Azzindani/Open_Reaction_Data huggingface dataset:
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].O=S(Cl)Cl.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O.C1COCC1>[O:8]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:6]1[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: COc1ccc(C(=O)O)cc1C#N
Reactant: Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccccc3o2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-cyano-4-methoxy-benzoate (1.5 g, 7.9 mmol) in CH3OH/H2O (25 mL; 1:1), was added LiOH (2.5 g, 60.0 mmol). The reaction mixture was refluxed for 2 h, cooled at rt and 6M HCl was added dropwise until pH 2 was obtained. The precipitate was collected, washed with H2O (3×20 mL), dried in vacuo to afford 3-cyano-4-methoxy-benzoic acid. MS (ESI) 178 (M+H)+. To a 100 mL round-bottom flask with 3-cyano-4-methoxy-benzoic acid (1.4 g, 7.8 mmol), was added SOCl2 (15 mL) dropwise. The reaction was refluxed for 1 h and was cooled to rt. The excess of SOCl2 was removed in vacuo and the oily acid chloride was dissolved in THF (15 mL). The resulting solution was added dropwise to a mixture of 2-aminophenol (1.3 g, 11.7 mmol), triethylamine (1.3 g, 11.7 mmol) and THF (30 mL) at 0° C. The reaction was warmed up to rt and stirred an additional 3 h. The precipitate was removed by filtration and the filtrate was concentrated and dried in vacuo. The dark brown solid residue was dissolved in toluene (20 mL) and p-toluenesulfonic acid (6.0 g, 46.8 mmol) was added. The reaction was refluxed overnight, cooled to rt, and EtOAc (300 mL) was added. The EtOAc solution was washed with brine (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, CHCl3:CH3OH 8:1) to afford 5-(1,3-benzoxazol-2-yl)-2-methoxy benzonitrile. MS ESI) 251(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38](OS(C(F)(F)F)(=O)=O)[N:37]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:38]4[N:37]=[C:36]([CH3:35])[C:45]5[C:40]([CH:39]=4)=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)cc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (97.5 mg, 0.208 mmol), trifluoromethanesulfonic acid 1-methylisoquinolin-3-yl ester (62.3 mg, 0.214 mmol), and Pd(PPh3)4 (15 mg, 0.013 mmol) in 1,4-dioxane (3.2 mL, 41 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (135 mg, 0.413 mmol) in H2O (0.95 mL, 53 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried over MgSO4. The EtOAc extract was diluted with DCM (to give DCM:EtOAc≈1:1) and filtered through a plug of silica gel. The silica gel was then washed with DCM:EtOAc 1:2, DCM:EtOAc 1:5, and EtOAc until no more product eluted. Filtrate/washings that contained product were concentrated in vacuo. The crude material was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→DCM:EtOAc 2:1→DCM:EtOAc 1:1→DCM:EtOAc 1:2→EtOAc]. Mixed fractions were combined, concentrated in vacuo, and purified by prep. TLC [20×20 cm plates, 500 μm, eluting with 2% MeOH/DCM (1×) and 4% MeOH/DCM (3×)]. Clean material from prep. TLC was combined with pure fractions from the column chromatography and dried in vacuo, yielding the title compound as viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.0 Hz, 1H), 8.15 (dd, J=0.8, 8.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J=0.4 Hz, 1H), 7.72 (ddd, J=1.2, 7.2, 8.2 Hz, 1H), 7.66 (d, J=0.4 Hz, 1H), 7.62 (ddd, J=1.2, 6.8, 8.2 Hz, 1H), 6.49 (brs, 2H), 4.38-4.20 (m, 3H), 3.03 (s, 3H), 2.92 (brt, J=12.0 Hz, 2H), 2.19 (brd, J=12.0 Hz, 2H), 1.98 (dq, J=4.4, 12.2 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.18 (100) [MH+], 429.06 (39) [MH+-isobutene]. HPLC: tR=2.76 min (polar—5 min, ZQ3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:17]([CH2:20]C(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:6]([C:5]1[CH:4]=[C:3]([CH2:2][CH2:18][C:17](=[O:19])[CH3:20])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Yield: 39.7 %

Procedure:
A mixture of 3-bromomethylbenzophenone (2.75 g.), acetylacetone (1 g.), potassium carbonate (1.4 g.) and ethanol (50 ml) was refluxed for 2 hours. The solvent was then evaporated and the residue extracted with ether. Distillation of the concentrated extracts gave 4-(m-benzoylphenyl)-2-butanone (1 g.), b.p. 220° C. (4 mm). [An alternative preparation of this compound appears in German Offenlegungsschrift No. 2243444].
