Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([Cl:35])=[C:24](B3OCC(C)(C)CO3)[CH:25]=2)[NH:20][CH:19]=1)=[O:17].C([O-])(=O)C.[K+]>O1CCOCC1>[Cl:35][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][NH:20]2)=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: O=C1CCCN1c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCCC4=O)cc3)cc12
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
To a mixture of 1-(4-bromophenyl)pyrrolidin-2-one (120 mg, 0.50 mmol), methyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (160 mg, 0.50 mmol) and potassium acetate (147 mg, 1.50 mmol) in 1,4-dioxane (3 mL) was added PddppfCl2 (36.5 mg, 0.050 mmol). The mixture was degassed and purgerd with nitrogen for 5 minutes, then allowed to heat to 100° C. and stirred under microwave irradiation for 40 minutes. The reaction mixture was concentrated in vacuo to give a brown residue. The residue was purified by combi flash silica gel chromatography to give the title compound (112 mg, 61% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:13][N:14]([CH3:16])[CH3:15])=[O:12])[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:13][N:14]([CH3:16])[CH3:15])=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CN(C)NC(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)NC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 170 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
A mixture of 7-chloro-N′,N′-dimethylthieno[3,2-b]pyridine-2-carbohydrazide (237) (798 mg, 3.13 mmol), 2-fluoro-4-nitrophenol (740 mg, 4.70 mmol), K2CO3 (830 mg, 6.26 mmol) and Ph2O (4.2 mL) was stirred in a sealed tube for 12 h at 170° C. The mixture was diluted with DCM, extracted with water, the organic phase dried with anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes 1:1) giving 238 (772.5 mg, 2.05 mmol, 66% yield) as a brown foam. MS (m/z): (M+1) 377.0 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([S:9](F)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:9]([C:6]1[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: CNc1ccccc1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Product: COc1ccc(S(=O)(=O)N(C)c2ccccc2)nn1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture was prepared of 6-methoxy-pyridazine-3-sulfonyl fluoride from Example 11 (1.62 mmol, 312 mg) and N-methyl aniline (24.3 mmol, 0.26 mL) and heated at 100° C. for 12 hours. The mixture was then cooled. The resulting solid residue was purified by silica gel chromatography to isolate the title compound (53%, 240 mg); M+, 279.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7].CN(C)[CH:22]=[O:23]>>[CH:6]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:22]=[O:23])=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7]
Reactant: COc1ccc2[nH]c(C(C)C)cc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C(C)C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Dimethylformamide (2 mL) was cooled to 0° C. Phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 2-isopropyl-5-methoxyindole (200 mg, 1.05 mmol) in dimethylformamide (3 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (50 mL) and stirred for 10 minutes. The precipitate was collected and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator set at 40° C. yielding a light brown solid (318 mg, 86%): TLC Rf 0.71 in 4:1 ethyl acetate/hexanes. Melting point=181-183° C. 1H NMR (600 MHz, CDCl3) δ 10.22 (s, 1H), 8.63 (s, 1H), 7.79 (d, 1H, J=2.46 Hz), 7.26-7.24 (d, 1H, J=8.94 Hz), 6.89-6.87 (dd, 1H, J1=2.52 Hz, J2=8.76 Hz), 3.87 (s, 3H), 3.79-3.74 (m, 1H), 1.46-1.45 (d, 6H, J=7.02 Hz); 13C NMR (150 MHz, CDCl3) δ 184.1, 156.52, 156.51, 129.4, 126.9, 113.5, 113.2, 111.6, 103.0, 55.8, 25.8, 22.7. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.59; H, 6.98; N, 6.39.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH2:13]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:4][CH2:3][CH:2]([OH:13])[CH3:11])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1c(Br)cnc2ccccc12
