature: 0 °C
Yield: 47.8 %

Procedure:
10 g of 2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were dissolved in 100 ml of tetrahydrofuran under a nitrogen atmosphere. 1.4 g of sodium hydride in the form of an 80% oily suspension were added in portions to the solution under the nitrogen atmosphere, and the reaction mixture was heated to reflux for 30 minutes. 9.2 g (=5.5 ml) of iodopentane were slowly added dropwise, the mixture was heated to reflux for a further 1.5 hours and then another 0.3 g of sodium hydride in the form of an oily suspension was added and, after a further 10 minutes, another 5.5 ml of iodopentane were added dropwise, and the mixture was heated to reflux for a further hour. To work up the reaction mixture, ice-water was added to the reaction mixture and it was diluted with dichloromethane, the aqueous phase was separated, and the organic phase was washed to neutrality with water, dried over sodium sulfate, filtered and evaporated. 13.5 g of crude product were obtained and were purified by flash chromatography on about 300 g of silica gel using cyclohexane/ethyl acetate 1:1 as the eluent. The purified product was crystallized from cyclohexane and dried. 6.2 g of pure 2-oxo-1-n-pentyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine having a melting point of 93-95° C. were obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([O:12]C2CCCCO2)[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([OH:12])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(=O)OCC1CC(O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of the product of step G (710 mg, 2.3 mmol) in methanol (20 mL) was added p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol). After stirring at ambient temperature for 4 h the solution was concentrated in vacuo to afford the crude product. Purification by flash column chromatography (SiO2, 19:1 to 7:3, hexanes/ethyl acetate) afforded tert-butyl 2-(acetoxymethyl)-4-hydroxypiperidine-1-carboxylate (506 mg, 83%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 4.49-4.41 (m, 2H), 4.33-4.05 (m, 3H), 3.94-3.88 (m, 1H), 3.29-3.21 (s, 1H), 2.05 (s, 3H), 1.89-1.80 (m, 1H), 1.76-1.69 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[N:23]1[C:32]2[C:27](=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:27]=3[CH:26]=[CH:25][CH:24]=[N:23]4)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1cccc2ncccc12
Product: CC(On1ccc2ncc(-c3cccc4ncccc34)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and quinolin-5-ylboronic acid according to the procedure described in example 4.