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22])[OH:20]>CN(C=O)C>[CH2:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:20][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[OH:22])[CH3:12]
Reactant: CCN(CCCl)c1ccccc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CCOc1ccccc1O)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
A mixture of compound 3a (500 mg, 2.7 mmol), K2CO3 (750 mg, 5.4 mmol), KI (90 mg, 0.54 mmol) in DMF (50 mL) was bubbled with argon for 10 min Catechol (600 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with CH2Cl2 to provide the compound 19 (400 mg, 1.55 mmol, 57%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.86 (s, 1H), 7.15 (t, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 1H), 6.78 (m, 5H), 6.57 (t, J=7.2 Hz, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H), 3.45 (q, J=6.8 Hz, 2H), 1.10 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 148.00, 146.35, 145.81, 129.47, 122.24, 120.06, 117.24, 115.04, 112.86, 67.44, 49.79, 45.65, 12.19; HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.1494, found: 258.1465; calcd. for C16H19NO2Na [M+Na]+: 280.1313, found: 280.1345.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.CC(C)=O>CCCCCC>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C1CCc2ccc(OCCCCCl)cc2N1
Yield: 78 %

Procedure:
1-bromo-4-chloro-butane (3.4 g, 20 mmol), anhydrous potassium carbonate powder (4.14 g, 30 mmol) and 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (1.63 g, 10 mmol) are added to 10 ml of acetone and reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness, to obtain a light yellow powder. The resulting powder is slurried with n-hexane (20 ml×3), filtered, and dried to obtain 1.98 g of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone, with a yield of 78%.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.Cl.[NH2:31][NH:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:33]([NH:32][N:31]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1)(=[O:34])[NH2:35]
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 47.4 %

Procedure:
A mixture of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (231 mg), semicarbazide hydrochloride (101 mg), potassium carbonate (125 mg), water (2 ml), and ethanol (10 ml) was heated under reflux for 4 hours. Ethanol was evaporated in vacuo and the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). After an additional extraction with dichloromethane, the combined extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to give colorless crystals of 3-[2-(2-carbamoylhydrazonocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (125.8 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in General Procedure A. Purification on silica yielded 129. NMR (MeOD): 1.72-1.90 (2H, m), 2.05-2.10 (2H, M), 2.60 (3H, s, Me), 2.85-2.88 (1H, m), 3.08-3.14 (2H, m), 3.30-3.33 (2H, m), 3.80 (2H, s, CH2), 3.83-3.87 (4H, m, CH2), 3.94-3.98 (4H, m, CH2), 6.53 (1H, d, J 8.5, Ar), 7.19 (1H, s, Ar), 8.32 (1H, dd, J 8.5 and 1.8, Ar) and 8.92 (1H, d, J 1.8, Ar). MS: (ESI+): MH+=489.27
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:3]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:26][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1C(=O)c1ccccc1CBr)c1ccccc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (5.1 g, 14.6 mmol) and N-bromosuccinimide (2.85 g, 16 mmol) in CCl4 (150 mL) was added 2,2′-azobisisobutylnitrile (0.2 g, 1.5 mmol). The solution was refluxed for 4 h. The solution was then cooled to room temperature, diluted with CH2Cl2 (150 mL) and washed with H2O (3×50 mL). The organic portion was dried over Na2SO4 and evaporated to dryness in vacuo to provide N-[2-(2-bromomethyl-benzoyl)-4-chloro-phenyl]-benzamide (4.6 g, 74%). A solution of the benzamide (2.3 g, 5.4 mmol) in CH2Cl2 (50 mL) was saturated with dimethylamine, stirred for 