Reactant: O
Product: CC(O)CNc1c(Br)cnc2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 3 g of 3-bromo-4-chloro-quinoline and 10 g of aminopropanol-2 was heated to 150° C. for 20 minutes. The mixture was cooled and poured into 120 ml of water and the product was extracted with 100 ml of ether. The ether layer was dried over sodium sulfate, the solvent removed by evaporation and the residue recrystallized from ether/hexane. The yield was 2.6 g, mp 82°-83° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.[NH3:21]>C(O)C>[NH2:21][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: CCO
Product: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 4-chloro-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and ethanol was saturated with ammonia gas and reacted under heating in a shield tube to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:10]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(Cl)cccc1OCc1ccccc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 143 g (1.0 mol) of 3-chloro-2-methylphenol, 139 g (1.1 mol) of benzyl chloride, 276 g (2.0 mol) of potassium carbonate and 680 g of methyl ethyl ketone (MEK) is heated under reflux with stirring. After 8 hours, a further 25 g (0.18 mol) of potassium carbonate are added and the mixture is then heated under reflux for a further 8 hours. The batch is filtered and the filter cake is washed with MEK. After working up by distillation, 206 g of 2-benzyloxy-6-chlorotoluene (b.p. 161 ° C., 3 mbar) are obtained as a pale yellow liquid in 99.6% purity (surface area % according to GC). This corresponds to a yield of 88.3% of theory.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)CCCC(=O)O)c1
Reaction time: 0.08 h

Procedure:
A stirred solution of 0.61 g. of N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide, prepared in a manner analogous to Preparation 27, in 25 ml. of toluene, was heated on a steam bath and then 0.23 g. of glutaric anhydride was added in one portion. After 5 minutes, the reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was recrystallized twice from acetonitrile, to give 370 mg. of the title compound, m.p. 136°-140° C. This latter material was recrystallized from isopropanol/water to give 196 mg. of material having a melting point of 140°-141.5° C. The IR spectrum (KBr disc) showed absorptions at 3390, 2895, 1724, 1681, 1613 and 1575 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.90 (m, 3H), 1.08 (m, 3H), 1.26 (s, 16H), 1.89 (m, 2H), 2.40 (m, 7H, under DMSO-d6), 3.80 (m, 1H), 6.19 (s, 1H), 7.51 (m, 6H), and 9.90 (s, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][Br:29])=[CH:19][CH:20]=3)=[N:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(-c2nnc(-c3cccc([N+](=O)[O-])c3)s2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2nnc(-c3ccc(CBr)cc3)s2)c1

Procedure:
To a solution of 2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole (0.66 g, 2.22 mmol) in CCl4 (75 ml) is added NBS (0.43 g, 2.44 mmol) and refluxed for 12 hours. The mixture is then concentrated and the residue is taken up In chloroform (50 ml) and washed with saturated NaHCO3 (50 ml) and brine (50 ml). The organic layer is dried over MgSO4 and concentrated to yield 2-(3′-nitrophenyl)-5-(p-bromomethylphenyl)-1,3,4-thiadiazole as a tan solid. (0.69 g, 83%).
