Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:54]=[CH:53][C:51]([NH2:52])=[C:50]([O:55][CH3:56])[CH:49]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(O)C>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:54]=[CH:53][C:51]([NH:52][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=5)[C:22]([NH:24][C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])=[O:23])[CH:5]=[CH:4][N:3]=4)=[C:50]([O:55][CH3:56])[CH:49]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 52 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.14 g, 0.28 mmol), 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (0.074 g, 0.25 mmol) and para-toluenesulfonic acid (0.12 g, 0.68 mmol) in iPrOH (5 mL) was heated at 180° C. for 10 min. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography followed by trituration with diethyl ether provided the title compound (0.099 g, 0.13 mmol, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 3H), 1.46 (s, 4H), 1.49-1.58 (m, 2H), 1.77 (d, J=10.4 Hz, 2H), 2.29 (s, 3H), 2.62 (t, J=12.0 Hz, 2H), 3.72 (d, J=11.9 Hz, 3H), 3.77 (s, 3H), 3.97 (s, 3H), 6.41-6.52 (m, 2H), 6.64 (s, 1H), 6.93 (t, J=7.3 Hz, 1H), 7.16 (t, J=8.1 Hz, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.32-7.43 (m, 3H), 7.67 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 8.13-8.21 (m, 1H), 8.42 (s, 1H), 9.34 (br. s., 1H), 9.76 (s, 1H). MS (M+H, ES+) 745.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>C(O)C>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=CCCCCc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 4.2 g (10 mmol) of 5-phenylpentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 2.627 g (quant., brown oily substance) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.[N+]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH:24]=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:32]1([C:30]([NH:29][C:25]2[CH:24]=[C:23]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]4)=[CH:4][CH:3]=3)[CH:28]=[CH:27][N:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (2.07 g, 0.00707 mol), N-(4-nitropyridin-2-yl)cyclopropanecarboxamide (1.46 g, 0.00707 mol) and cesium carbonate (6.92 g, 0.0212 mol) in DMF was heated with stirring at 65° C. overnight. The reaction mixture was extracted with EtOAc. The organic solution was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to tert-butyl [7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate. 1H NMR (CDCl3, 300 MHz) δ: 9.18 (s, 1H); 8.02 (d, 1H); 7.82 (d, 1H); 7.32 (dd, 1H); 7.11 (d, 1H); 6.90 (d, 1H); 6.78 (s, 1H); 6.58 (dd, 1H); 4.60 (s, 1H); 4.1 (m, 1H); 3.96 (s, 1H); 3.10 (d, 1H); 2.86 (m, 2H); 2.61 (dd, 1H); 2.08 (m, 1H); 2.04 (m, 1H); 1.75 (m, 1H); 1.60 (m, 1H); 1.45 (s, 9H); 1.25 (m, 1H); 1.07 (m, 2H); 0.87 (m, 2H). LCMS ES+ 424.4; ES− 422.5.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O[CH2:11][C:12]([CH3:24])([CH3:23])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:16]([O:15][C:13]([C:12]([CH3:24])([CH3:23])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl hydroxypivalate (4.7 g) and triphenylphosphine (6.4 g) in tetrahydrofuran (22 mL) was added diethyl azodicarboxylate (40% toluene solution, 11 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give the title compound (0.97 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:21]1
Reactant: OC1CCCNC1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCCC(O)C2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 5.2 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 300 ml. of methylene chloride is treated with 12.4 g. of 3-hydroxy-piperidine and stirred for 60 hours under an argon atmosphere. The residue is then filtered off and the filtrate is concentrated, a white precipitate separating out. This precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl racemic-6-(3-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 255° C. (decomposition).
Reaction SMILES: [Br:1][CH:2]1[CH:10](O)[CH2:9][C:8]2[C:7](=[O:12])[N:6]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][C:21]#[CH:22])[C:16]([Cl:23])=[CH:15][C:14]=3[F:24])[C:5](=[O:25])[C:4]=2[CH2:3]1.CCN(S(F)(F)[F:32])CC.O>ClCCl>[Br:1][CH:2]1[CH:10]([F:32])[CH2:9][C:8]2[C:7](=[O:12])[N:6]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][C:21]#[CH:22])[C:16]([Cl:23])=[CH:15][C:14]=3[F:24])[C:5](=[O:25])[C:4]=2[CH2:3]1
Reactant: C#CCOc1cc(N2C(=O)C3=C(CC(Br)C(O)C3)C2=O)c(F)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C#CCOc1cc(N2C(=O)C3=C(CC(Br)C(F)C3)C2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 995 mg (2.32 mmol) of 5-bromo-2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4,5,6,7-tetrahydro-6-hydroxy-1H-isoindole-1,3(2H)-dione in 15 mL of dichloromethane was added 430 μL of DAST at 0° C. The mixture was stirred at the same temperature for 1 h. The reaction mixture was then poured into 50 mL of cold water. The aqueous layer was extracted with three 50 mL portions of ethyl acetate. The organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and n-hexane to give 626 mg of the title product of Example 4, a compound of the invention, as a whim solid melting at 135°-136.5° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH3:26])[C:11]([N:13]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][CH2:9][CH:10]([CH3:26])[C:11]([N:13]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O

