Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1NC1CCCC1

Procedure:
4,6-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.83 mmol) was treated with cyclopentylamine following general procedure B to afford 6-chloro-4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C1C2C(COC([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([N:49]=[N+:50]=[N-:51])=[CH:45][CH:44]=3)=[O:40])[C:31]([OH:33])=[O:32])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:29][C@@H:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([N:49]=[N+:50]=[N-:51])=[CH:47][CH:48]=1)=[O:40])[C:31]([OH:33])=[O:32]
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(COC(=O)NCCCC[C@H](N)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
DBU (0.064 mL, 0.425 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((((4-azidobenzyl)oxy)carbonyl)amino)hexanoic acid (Compound SP661) (210 mg, 0.386 mmol) in DMF (0.7 mL) at room temperature under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 20 minutes and then purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (S)-2-amino-6-((((4-azidobenzyl)oxy)carbonyl)amino)hexanoic acid (Lys(Acbz)) (Compound tk34) (100 mg, 81%).
Reaction SMILES: [OH-:1].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].Cl>CS(C)=O>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:1])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O

Procedure:
87.6 g of finely powdered sodium hydroxide was added in portions over an 8-hour period to a stirred solution of 164.0 g of 2-nitro-4-(trifluoromethyl)chlorobenzene in 220 ml of dimethyl sulfoxide at room temperature. The mixture was acidified to pH 1 with concentrated hydrochloric acid. An oil formed; it was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent under reduced pressure. The residue was mixed with cold sodium hydroxide solution. The mixture was extracted with petroleum ether. The water layer was acidified with concentrated hydrochloric acid. An oil that formed was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent to give 2-nitro-4-(trifluoromethyl)phenol (A).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].O>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:15][C:11]=2[CH:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Fc1ccc2occc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(F)ccc2o1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
Butyllithium (1.5 mL, 2.4 mmol, 1.6 M) was added at −75° C. to a solution of 5-fluorobenzofuran (0.3 g, 2.2 mmol) in THF (10 mL). Tributyltin chloride (0.98 g, 1 mL) was added at −75° C. and the mixture was allowed to warm to 25° C. over a period of 2 hours. Water (25 mL) was added and the aqueous layer was extracted with diethyl ether (2×25 mL). The combined organic extracts were dried over Na2SO4 and concentrated. Silica gel chromatography (pentane) provided tributyl-(5-fluorobenzofuran-2-yl)-stannane (210 mg).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]([N:18]=[CH:19][N:20](C)C)=O)[N:15]=[C:5]3[C:4]=2[CH:3]=1.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:19][N:18]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Temperature: 85 °C

Procedure:
A mixture of 660 mg (2.06 mmol) of 10-chloro-N-((dimethylamino)methylene)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide and isopropylhydrazine hydrochloride (0.332 g, 3.00 mmol) in 44 ml of acetic acid was heated at 85° C. for 3 hours. The mixture was cooled, filtered and mixed with 15 ml of water. A precipitate was filtered out, washed with water and dried in high vacuum. The above solid was triturated with 1 o ml of ethyl acetate, filtered out, washed with ethyl acetate, ethyl ether and dried on air. Yield 0.710 g. MS: 331.2. 1H NMR (500 MHz, DMSO) δ 8.26 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 5.76 (dt, J=13.1, 6.6, 1H), 4.62 (q, J=5.6, 4H), 1.50 (d, J=6.6, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C:69]([O:71][CH2:72][CH3:73])=[O:70])[N:68]=1>>[CH2:72]([O:71][C:69]([C:67]1[N:68]=[C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[S:65][CH:66]=1)=[O:70])[CH3:73]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1csc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)n1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with ethyl 2-aminothiazole-4-carboxylate (Oakwood) (0.13 g, 0.78 mmol) to give rac-2-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-thiazole-4-carboxylic acid ethyl ester as a off white solid (Yield 0.1 g, 31%).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2CCC1(Cl)Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2CCC1Cl

Procedure:
A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (20 g, 0.174 mol) and anhydrous sodium acetate (15.4 g, 0.188 mol) in glacial acetic acid (920 ml) was hydrogenated at atmospheric pressure using 5% Pd-C (1.72 g) as catalyst until the uptake of hydrogen ceased. The catalyst was filtered off and the acetic acid evaporated under reduced pressure. The residue was equilibrated between 10% NaHCO3 (900 ml) and dichloromethane (300 ml). The aqueous layer (pH 8) was further extracted with dichloromethane (3×300 ml) and the combined organic solutions were dried over anhydrous sodium sulfate and evaporated to give 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 163°-167°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][O:11][CH2:12][CH:13](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:14]>C1(C)C=CC=CC=1.CCOCC>[CH3:10][O:11][CH2:12][CH:13]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])[CH3:14]
Reactant: COCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cccc(C)c1N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCC(C)Nc1c(C)cccc1C