Reaction SMILES: C1(O[C:8](=[O:27])[CH:9]([C:11]2([OH:26])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:13][CH2:12]2)[CH3:10])C=CC=CC=1>C(N)CCC>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][C:11]([CH:9]([CH3:10])[C:8]([NH:14][CH2:13][CH2:12][CH2:11][CH3:9])=[O:27])([OH:26])[CH2:16][CH2:15]1
Reactant: CC(C(=O)Oc1ccccc1)C1(O)CCN(CCc2ccccc2Cl)CC1
Solvent: CCCCN
Product: CCCCNC(=O)C(C)C1(O)CCN(CCc2ccccc2Cl)CC1

Procedure:
A solution of 5 g of 2-(1-o-chlorophenethyl-4-hydroxy-4-piperidyl)propionic acid phenyl ester and 50 cc of n-butylamine is boiled at reflux for 18 hours in an atmosphere of nitrogen. The excess n-butylamine is then removed by evaporation at reduced pressure, the residue is taken up in chloroform and the organic phase is washed twice with water and dried over magnesium sulphate. The chloroform is evaporated at reduced pressure. The residue is treated with maleic acid in acetone and the title compound is crystallized from acetone/ether (M.P. of hydrogen maleate 132°-133° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1.O1CCOCC1>Cl>[CH3:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(C)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(C)c(N3CCC[C@H](N)C3)n2)n1
Yield: 54.9 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (34 mg, 0.068 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 1,4-dioxane 2.0 mL was stirred at RT 18 h. The crude product was submitted for reverse phase HPLC to give 228 (15 mg, 56% yield). MS (ESI) m/z: 402.2. 1H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 9.44 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 3.67 (d, J=12.3 Hz, 2H), 3.19 (t, J=11.3 Hz, 1H), 2.93 (s, 1H), 2.73 (dd, J=12.1, 9.1 Hz, 1H), 2.64 (s, 3H), 2.54 (s, 3H), 1.94 (d, J=10.2 Hz, 2H), 1.74 (d, J=11.1 Hz, 1H), 1.39-1.26 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[O:10]C=CC=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:15])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1-c1ccco1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1ccc(Cl)nc1C(=O)O
Temperature: 0 °C
Yield: 67.7 %

Procedure:
3-Amino-6-chloro-2-(2-furanyl)pyridine (1.06 g) was dissolved in acetone (25 mL) and cooled in an ice bath to 0° C. A solution prepared of potassium permanganate (2.57 g) in water (40 mL) was added drop wise to this solution. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for hours. The mixture was cooled again to 0° C. and a second portion of potassium permanganate (858 mg) in water (15 mL) was added and the cool bath removed. After stirring for 2 hours, the reaction mixture was filtered through a pad of celite, the filter cake was washed carefully with water, methanol and ethyl acetate and concentrated to approx. 20 mL on a rotary evaporator. 2N Sodium hydroxide solution was added to adjust the pH-value to −12 and the aqueous layer was washed 2× with MTB-ether. The aqueous layer was adjusted to pH ˜2 by addition of 6N hydrochloric acid and extracted 3× with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 636 mg of the title compound of the formula
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[C:22]1(=O)[CH:27]=[CH:26][C:25](=[O:28])[CH:24]=[CH:23]1.B(F)(F)F>>[CH3:1][O:2][C:3]([C:4]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=2)[C:22]2[C:27]([C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:21]
Reactant: COC(=O)/C=C(\Nc1ccc(OC(C)C)cc1)C(=O)OC
Reactant: O=C1C=CC(=O)C=C1
Agent: FB(F)F
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12

Procedure:
The sub-title compound was prepared from N-(4-isopropoxyphenyl)aminofumaric acid dimethyl ester (1.57 g, 5.40 mmol), p-benzoquinone (0.60 g, 5.6 mmol) and BF3 etherate (0.83 m L, 5.8 mmol), see procedure in GDR No. 61800 (1967). Yield 1.40 g (71%).
