Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]=[N:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[C:29]#[N:30]
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: N#Cc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C2CCCC(c3ncccc3C)N2Cc2cccc(C#N)c2)N=CCC1
Yield: 75 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.414 g, 1.55 mmol), α-bromo-m-tolunitrile (0.466 g, 2.38 mmol), KI (53 mg, 0.32 mmol), and DIPEA (0.55 mL, 3.16 mmol) in DMF (8 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.447 g (75%) of 3-(3,3″-dimethyl-3′,4′,5 ,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a beige solid. 1H NMR (CDCl3) δ 1.56-1.72 (m, 3H), 2.05-2.10 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.53 (s, 2H), 4.10 (d, 2H, J=11.1 Hz), 6.71 (s, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.93-7.00 (m, 3H), 7.13 (d, 1H, J=7.5 Hz), 7.25-7.27 (m, 2H), 8.39 (dd, 2H, J=4.8, 1.2 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.CC(C)([O-])C.[K+].S(OCCC#C)([C:25]1[CH:31]=CC(C)=[CH:27][CH:26]=1)(=O)=O>CN(C)C=O>[CH2:27]([N:2]1[C:3](=[O:14])[C:4]2[CH:13]=[CH:12][CH:11]=[C:6]3[C:5]=2[C:10](=[CH:9][CH:8]=[CH:7]3)[C:1]1=[O:15])[CH2:26][C:25]#[CH:31]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCN1C(=O)c2cccc3cccc(c23)C1=O
Reaction time: 1.5 h

Procedure:
A mixture of 6 g (0.03 mol) of 1H-benz[de]isoquinoline-1,3(2H)-dione. 4 g (0.0355 mol) of potassium t-butoxide, 9 g (0.04 mol of 4-tosyloxy-1-butyne [ref. G. Eglinton and M. C. Whiting, J. Chem. Soc. 3650 (1950)] and 150 ml of dimethylformamide was heated on the steam bath with stirring for 1.5 hours. The bulk of the solvent was then removed under reduced pressure and the remaining suspension was filtered. The filtrate was diluted with water and the precipitated product was collected by filtration and dissolved in methylene chloride. The solution was dried and passed over a plug of silica gel using methylene chloride for elution. The fractions containing clean product were combined and evaporated. Crystallization from methylene chloride/ethanol gave the title compound as colorless needles with m.p. 191°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C1C=CC=CC=1)([O-])=O>[C:21]([C:9]1([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:10][CH:11]=[CH:12][CH:13]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:23])[CH3:22]
Reactant: Brc1ccc(-c2ccccc2-c2ccc(Br)cc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)C1(c2ccc(Br)cc2)CC=CC=C1c1ccc(Br)cc1
Temperature: 80 °C

Procedure:
To 3.8 (0.01 mole) 4,4"-dibromoterphenyl in 200 ml nitrobenzene is added 0.86 g (0.011 mole) acetyl chloride and 1.46 g (0.011 mole) aluminum trichloride. The mixture is heated to 80° C. under inert atmosphere for three hours. The mixture is cooled to room temperature and washed with 1 m HCl. The organic layer of 2'-acetyl-4,4"-dibromoterphenyl is separated and the solids filtered and washed with several portions of ethanol, and dried.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([NH:16][C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[N:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:27](I)[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[N:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4cccc(F)n4)cc3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 140 °C
Yield: 94.1 %

Procedure:
2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (422 mg, 1.2 mmol), isobutyl iodide (276 μL, 2.4 mmol) and potassium carbonate (497 mg, 3.6 mmol) are place in a Biotage microwave vial, and then DMF (6 mL) is added. The mixture is heated in a Biotage microwave instrument at 140° C. for 30 min. The mixture is diluted with water (150 mL), and then extracted with methylene chloride three times. The combined organic phase is evaporated to dryness to give 460 mg of crude product as pale yellow solids, which is used in the next step without further purification. MS (ESI) m/z 408.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6][OH:7].[Cl:14]N1C(=O)CCC1=O>>[OH:7][N:6]=[C:5]([Cl:14])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:12])([F:13])[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1C(F)(F)F
Product: ON=C(Cl)c1ccccc1C(F)(F)F
Reaction time: 15 h
Yield: 92.5 %