16 h and evaporated to dryness in vacuo. The resulting residue was dissolved in MeOH (50 mL) and KOH (0.9 g, 16 mmol) in H2O (5 mL) was added. The solution was refluxed for 24 h. The solution was concentrated in vacuo and then diluted with EtOAc (150 mL) and H2O (50 mL). The organic portion was washed with H2O (3×50 mL), dried over Na2SO4 and purified by column chromatography (silica gel, 18:80:2 MeOH:CH2Cl2:NHOH) to provide 1q (0.9 g, 53% yield) MS m/z=289 (M+H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:14])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: C#CC[C@H]1CC[C@H](CO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: CC#N
Product: C#CCC1CCC(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a suspension of Compound 9 (2.45 g, 16 mmol) in 50% acetonitrile/water (35 mL) cooled to 0° C. was added bis-acetoxy-iodobenzene (BAIB) (11.4 g, 35 mmol) and TEMPO (502 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. for 1 hour, then for 90 minutes at room temperature. The solvents were evaporated, and the residue dissolved in 1/1 CH3CN/H2O (100 mL). Once again the solvents were evaporated, and this procedure repeated to remove iodobenzene as its azeotrope. The resulting Compound 11 (2.53 g, 95%) was obtained as a brown sticky solid that was not further purified but carried forward into the next step. 1H-NMR (600 MHz, CD3OD): 1.13 (dq, 2H), 1.45 (dq, 2H), 1.48 (m, 1H), 1.93 (dd, 2H), 2.03 (dd, 2H), 2.12 (dd, 2H), 2.2-2.3 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:9]2[C:15](=[O:16])[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:25][C:26]([O:29][C:30]([N:32]([CH3:37])[CH2:33][C:34](O)=[O:35])=[O:31])([CH3:28])[CH3:27].O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:37][N:32]([CH2:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:9]2[C:15](=[O:16])[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:35])[C:30](=[O:31])[O:29][C:26]([CH3:28])([CH3:25])[CH3:27]
Reactant: Cc1cccc(Nc2nc(NCCCN)nc3cc[nH]c(=O)c23)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cccc(Nc2nc(NCCCNC(=O)CN(C)C(=O)OC(C)(C)C)nc3cc[nH]c(=O)c23)c1
Reaction time: 2.5 h
Yield: 58.4 %

Procedure:
To a solution of 2-[(3-aminopropyl)amino]-4-[(3-methylphenyl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one (50 mg, 0.114 mmol) in N,N-Dimethylformamide (DMF) (1.5 mL) were added N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-methylglycine (25.9 mg, 0.137 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (34.9 mg, 0.228 mmol), 4-methylmorpholine (57.7 mg, 0.570 mmol), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (28.4 mg, 0.148 mmol), and the reaction mixture was stirred for 2.5 h. It was then concentrated and the residue was subjected to reverse-phase HPLC purification to give 33 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4ccnc5ccccc45)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 4-quinolinecarboxaldehyde (824 mg, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 249.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [C:1](=[C:4]1[CH:8]2[C:9]([CH3:11])=[CH:10][CH:5]1[C:6]([CH2:13][OH:14])([CH3:12])[CH2:7]2)([CH3:3])[CH3:2].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.ClCCl.O>[C:1](=[C:4]1[CH:8]2[C:9]([CH3:11])=[CH:10][CH:5]1[C:6]([CH2:13][O:14][C:21](=[O:23])[CH3:22])([CH3:12])[CH2:7]2)([CH3:3])[CH3:2]
Reactant: CC1=CC2C(=C(C)C)C1CC2(C)CO