Procedure:
The (3S)-2-[(2RS)-3-tert.butoxycarbonylamino-2-methylpropanoyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline obtained is treated with trifluoroacetic acid according to the method in Example 1 (Step E), providing (3S)-2-[(2RS)-3-amino-2-methylpropanoyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline trifluoroacetate, which is transformed into the hydrochloride by being dissolved in an excess of normal HCl and concentrated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH3:11])=[C:9]([C:12]([OH:14])=[O:13])[S:8][C:7]=2[CH:15]=1.Cl.[CH3:17]O>>[CH3:17][O:13][C:12]([C:9]1[S:8][C:7]2[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[CH3:11])=[O:14]
Reactant: CO
Reactant: COc1ccc2c(C)c(C(=O)O)sc2c1
Agent: Cl
Product: COC(=O)c1sc2cc(OC)ccc2c1C

Procedure:
A solution of 6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid (7.50 g.) in methanol (400 ml.) was saturated with hydrogen chloride gas and the solution was heated under reflux for 2 hours and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed successively with water, sodium bicarbonate solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from methanol to give 6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (5.59 g.), m.p. 118°-120° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.O>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:17][C:14]([F:15])([F:16])[C:4]1([OH:3])[CH2:5][CH2:6][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCC2(CC1)OCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 12.20 g (40.89 mmol) of trimethyl {[8-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}silane (Example 5A) were dissolved in 164 ml of 1 molar tetrabutylammonium fluoride solution in tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. For work-up, about 600 ml of water were added to the reaction, and the target molecule was extracted with dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. Drying gave 9.33 g (100% of theory) of the title compound as a brownish oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[ClH:16].C(O)(C)C>CO>[ClH:16].[ClH:16].[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CCC1Cc2ccc(N)cc2CN1

Procedure:
To a pressure bottle charged with 3-ethyl-7-nitro-3,4-dihydroisoquinoline (3.6 g, 17 mmols) dissolved in methanol (100 ml) and saturated isopropanol-HCl (20 ml) was added 10% Pd--C (250 mg), and the reaction hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to yield 3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-amine dihydrochloride (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[C:5](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].O=P(Cl)(Cl)Cl.[NH4+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:17][C:16]([NH:18][CH:2]3[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]3)=[N:15][N:14]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: COc1cc(C(=O)O)cc(Cl)c1O
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(NC3CCCCC3)s2)cc(Cl)c1O
Temperature: 95 °C
Yield: 161 %

Procedure:
To a mixture of 3-chloro-4-hydroxy-5-methoxybenzoic acid (2.468 mmol, 500 g), thiosemicarbazide (5b) (2.468 mmol, 427 mg) in dioxane (10 mL) at 65° C., POCl3 (3.2 mmol, 300 μL) was added, and the mixture was warmed at 95° C. for 3 hours 30 minutes. The solvent was removed by distillation under reduced pressure to give a crude material which was basified with a solution of diluted NH4OH. The precipitate obtained was collected by filtration, washed with water before drying under vacuum over P2O5 to give 675 mg of the desired product. Yield: 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])/[CH:5]=[C:6]1\[N:7]=[C:8]([CH3:12])[O:9][C:10]\1=O.[CH3:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])/[CH:5]=[C:6]1\[N:7]=[C:8]([CH3:12])[N:18]([CH3:17])[C:10]\1=[O:9]
Reactant: CN
Reactant: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(Z)-4-(3-fluoro-4-hydroxybenzylidene)-2-methyloxazole-5(4H)-one (13.2 g, 0.05 mol) was suspended in ethanol (100 mL), and water solution of methylamine (40%, 11.6 g, 0.15 mol) was added. The reaction mixture was stirred at r.t. for 2 hours, then potassium carbonate (13.8 g, 0.1 mol) was added, and the mixture refluxed for 4 hours. Then it was cooled down to r.t., diluted with water (400 mL) and acidified with HCl (10% in water) until the precipitate stopped to form. The precipitate was filtered, washed with cold (−20° C.) ethanol, then diethyl ether and dried under vacuum: 8.78 g. (Yield 75%)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[P:13](=[O:22])([O:18][CH:19]([CH3:21])[CH3:20])[O:14][CH:15]([CH3:17])[CH3:16])(C(C)(C)C)(C)C>C(O)(=O)C.O>[OH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[P:13](=[O:22])([O:14][CH:15]([CH3:17])[CH3:16])[O:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)OP(=O)(/C=C/CCO[Si](C)(C)C(C)(C)C)OC(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Yield: 75.8 %

