Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:37][C:22]3=[CH:23][C:24]4[C:25](=O)[N:26]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27](=[O:30])[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1.[C:38](O)(=O)C>[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:37][C:22]3=[CH:23][C:24]4[CH2:25][N:26]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27](=[O:30])[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1
Reactant: CC(=O)O
Reactant: CC(Cc1cccc(F)c1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Agent: [Zn]
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCN(C)C)C3=O
Yield: 74 %

Procedure:
Compound 2-(4-(1-(5-fluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.32 g, 2.56 mmol) and zinc powder (4.01 g, 61.32 mmol) were suspended in acetic acid (60 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.85 g, 74% yield. MS: 503.1 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.07 (s, 1H), 11.17 (s, 1H), 11.09-11.05 (m, 1H), 7.97 (s, 0.5H), 7.86 (s, 0.51-1), 7.80 (s, 0.5H), 7.70 (s, 0.5H), 7.30-7.10 (m, 3H), 6.92-6.84 (m, 1H), 6.15-6.11 (m, 1H), 4.54 (s, 2H), 4.18-4.14 (m, 1H), 3.64 (t, 2H, J=6.0 Hz), 3.02-2.97 (m, 2H), 2.53-2.49 (m, 2H), 2.36 (d, 3H, J=3.9 Hz), 2.20 (s, 6H), 1.35-1.33 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].C(Cl)CCl.[CH:23]1[CH:24]=[CH:25]C2N(O)N=[N:29][C:27]=2[CH:28]=1.N1CCCCC1>C(Cl)Cl>[N:29]1([C:12]([C:11]2[CH:15]=[CH:16][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:18][CH:17]=3)=[N:9][CH:10]=2)=[O:14])[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27]1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: ClCCCl
Product: O=Cc1ccc(Oc2ccc(C(=O)N3CCCCC3)cn2)cc1
Yield: 45.1 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinic acid (250.0 mg, 1.03 mmol), EDC (237.0 mg, 1.23 mmol), HOBt (166.2 mg, 1.23 mmol), and Piperidine (0.10 mL, 1.03 mmol) in CH2Cl2 (6 mL). After reaction stirs at room temperature under a Nitrogen atmosphere for 24 hours, concentrate the reaction mixture using a rotovap, add Ethyl acetate and wash with 0.1N HCl, 10% NaHCO3, Brine, and dry over Na2SO4. After concentrating the reaction mixture, flash chromatograph using 2:1 Ethyl acetate:Hexanes to afford 144.1 mg (45% yield) of the title compound as a white foam: 1H NMR (500 MHz, CDCl3); 1.5-1.8 (6H, m), 3.3-3.8 (4H, m), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.8-8.0 (3H, m), 8.3 (1H, m), 9.9 (1H, s); MS m/z 311 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:9])[CH3:8])[CH:2]=1.[C:10](Cl)(Cl)=[O:11].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:10]([NH:9][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH3:8])=[O:11])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(N)c1cccnc1
Agent: Cl
Product: CC(NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)c1cccnc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 1-pyridin-3-ylethanamine (Enamine, Cat. #EN300-12752), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=473.1.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[C:12]=2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: c1nc[nH]n1
Reactant: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCCC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 3, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxyquinoline was reacted with 1H-1,2,4-triazole to give 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 151°-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[OH:31]O.[OH-].[Na+].Cl>C1COCC1.O>[OH:31][C:5]1[CH:6]=[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=1)[O:11][CH:10]([C:13]([F:14])([F:16])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: OO
Reactant: CCOC(=O)C1=Cc2cc(B3OC(C)(C)C(C)(C)O3)cc(OC)c2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(O)cc(OC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 424.6 %

Procedure:
The ethyl 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.21 g, 0.49 mmole) was dissolved in THF (3 mL) and cooled to 0° C. (ice bath). Hydrogen peroxide (0.25 g, 0.074 mmole) followed by 2.5N sodium hydroxide (0.20 mL) was added dropwise and the resulting solution was stirred for 3 hours. The contents were poured into water (20 mL) and acidified using 2.4 N HCl to pH around 1 and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to flash chromatography (silica gel) and eluted with 0-35% EtOAc/ hexanes to give yellow solid (0.1 g, 65%). LCMS m/z 319.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.66 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 3.86 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O.[H-].[Na+].Cl>O1CCCC1>[S:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.[S:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[C:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CCCSc1ccccc1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccccc2SCC1
Product: O=C(O)C1=Cc2ccccc2SCC1
Reaction time: 1 h
Yield: 44 %
Yield: 6.4 %