Procedure:
2-(trifluoromethyl)benzaldehydeoxime (30.0 g, 158.60 mmol) was dissolved in dimethylformimide (300 mL), and added with N-chlorosuccinimide (23.31 g, 174.46 mmol), followed by stirring for 15 hours. After the reaction was completed, the resultant solution was vacuum evaporated, added with ethylacetate (1,500 mL), washed with saturated sodium chloride aqueous solution (1,000 mL) and purified water (1,000 mL), respectively, dried with anhydrous sodium sulfate, and vacuum-evaporated to provide a pale yellow solid required compound (32.81 g, 146.70 mmol, 93%).
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9]1[CH:21]=[CH:20][C:12]([C:13](C2NC=CN=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43]>C(Cl)(Cl)Cl>[CH2:22]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:14])=[CH:20][CH:21]=1)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCC=CCCCN(C(=O)OC(C)(C)C)c1ccc(C(=O)c2ncc[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of [N-(t-butyloxycarbonyl)-4-(4-pentadecenylamino)benzoyl]imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The mixture is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the resulting oil is crystallized from acetone to yield the product as light yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(I)c1
Yield: 64.5 %

Procedure:
A solution of 3-iodophenol (3 g, 13.6 mmol), acetyl chloride (2.9 ml, 40.9 mmol) and potassium carbonate (9.42 g, 68.2 mmol) in N,N-dimethylformamide (75 ml) was stirred for 16 h at room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with 1N NaOH, dried over magnesium sulfate, and evaporated under vacuum. The crude product was chromatographed over silica gel, eluting with 20% ethyl acetate/hexanes to yield 2.3 g (65%) of 3-iodophenyl acetate.
Reaction SMILES: [C:1]([CH:4]([C:6]1[N:11]=[C:10]([C:12](=O)[CH2:13]Br)[CH:9]=[CH:8][CH:7]=1)[OH:5])([OH:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH:4]([C:1]([OH:3])=[O:2])[OH:5])[N:11]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(CBr)c1cccc(C(O)C(=O)O)n1
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1-carboxy-1-hydroxymethyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1-carboxy-1-hydroxymethyl)-2-pyridyl]thiazole
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[CH:28][CH:27]=3)=[O:25])=[CH:17][C:16]=2[O:43][CH3:44])[CH2:10][C@H:9]1[CH3:45])C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[CH3:45][C@H:9]1[NH:8][C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[CH:28][CH:27]=3)=[O:25])=[CH:17][C:16]=2[O:43][CH3:44])[CH2:10]1
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C1)N(C(=O)c1ccc(-c3cccc(C)n3)c3ccccc13)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(=O)c1ccc(-c3cccc(C)n3)c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 70 h
Yield: 98.7 %

Procedure:
A solution of D6 (380 mg, 0.64 mmole) in EtOH (50 ml) and THF (50 ml) was treated with 10% Pd-C (300 mg) and stirred under a hydrogen atmosphere at ambient temperature and pressure for 70 h. The mixture was filtered through Kieselguhr and concentrated under vacuum. The residue was purified by chromatography on basic alumina eluting with EtOAc followed by crystallisation from Et2O to afford the title compound as a yellow solid (320 mg, 98%). MH+507.
Reaction SMILES: [OH:1][C:2]1[C:7](C(O)=O)=[CH:6][N:5]=[C:4]([OH:11])[CH:3]=1.P(=O)(O)(O)O.C(O)(=O)C.[N+:21]([O-])([OH:23])=[O:22].O>>[OH:11][C:4]1[C:3]([N+:21]([O-:23])=[O:22])=[C:2]([OH:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1cnc(O)cc1O
Reactant: O=[N+]([O-])O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 55.5 %