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1(C)CC2C(C)=CC1C2=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of (7-Isopropylidene-2,5-dimethyl-bicyclo[2.2.1]hept-5-en-2-yl)-methanol (4.32 g, 22.5 mmol), pyridine (3.55 g, 45 mmol) and DMAP (50 mg) in dichloromethane (50 ml) was added acetyl chloride (2.47 g, 31.5 mmol) with cooling. The mixture was stirred at room temperature for 1 h and was then diluted with water and extracted with pentane (3×80 ml). the organic phase was washed with 1N HCl, water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane:MTBE=9:1) to yield 4.25 g of a colorless oil as a mixture of isomers. Odor description: cedarwood oil, carrot, verdyl, musky. 1H-NMR (CDCl3, 400 MHz): 5.93–5.72 (m, 1H), 3.94–3.73 (m, 2H), 3.10–2.78 (m, 2H), 2.09–2.03 (m, 3H), 1.85–1.53 (m, 9H1.50–1.15 (m, 2H), 1.09/0.97/0.92/0.89 (4s, 3H) ppm. GC/MS (EI): main isomer: 234 (M+, trace), 159 (3), 120 (100), 105 (46), 91 (11), 77 (7), 43 (15), IR (atr): 2927m, 2726w, 1741s, 1446m, 1369m, 1233vs, 1031s, 986m, 802m cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19]>C1COCC1.CCOC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(NC(=O)OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
To a 0° solution of 4′-aminoacetophenone (35 g, 259 mmol) in THF (400 mL) was added pyridine (26 mL, 324 mmol) and isobutyl chloroformate (37 mL, 285 mmol). The resulting heterogeneous mixture was stirred at 0° for 30 min and at room temperature for an additional 30 min. The reaction mixture was then diluted with EtOAc, washed serially with 10% (w/v) aqueous citric acid, 4 N aqueous HCl, H2O, saturated aqueous NaHCO3 and brine, then dried (MgSO4) and concentrated under reduced pressure to yield 2-methylpropyl N-(4-acetylphenyl)carbamate (65 g, quantitative yield) as an off white solid: 1H NMR (400 MHz, CDCl3) δ7.95 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 6.85 (s, 1H), 3.99 (d, 2H, J=6.7 Hz), 2.57 (s, 3H), 2.03 (m, 1H), 0.90 (d, 6H, J=6.7 Hz); MS (FAB) m/z 236 (MH)+. This product was used as such in the next reaction (section (b)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([F:15])[C:12]([N+:21]([O-:23])=[O:22])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cc1OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1OCC
Temperature: 0 °C
Reaction time: 3.4 h

Procedure:
In nitrogen atmosphere, to ethyl 2-ethoxy-4-fluorobenzoate as synthesized in above Production Example 31, 6.51 g, conc. sulfuric acid 34 mL was added under cooling with ice. Potassium nitrate 3.26 g was further added little by little, under cooling with salt-ice, followed by stirring for 3.4 hours under cooling with ice. The reaction liquid was poured in ice water, and the precipitated crystals were recovered by filtration and washed with water. Recrystallizing the crystals from tert-butyl methyl ether-hexane mixed solvent, 4.49 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:21]=[C:20]2C([N:17]=[CH:18][N:19]2[CH3:22])=C(Cl)[N:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([Cl:12])[N:21]=[C:20]3[C:10]=2[N:17]=[CH:18][N:19]3[CH3:22])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: Cn1cnc2c(Nc3ccc(Br)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-bromo-phenyl)-acetamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [CH2:1]([C:5]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=O)=[O:7])[CH2:2][CH2:3][CH3:4].FC1C=CC(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)=CC=1>>[CH2:19]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[C:23]2[C:28](=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9]([OH:11])=[CH:8][C:6]1=[O:7])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(CCCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccc(F)cc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccc(F)cc1
Product: CCCCC1(CCCC)C(=O)C=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 14G, substituting the compound of Example 18E for the compound of Example 14F. 1H NMR (300 MHz, CDCl3): δ 0.52 (m, 2 H) 0.68 (t, J=7.35 Hz, 6 H) 0.88 (m, 2 H) 1.09 (m, 4 H) 1.82 (m, 2 H) 2.23 (m, 2 H) 6.17 (s, 1 H) 7.27 (m, 1 H) 7.42 (m, 1 H) 7.80 (dd, J=9.38, 2.76 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCOCC1)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), morpholine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 101 (5), 100 (bp), 98 (4), 56 (5).