Procedure:
Ethyl 4-(2-formylphenylthio)butyrate (537 mg) was dissolved in 6 ml of tetrahydrofuran and a suspension of 60% sodium hydride (102 mg) in 5 ml of tetrahydrofuran was dropped at room temperature. Stirring was conducted at room temperature for 1 hour. The mixture was stirred for 30 minutes under reflux. During cooling in ice, 4 ml of a 1N hydrochloric acid was added. Extraction with 10 ml of ethyl acetate was conducted. The organic layer was washed with 20 ml of water three times. The quantitative analysis by HPLC found 220 mg (Yield 44%) of ethyl 2,3-dihydro-1-benzothiepine-4-carboxylate and 28 mg (Yield 6.4%) of 2,3-dihydro-1-benzothiepine-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[O:32]=[C:28]1[CH2:29][CH2:30][CH2:31][N:27]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)nc1C

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (378 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1.[CH3:19][NH:20][CH3:21]>CN(C=O)C.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:20]([CH3:21])[CH3:19])[N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1
Reactant: CNC
Reactant: Cc1nc2nc(Cl)c(-c3ccccc3)c(Cl)n2n1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2nc(Cl)c(-c3ccccc3)c(N(C)C)n2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 500 mg 5,7-dichloro-2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described above) in 25 mL DMF were added 0.8 mL of a dimethylamine solution (60% in water). The mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and dichloromethane. The phases were separated and the water layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The residue was suspended in diethylether and stirred for 5 hours. The desired product was filtered, dried and was used without further purification for the next step.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=O)=[O:20]>ClCCl>[C:1]([O:9][C:18]1[C:19](=[O:20])[C:21]2[C:22](=[CH:27][CH:28]=[C:29]([F:31])[CH:30]=2)[N:23]([CH3:26])[CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1ccc(F)cc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of benzoic acid (6.7 g) and triethylamine (9.9 ml) in dichloromethane (80 ml) was added to the solution of 2'-(2-chloroacetyl)-4'-fluoro-N-methylformanilide at 0°. The mixture was stirred at ambient temperature for 24 hours and then heated under reflux for 2 hours. The mixture was washed with water (2×50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue added to potassium carbonate (1.76 g) and dry dimethylformamide (30 ml). The mixture was heated under nitrogen at 60° for 6 hours. Further potassium carbonate (1.0 g) was added and the heating continued for 6 hours. The solvent was removed under reduced pressure at 60° C., the residue triturated with water (30 ml), and the solid collected by filtration to give the novel compound 6-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p. ]88°-190°.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(CCc2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(CCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A mixture of 3-{2-[4-(1-methylethyl)phenyl]ethyl}pyridin-2-amine (150 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 125 mg) and 2-chloroethanesulfonyl chloride (305 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (149 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34](O)=[O:35])[CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:26]3[CH:25]=[N:24][C:33]4[C:28]([CH:27]=3)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cnc2ccccc2c1
Yield: 28.5 %

Procedure:
Using the general method of Example 181 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.37 mmol) was reacted with quinoline-3-carboxylic acid (1.33 g, 7.66 mmol) to provide 850 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}quinoline-3-carboxamide as a yellow solid, m.p. 114-116° C. Analysis: Calculated for C27H28N6O2.0.2 H2O: % C, 68.68; % H, 6.06; % N, 17.80. Found: % C, 68.68; % H, 5.85; % N, 17.76.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(-c2cc(=O)n(-c3ccc(OCC(C)(C)O)c(OC)c3)cn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-pyrimidin-4(3H)-one Part A of Procedure 11 (11 mg, 0.03 mmol), 4-ethylphenylboronic acid (7.6 mg, 0.05 mmol), potassium phosphate tribasic (21.57 mg, 0.102 mmol), and PalladiumTetrakis (4 mg, 3.39 μmol) in DMF (0.5 mL) was stirred at 90° C. overnight. The reaction was diluted with CH2Cl2, filtered, and concentrated. The crude was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 6-(4-ethylphenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one M-1 (9.93 mg, 0.02 mmol, 69.1% yield) as a light yellow solid. LC/MS 395 (M+H)+, tR 0.95 min (method 5). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 8.25 (1H, s), 7.93 (2H, d, J=8.32 Hz), 7.34 (2H, d, J=8.32 Hz), 7.02 (1H, d), 6.91-6.96 (3H, m), 3.90 (3H, s), 3.89 (2H, s), 2.74 (2H, q), 1.38 (6H, s), 1.30 (3H, t, J=7.63 Hz)
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[NH2:19][NH:20][C:21]([NH2:23])=S>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:21]([NH2:23])=[N:20][N:19]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: NNC(N)=S
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CC(=O)N(C)c1cccc(-c2ccc3nnc(N)n3n2)c1
Yield: 25.3 %