Procedure:
Manufacture of the starting material: A solution of 484 g (4 mole) of 2,6-xylidine and 490 g (2 mole) of p-toluenesulphonic acid-(1-methoxyprop-2-yl)-ester in 1000 ml of toluene is refluxed for 25 hours. The reaction mixture is cooled, then made alkaline and diluted with ether. The organic phase is repeatedly washed with water and dried with magnesium sulphate. Evaporation of the solvent and subsequent distillation of the residue yields the desired N-(1-methoxyprop-2-yl)-2,6-xylidine with a boiling point of 70°-72° C/0.4 Torr.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1.S(Cl)(Cl)=O.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([NH2:42])[CH:33]=[C:34]([N:36]2[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]2)[CH:35]=1.[OH-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:42][C:32]2[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([N:36]3[CH:37]=[N:38][C:39]([CH3:41])=[CH:40]3)[CH:33]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:13]=[CH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)[N:17]=1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Temperature: 60 °C
Yield: 90.2 %

Procedure:
To a 1 liter reactor was fed 40 g of 4-methyl-3-(4-(pyridine-3-yl)pyrimidin-2-ylamino)benzoic acid (0.13 mol), 200 ml of N-methylpyrrolidone (NMP) (5V) and 13 ml of thionyl chloride (0.18 mol). The reactor was heated to 60° C. and maintained at 60° C. for 1.5 hr. After 1.5 hr of heating, 31.5 g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine (0.13 mol) was fed into the reactor. The reactor was then heated to 90° C., and maintained for 30 minutes at this temperature. Then 200 ml (5V) of water was added. The resulting mixture was maintained for 2 hours at 90° C. Then, an additional 240 ml (6V) of N-methylpyrrolidone was added, followed by 26.5 ml of sodium hydroxide (47% aqueous) to raise the pH to 6.5-7. The reactor was then cooled to 40° C. and maintained for 3 hours. The mixture was then filtered and the filter cake was washed with ethanol and water. The washed material was then dried in a vacuum tray oven overnight to provide dry Nilotinib base (62.1 g, Yield 90%)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][OH:10])[N:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC#N>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:10][CH2:9][CH2:8][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1cc(C)n(CCO)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2nc(C)cc2C)cc1
Yield: 46 %