Procedure:
A solution of diisopropyl (E)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate (0.84 g, 2.40 mmol) in acetic acid-water (2:1) (10 ml) was stirred at 70° C. for 2 hr. The solvent was removed and the residue purified by column chromatography on silica gel eluting with acetone-hexane (1:1) to give diisopropyl (E)-4-hydroxybut-1-enylphosphonate as a gum (0.43 g, 76%); νmax (film) 3380, 2970, 1625, 1460, 1380, 1370, 1220 and 980 cm-1 ; δH (CDCl3) 1.32 (12H, dd, J 9 Hz and 6 Hz, CH(CH3)2), 1.85 (1H, br.s, OH), 2.50 (2H, m, CH2), 3.76 (2H, t, J 6 Hz, CH2O ), 4.69 (2H, m, CH(CH3)2), 5.80 (1H, dd, J 16 Hz and 18 Hz, PCH=CH) 6.75 (1H, ddt, J 7 Hz, 17 Hz and 22 Hz, PCH=CH); CIMS (isobutane) 237 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23]CC)=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)OCC)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)O)CC2
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of ethyl 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate in dioxane (3.5 M solution) was treated with 2N sodium hydroxide (3.0 eqv) and stirred at room temperature. After stirring for 4 hours, the dioxane was removed from the reaction, and the remaining solution was diluted with water and acidified with 5N hydrochloric acid. The resulting milky solution was extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and filtered. Solvent removal gave a white solid. The solid was purified by flash chromatography on silica gel eluting with 50% ethyl acetate/hexane, and the resulting solid was crystallized from ethyl acetate and hexane. The desired acid was obtained in 47% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCNc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Product: Nc1nc(NCCNc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and N-phenylethylenediamine in dioxane. ES-MS m/e (%): 376 (M{81Br}+H+, 100), 374 (M{79Br}+H+, 95).
Reaction SMILES: [NH4+].[OH:2][C:3]([CH3:12])([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([NH2:7])=[O:6]>O>[OH:2][C:3]([CH3:12])([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([NH2:7])=[O:6]
Reactant: CC(O)(CC(N)=O)CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(O)(CC(N)=O)CC(=O)O

Procedure:
A solution of 1.78 g. (0.01 moles) of 3-hydroxy-3-methylglutaric acid monoamide, ammonium salt in 50 ml of water is passed through a 100 ml column of Dowex 50 (H+) resin. The resulting eluate is then evaporated to dryness to afford 3-hydroxy-3-methylglutaric acid monoamide.
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1>>[CH2:4]([CH:3]([CH2:6][CH3:7])[CH2:2][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1)[CH3:5]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CCC(CC)CBr
Product: CCC(CC)Cn1ccc2c(C=O)cccc21
Yield: 60.8 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.55 g of 1-bromo-2-ethylbutane and 2.00 g of indole-4-carbaldehyde as a starting material to give 1.92 g of 1-(2-ethylbutyl) indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)#[CH:28]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:28]#[C:27][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#Cc1ccccn1
Product: O=C(N1CCc2ccc(Cl)c(C#Cc3ccccn3)c2CC1)C(F)(F)F
Yield: 90.3 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with 2-ethynyl-pyridine (0.20 mL, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 7-chloro-6-pyridin-2-ylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (342 mg, 90%). MS (ES+) m/z: 379 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][S:9](=[S:12])([O-:11])=[O:10].[Na+].CN(C=O)C>O>[CH3:8][S:9](=[S:12])([O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10]
Reactant: CS(=O)([O-])=S
Reactant: CCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOS(C)(=O)=S
Temperature: 60 °C
Yield: 165 %

Procedure:
The reaction mixture of 1-bromohexane (1.046 g, 0.00635 mol), sodium methanethiosulfonate (0.850 g, 0.00635 mol) and dry DMF (6 mL) was heated at 60° C. for 2 hr. At room temperature, water (15 mL) was added and the resulting mixture was extracted with ether (3×30 mL). The extracts were washed with brine, dried, concentrated and the residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4) to afford a colorless liquid (2.057 g, 82%). IR (CDCl3 cast): 3030 (w), 3010 (w), 2955 (st), 2930 (st), 2860 (st), 1460 (m), 1320 (st), 1133 (st), 955 (st), 747 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.33 (s, 3H, CH3SO2S), 3.18 (t, J=7.4 Hz, 2H, SCH2CH2), 1.77 (pseudo p, J=7.2 Hz, 2H, SCH2CH2), 1.50-1.20 (m, 6H, CH2CH2CH2CH3), 0.90 (m, 3H, CH2CH3); 13C NMR (50 MHz, CDCl3): δ 50.64, 36.50, 31.13, 29.46, 28.26, 22.44, 13.96.
Reaction SMILES: N#N.Cl[C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][N:9]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1>O.O1CCOCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[C:4]([C:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: N#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a N2 purged solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (4.891 g, 16.37 mmol), potassium acetate (6.54 g, 66.6 mmol), dioxane:water (160 mL, 10:1), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (6.03 g, 19.50 mmol) was added A-Phos (1.5 g, 2.118 mmol). The vial was capped and placed in a preheated oil bath (120° C.) and stirred for 1.5 hours. The solution was allowed to cool to room temperature and poured into water. The aqueous solution was extracted with EtOAc (3×70 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with 0% to 50% EtOAc in hexane, to provide tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow foam. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) 0.01298.