Procedure:
A solution of 2.2 g of N-methyl-N-[-3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 1.5 g of thiosemicarbazide in 100 ml of ethanol was refluxed for 5 hours, then the solvent was removed in vacuo. To the residue was added 100 ml of glacial acetic acid, this mixture was refluxed 18 hours, then the acetic acid was removed in vacuo. Saturated aqueous sodium bicarbonate was added to neutralize the mixture which was then extracted with dichloromethane:methanol (9:1). The extract was washed with water, dried and evaporated. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (9:1). The product was crystallized from dichloromethane-hexane, giving 0.6 g of the desired compound as yellow crystals mp 196°-197° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:30])[C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].Cl>C1COCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:30])[C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)OC)c(O)c2)cc1C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
1.7 g (4.3 mmol) of methyl 4-[3-(3-tert-butyl-4-diethylaminophenyl)-3-hydroxyprop-1-ynyl]-2-hydroxybenzoate are dissolved in 50 ml of THF with 1 ml of methanol and 2 ml of 1N aqueous NaCH. The solution is stirred at ambient temperature for 2 hours and then 2 days at reflux. The reaction medium is poured into a saturated solution of ammonium chloride, and the aqueous phase is brought to acidic pH with 1N HCl and then extracted twice with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated to dryness. The residue is purified by chromatography (heptane/ethyl acetate: 50/50). 760 mg of 4-[3-(3-tert-butyl-4-diethylaminophenyl)-3-hydroxy-prop-1-ynyl]-2-hydroxybenzoic acid are obtained in the form of a whitish solid (Mp=245° C., yield=45%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccccc2)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccccc1
Yield: 95 %

Procedure:
Cyclohexylamine (3.41 mL, 29.64 mmol) was added to a solution of Compound 15 (5.0 g, 14.82 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 5.5 g (95%) of white solids. M.P. 87° C. 1H NMR (DMSO-d6): δ 1.22 (m, 1H), 1.36 (m, 4H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H), 3.87 (m, 1H), 5.51 (s, 2H), 7.14–7.33 (m, 6H), 7.47 (d, J=8.6 Hz, 1H), 7.90 (s, 1H), 10.44 (s, 1H). EIMS m/z 391 (M+1).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1.[CH:33](=O)[CH3:34].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1)[CH3:34]
Reactant: CC(Nc1cc(-c2cc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Reactant: CC=O
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN1C[C@@H]2C[C@H]1CN2c1cc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 60 mg (0.14 mmol) {4-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.1 mL (1.8 mmol) acetaldehyde, 113 mg (1.8 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+): 450 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C-:22]#[N:23].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:22]#[N:23])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 20 h

Procedure:
5.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine and 1.5 g of potassium cyanide in 50 ml of dimethylformamide were heated at 50° C. for 4 hours and then stirred at 23° C. for 20 hours. The mixture was then poured into 200 ml of water. The aqueous phase was extracted three times with 100 ml of tertbutyl methyl ether each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=9:1). Yield: 2.7 g (53%) of a yellow oil which slowly crystallized.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH:18]([NH2:20])[CH3:19])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[CH:24][N:23]=1.CC[N:32](C(C)C)C(C)C.O>C(O)CCC>[NH2:32][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][CH:18]([C:10]2[N:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)[CH3:19])[N:25]=[CH:24][N:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cncnc1Cl
Reactant: CC(N)c1nc2cccnc2n1-c1cc(F)cc(F)c1
Solvent: CCCCO
Solvent: O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2n1-c1cc(F)cc(F)c1
Temperature: 120 °C

Procedure:
1-(-(3,5-Difluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (600 mg, 2.18 mmol) and 4-chloro-pyrimidine-5-carbonitrile (300 mg, 2.18 mmol) were dissolved in n-butanol (30 mL). After the addition of DIPEA (422 mg, 3.28 mmol) the reaction mixture was heated at 120° C. overnight. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (300 mL), dried over sodium sulfate and concentrated in vacuo to provide a crude product. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-50% EtOAc in hexane to provide 4-amino-6-(1-(3-(3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-ethylamino)pyrimidine-5-carbonitrile: 1H NMR (400 MHz, DMSO-d6) δ 1.580 (d, J=6.8 Hz, 3H), 5.683-5.753 (m, 1H), 7.205 (br s, 2H), 7.307-7.367 (m, 4H), 7.768 (d, J=8 Hz, 1H), 7.888 (s, 1H), 8.149-8.172 (m, 1H), 8.276-8.292 (m, 1H); LC-MS (ESI) m/z 393.0 [M+H]+.