Procedure:
A cooled (0° C.) mixture of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-ethanol (0.48 g, 3.4 mmol) and triethylamine (0.47 mL, 3.4 mmol) in MeCN (5 mL) was treated with 4-methylbenzenesulfonyl chloride (0.72 g, 3.8 mmol), after which the mixture was kept cool in a refrigerator for 2 days. The mixture was then concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with ethyl acetate hexane (1:1), to give 0.46 g (46%) of the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][CH:37]=1)[CH2:12][N:13]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[N:15]([C:21]2[CH:22]=[N:23][N:24]([CH2:26][C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[CH:25]=2)[C:14]1=[O:34])(C(C)(C)C)(C)C.Cl>CO>[CH3:33][C:28]1[C:27]([CH2:26][N:24]2[CH:25]=[C:21]([N:15]3[C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[N:13]([CH2:12][C:11]4[CH:35]=[CH:36][CH:37]=[C:9]([OH:8])[CH:10]=4)[C:14]3=[O:34])[CH:22]=[N:23]2)=[C:31]([CH3:32])[O:30][N:29]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)C(C)(C)C2=O)cn1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(O)c3)C(C)(C)C2=O)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
1-(3-(tert-butyldimethylsilyloxy)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-1a) (2.00 g, 3.82 mmol) was dissolved in methanol (200 mL) and treated with HCl (2.0 M solution in diethyl ether, 10 equivalents). The solution was stirred for 16 hours at 50° C. then allowed to cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethanol and recristallized at 4° C. to give 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (1.50 g, 3.67 mmol, 96%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): 1.31 (s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 4.47 (s, 2H), 5.20 (s, 2H), 6.65 (ddd, J=0.8, 2.4, 8 Hz, 1H), 6.79 (m, 2H), 7.11 (t, J=8 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H), 9.36 (s, H). MS 410 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.05 μM
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])=[O:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(OC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2.0 g of 4-methoxybenzoyl chloride in 25 ml of dichlormethane were added dropwise at 0° C. while stirring within 30 min. to a solution of 3.5 g of 4-methacryloyloxybutyl (E)-3-(4-hydroxyphenyl)acrylate and 1.2 g of triethylamine in 40 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, then filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 7:3) and two-fold recrystallization from ethanol gave 4.5 g of 4-methacryloyloxybutyl (E)-3-[4-(4-methoxyphenylcarbonyloxy)phenyl]acrylate, m.p. 89°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]
Reactant: COc1cc(C(=O)O)ccn1
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (2.00 g, 13.06 mmol) in anhydrous tetrahydrofuran (80 mL) was added 4-methyl morpholine (1.84 g, 18.28 mmol). After cooling to 0° C., isobutyl chloroformate (2.31 g, 16.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 6 hours, followed by the addition of aniline (1.70 g, 18.28 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2-methoxy-N-phenylisonicotinamide (2.50 g, 86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H), 10.31 (s, 1H), 7.75-7.60 (m, 2H), 7.47 (d, J=4.6 Hz, 1H), 7.35-7.20 (m, 2H), 7.12-7.04 (m, 1H), 6.83-6.80 (m, 1H), 6.54-6.42 (m, 1H); MS (ES+) m/z 229.2 (M+1).
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOC(C)=O>C1COCC1>[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38](/[CH:39]=[C:6](\[CH3:7])/[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (carbethoxyethylidene)triphenylphosphorane (5.50 g, 15.2 mmol) (commercially available from Aldrich, catalog #377708) in THF (25 mL) was added 4-(benzyloxy)benzaldehyde (12.1) (2.93 g, 13.8 mmol) (commercially available from Lancaster, catalog #6285) in THF (10 mL) under nitrogen at −78° C. The reaction was allowed to slowly warm to room temperature and stirred for 2 hours. EtOAc (100 mL) was added, and the mixture was washed with brine (30×2 mL). The organic layer was dried over MgSO4. The solvent was removed by evaporation. The crude product was purified by passing through a short silica gel column, eluting with hexane/EtOAc (85/15) to give the title compound. 1H NMR (CDCl3) δ 7.65 (s, 1H), 7.46-7.35 (m, 7H), 7.01 (d, 2H), 5.11(s, 2H), 4.28 (q, 2H), 2.14 (s, 3H), 1.36 (t, 3H).
Reaction SMILES: C(O)(C)C.Cl.Cl[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[F:13].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([NH2:24])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[F:13][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[NH:24][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH3:14])=[CH:16]1
Reactant: Cc1cn(N)c2ccccc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cn(Nc2ccncc2F)c2ccccc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
To 200 ml isopropanol was added 4-chloro-3-fluoropyridine hydrochloride (10 g) and 3-methyl-1H-indole-1-amine (5.9 g). The mixture was stirred at 90° C. for four hours, cooled; then poured into 500 ml iced-water, pH adjusted to 10 with Na2CO3 solution, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil, which was eluted on a silica gel column with CH2Cl2 (DCM) then with ether:petroleum ether (1:1) via flash chromatography. The desired fractions were combined then evaporated to yield 6.2 g of a solid, 45° C. A sample of this material was recrystallized from isopropyl ether/hexanes (1:1) to give a solid, m.p. 141°-142° C.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)#[N:17].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(OC(=O)CCC2CCN(C(=N)N)CC2)cc1
Reaction time: 0.33 h
Yield: 60.1 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.0 g of p-cyanophenol and 3.5 g of dicyclohexylcarbodiimide was stirred overnight at room temperature in 20 ml of dry pyridine. Any insoluble materials were filtered, washed with pyridine and extracted with a solution of 20 ml of water and 20 ml of t-butanol, followed by stirring for about 20 minutes. The filtrate, washings and extract were combined together, and the solvent was removed under reduced pressure. The residue was recrystallized from water to obtain 3.4 g (yield: 59%) of p-cyanophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 164.5° to 169° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:29][NH:28][CH2:27]2)[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:28]3[CH2:29][CH:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:27]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: C1CC(C2CNC2)CCO1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.34 g) was reacted with 3-(tetrahydro-2H-pyran-4-yl)azetidine via General Procedure B to produce crude 4-(2-chloro-6-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][C:6]=2[CH:14]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[OH:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]#[N:16])=[CH:14][C:6]=2[CH:7]=1
Reactant: OCCCc1cc2cc(Br)ccc2o1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc3oc(CCCO)cc3c2)c1

Procedure:
The product from Example 170A(193 mg, 0.80 mmol) and 3-cyanophenylboronic acid is processed as described in Example 112C to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[OH:17])[NH:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[OH:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2
Reactant: CCOC(=O)c1c[nH]c2cccc(O)c2c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2cccc(O)c2c1=O
Yield: 87.7 %

Procedure:
A mixture of 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 3 mmol) in 10% NaOH (20 ml) was heated at reflux overnight. After cooling, the mixture was extracted with ether. The aqueous phase was separated and acidified with conc. HCl to pH 1-2. The resulting precipitate was collected via filtration to give 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-3) (540 mg, 87%). 1H NMR (DMSO-d6) δ 13.7 (br, 1H), 13.5 (br, 1H), 12.6 (s, 1H), 8.82 (s, 1H), 7.68 (t, J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H); ESI-MS 205.9 m/z (MH+).