Procedure:
A 3-neck 22 L flask equipped with a temperature probe with a chart recorder, mechanical stirrer, a Dean-Stark apparatus and a reflux condenser is charged with 4,6-dihydroxy nicotinic acid (88 %, 2.0 Kg, 12.81 mol), phosphoric acid (85%. 6 L, 103.15 mol). The off gases from the condenser are scrubbed by bubbling into 50% aqueous NaOH. The suspension is heated until a sufficient amount of water has been removed (about 1.2 L), i.e., dehydration of the phosphoric acid. Without the dehydration of the phosphoric acid, the carboxylation does not occur. For the internal temperature to reach 210° C.±5° C., a mantle temperature of 290° C. is applied over an elapsed time of 3.5 hours. After being stirred for 4-5 hours at that temperature, the disappearance of the starting material is confirmed by HPLC. The reaction mixture is then allowed to cool down to a temperature of less than 100° C., at which point acetic acid (6 L, 104.81 mol) is added and the temperature is maintained at 90° C. To this mixture is added nitric acid (485 mL, 12.11 mol) at a constant rate (5-6 mL/minute) until HPLC shows no more 4,6-dihydroxy nicotinic acid present. Water (6 L, 333.3 mol) is then added to the reaction and heating is stopped. A yellow solid starts appearing at a temperature of less than 80° C. and is allowed to precipitate with stirring overnight. Filtration in a scintered glass funnel (course porosity) yields a yellow solid which is then washed with 2.5 L of isopropyl alcohol. The resulting cake is air-dried for 48 hours and then put in a drying oven under vacuum (20 in. Hg with a air bleed) at 50° C. for 3 days. 2,4-dihydroxy-3-nitropyridine (1.050 Kg) is obtained in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:40]=[CH:39][C:17]([C:18]([NH:20][C@@H:21]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=3)[CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])=[C:16]([F:41])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[NH2:23][CH2:22][C@@H:21]([NH:20][C:18](=[O:19])[C:17]1[CH:39]=[CH:40][C:14]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:4]=2)=[CH:15][C:16]=1[F:41])[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (2-(4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-bromo-5-fluorophenyl)ethyl)carbamate (69 mg, 0.110 mmol) in DCM (1.0 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, then dissolved in DMSO and subject to prep HPLC. Pure fraction was combined and lyophilized to yield final product as a TFA salt. LCMS (m/z): 532.1/534.1 (MH+), 0.69 min; 1H NMR (400 MHz, Methanol-d4) δ ppm 7.94-7.84 (m, 2H), 7.73 (dd, J=1.4, 8.0 Hz, 1H), 7.66 (dd, J=1.4, 11.9 Hz, 1H), 7.55 (s, 1H), 7.49-7.39 (m, 1H), 7.29 (d, J=9.4 Hz, 1H), 5.48 (t, J=7.2 Hz, 1H), 4.04 (dd, J=2.9, 11.5 Hz, 2H), 3.57 (dt, J=2.2, 11.6 Hz, 2H), 3.51-3.41 (m, 2H), 3.01-2.85 (m, 1H), 1.97-1.76 (m, 4H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C[O:12][C:13](OC)([CH3:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:14][C:13]1([CH3:15])[NH:7][C:5](=[O:6])[C:4]2[CH:3]=[CH:2][CH:10]=[CH:9][C:8]=2[O:12]1
Reactant: NC(=O)c1cccc(O)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2ccccc2O1
Yield: 86 %

Procedure:
To a solution of 3-hydroxy-benzamide (50 g, 0.36 mol) in acetone (300 mL) was added 2,2-dimethoxy-propane (100 mL) and p-toluene sulfonic acid (5 g, 0.03 mol) and the mixture was heated to reflux overnight. The solvent was evaporated under vacuum to give crude 2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (55 g, 86%) that was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.91 (dd, J=1.8, 7.8 Hz 1H), 7.44 (t, J=7.8 Hz 1H), 7.35 (brs, 1H), 7.05 (t, J=7.8 Hz 1H), 6.91 (d, J=8.1 Hz 1H), 1.65 (s, 6H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][N:27]3[C:31](=[O:32])[C:30]4[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]3=[O:37])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 53.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (11.1 g) and N-(3-bromopropyl)phthalimide (8.0 g) were reacted and treated in the same manner as in Preparation Example 150 to give 7.7 g of 4-amino-5-chloro-N-(1-(3-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)propyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:19](OC)=[O:20].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:20]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Nc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Nc3ccccc3)ccc2c1O
Temperature: 25 °C