Reaction SMILES: [H-].[Na+].CN([CH:6]=[O:7])C.CO.[Cl:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3>O>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH3:6])[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: Cn1c(=O)c(-c2ccc(F)cc2Cl)cc2c3ccccc3n(C)c21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc3c4ccccc4n(C)c3n(C)c2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
3.25 g (81.1 mmol) of 60% NaH are added to 300 ml of DMF and 9.6 ml of MeOH. The mixture is left to stir for 5 minutes, and then 9.22 g (27.0 mmol) of compound A 3-(2-chloro-4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are added. The mixture is stirred at ambient temperature and then, as soon as no more gas is being given off, is heated at 80° C. for 16 h. The reaction medium is left to cool and poured into H2O, the yellow precipitate is filtered off and washed with H2O, the residue is taken up in MeOH and the product is concentrated to dryness.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1.O.[OH-].[Na+].[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:1][CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1c2c(cc3c1OCO3)C(OC(C)=O)CN(C)C2
Reaction time: 1 h
Yield: 99 %

Procedure:
4.74 g (20 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6) was dissolved in 70 ml of methylene chloride, to which 1.71 ml of acetyl chloride was added dropwise at room temperature. This solution was stirred at 20°-30° C. for one hour, added with 30 ml of water and then further added with 25% aqueous solution of sodium hydroxide to make the water layer basic. After separating the layers, the water layer was extracted with 20 ml of methylene chloride. The methylene chloride layers were joined together and washed with 30 ml of water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.53 g of 4-acetoxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (9) as a crystal (yield: 99%). This was then recrystallized from ethanol/n-hexane. Melting point: 109°-110° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1)[C:12]1[N:16]([CH3:17])[N:15]=[N:14][N:13]=1
Reactant: COCc1cccc(C(=O)c2nnnn2C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COCc1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a stirred solution of [3-(methoxymethyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (7.17 g, 31 mmol) in dry pyridine (50 mL) was added hydroxylamine hydrochloride (5.36 g, 77 mmol). The reaction mixture was stirred at 70° C. for 4 h, then concentrated in vacuo and diluted with ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, washed with water (100 mL) and dried (MgSO4). Evaporation of the solvent in vacuo afforded N-hydroxy-1-[3-(methoxymethyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine as a yellow oil [8.43 g, yield 99.5%; HPLC/MS:m/z=248 (M+H); log P(HCOOH)=1.54].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.C[O-].[Na+].CO.Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:15][CH2:16][CH2:17][Cl:18])=[N:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Sc1ccc(Cl)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ClCCCSc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
5-Chloropyridine-2-thiol (600 mg, 4.12 mmol) synthesized in Example (119a) was dissolved in methanol (15 mL), and 28% sodium methoxide/methanol solution (0.95 mL, 4.94 mmol) and 1-bromo-3-chloropropane (0.61 mL, 6.18 mmol) were added, followed by stirring at 60° C. for 1.5 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and vacuum drying was carried out to afford the desired compound (849 mg, yield 92%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:15](=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:15](=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:16]=1
Reactant: C#CCCc1nc2c(O)cccc2o1
Reactant: Brc1ccccn1
Product: Oc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 7364.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (203 mg, 1.29 mol) and 2-(but-3-ynyl)benzo[d]oxazol-4-ol (241 mg, 1.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH4OH 94:5:1 to 90:8:2) to yield 25 mg (95 mmol, 7%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol as an orange solid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (400 mg, 1.94 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (670 mg, 2.91 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (15 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-60% EtOAc in heptane) to give a pure product (114) as a white semisolid (682 mg, 84%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[S:21][CH:22]=[C:23]([C:25]([N:27]2[CH:36]3[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:30][CH2:29][CH2:28]2)=[O:26])[N:24]=1>COCCOC.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>[N:27]1([C:25]([C:23]2[N:24]=[C:20]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1](=[O:3])[CH3:2])[S:21][CH:22]=2)=[O:26])[CH:36]2[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: O=C(c1csc(Br)n1)N1CCCC2CCCCC21
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: [Na+]
Solvent: COCCOC
Product: CC(=O)c1ccccc1-c1nc(C(=O)N2CCCC3CCCCC32)cs1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
In a Microwave process tube, tetrakis(triphenylphosphine)palladium (5 mg, 0.004 mmol) was added to a degassed (nitrogen) mixture of 2-acetylphenylboronic acid (Aldrich; 38 mg, 0.15 mmol) and sodium carbonate (2 M in water, 0.2 mL, 0.4 mmol), and (2-bromo-thiazol-4-yl)-(octahydro-qunolin-1-yl)-methanone (from Step 1; 50 mg, 0.15 mmol) in DME (dry, 1.5 mL). The tube was submitted to 150 W Microwave Irradiation at 160° C. for 5 minutes. The reaction mixture was cooled to room temperature, filtered through celite and silica plug, and extracted with EtOAc and water three times. The organic layers were combined, concentrated and purified by C-18 reversed phase HPLC with a gradient of 10-100% Acetonitrile/Water to give 1-{2-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-phenyl}-ethanone (40 mg, 70%).