Procedure:
A mixture of methyl 4-hydroxy-7-(phenylamino)isoquinoline-3-carboxylate (30.0 mg, 0.09 mmol), 5-aminovaleric acid (216.3 mg, 1.9 mmol, Sigma-Aldrich) and NaOMe in MeOH (2.8 mL, 1.4 mmol, 0.5 M solution, Sigma-Aldrich) was heated to reflux for 20 hours before cooling to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (10 mL) and EtOAc (10 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 27 mg. MS: (+) m/z 380.11 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[N:4][CH:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:10][CH3:9])[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cncc(N)n1
Temperature: 100 °C

Procedure:
A MIXTURE OF 6-AMINO-2-CHLOROPYRAZINE (5.2 G, 40 MMOL) AND SODIUM THIOMETHOXIDE (3.3 G, 47 MMOL) IN DRY DMF (30 ML) WERE HEATED IN A SEALED TUBE AT 100°C. FOR 16 H. THE REACTION WAS COOLED AND PARTITIONED BETWEEN WATER AND METHYLENE CHLORIDE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24](=[O:45])[NH:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]=1[F:44])[CH3:28])([CH3:22])([CH3:21])[CH3:20]>>[F:44][C:30]1[CH:31]=[C:32]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:33]=[CH:34][C:29]=1[C@H:27]([CH3:28])[CH2:26][NH:25][C:24](=[O:45])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 36 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (380 mg, 1.2 mmol) was reacted with (S)-tert-butyl2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (400 mg, 1.1 mmol) to afford the desired product (190 mg, 36%) as a yellow solid: ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:28]([OH:30])=O.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:28]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([C:14]=2[OH:13])=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:30])=[CH:34][CH:33]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.892 g 1,1'-carbonyldiimidazole in 30 mL of tetrahydrofuran is added 1.29 g 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid. The reaction is stirred at room temperature for 1 h. A solution of 0.91 mL of 4-chlorobenzylamine in 10 mL of tetrahydrofuran is added dropwise. The reaction is allowed to warm slowly to room temperature and stirred for 18 h. The reaction mixture is concentrated in vacuo. The residue is taken up in 100 mL of dichloromethane and filtered. The filtrate is chromatographed twice, eluting with 5% methanol/dichloromethane. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid. The solid is recrystallized from ethyl acetate to yield 0.298 g of the title compound as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (3.66 g, 30 mmol),2-chloromethylquinoline hydrochloride (6.42 g, 30 mmol) and potassium carbonate (8.24 g, 60 mmol) in DMF (75 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was then poured into water (300 mL) and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with 1:2 ethyl acetate-hexane to provide 5.8 g (74%) of 4-(2-quinolinyl-methoxy)benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[CH:30](=O)C.[Na]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH3:30])[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Product: CCN1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (338 mg, 1.00 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3 was stirred for 10 minutes, then extracted with DCM and treated with acetaldehyde (88 mg, 2.0 mmol) and sodium triacethoxyborohydride (318 mg, 1.5 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-ethyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (200 mg) as a yellow oil. The ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-ethyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (210 mg) as a white solid (hydrochloride salt). The resulting acid was suspended in DCM (7 ml), TEA (0.13 ml, 0.93 mmol) was added, and the resulting clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-ethyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (180 mg) as a light yellow solid. The compound was dissolved in DCM (6 ml) and treated with 1 M HCl in diethyl ether (6 ml, 6 mmol) as described in Example 2, Step D, giving a light yellow solid (114 mg, hydrochloride salt)