Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+].[N+:9]([C:12]1[C:21]2[C:16](=[C:17]([N+:22]([O-])=O)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]>O.CO>[N+:9]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[C:17]2[NH2:22])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: Nc1cccc2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.2 %

Procedure:
A 70° C. solution of sodium sulfide (3.17 g, 32.97 mmol) and sodium bicarbonate in water (7 mL) was added dropwise to suspension of 1,5-dinitro naphthalene (2.0 g, 9.16 mmol) in methanol (30 mL) at reflux and the resultant mixture was stirred for 5 min. The mixture was cooled to 0° C., quenched with ice and stirred for a further 10 min followed by acidification with concentrated hydrochloric acid. The resulting mixture was stirred for 30 min then washed with ethyl acetate (2×50 mL). The aqueous layer was basified with aqueous ammonia and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulphate, filtrated and concentration in vacuo afforded of 5-nitronaphthalen-1-amine (710 mg, 42%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])N.N([O-])=O.[Na+].[BrH:15]>O.[Cu]Br>[Br:15][C:4]1[CH:6]=[C:7]([F:10])[C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Br
Reactant: Nc1cc(F)c(F)c(Cl)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(Br)cc(Cl)c1F
Temperature: 60 °C
Yield: 68.3 %

Procedure:
To a solution of 3-chloro-4,5-difluoroaniline (2.1 g, 12.96 mmol) in hydrobromic acid (40% in H2O, 18.7 mL) was added dropwise a solution of sodium nitrite (0.96 g, 13.6 mol) in 7.5 mL H2O at 0° C. Then the mixture was poured into a solution of copper(I) bromide (3.5 g, 23.7 mmol) in hydrobromic acid (40% in H2O, 15 mL) at 0° C. The cooling bath was then removed and the mixture was heated at 60° C. overnight. After cooling, the mixture was basified with a solution 2N NaOH solution to pH=9 and diluted with CH2Cl2. After separation, the combined organic layers were washed with brine, dried over Na2SO4 and then concentrated to get crude product, which was purified by column with PE/EtOAc (from 100:1 to 20:1) as eluant to afford 2 g product. Yield 68.3%; 1H NMR (400 MHz, CDCl3): δ 7.37-7.35 (m, 1 H), 7.30-7.25 (m, 1 H) ppm.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[S:6]([NH:9]C(=O)OC(C)(C)C)(=[O:8])=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[S:6]([NH2:9])(=[O:8])=[O:7]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)N1CCCO1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a cold (0° C.) solution of chlorosulfonyl isocyanate (0.437 mL, 5.02 mmol) in CH2Cl2 (10 mL) was added tert-BuOH (0.480 mL, 5.02 mmol) and the mixture was stirred for 1 h at 0° C. Then HCl salt of isoxazolidine (0.5 g, 4.56 mmol) and TEA (1.399 mL, 10.04 mmol) were added consecutively and the mixture was stirred overnight. Rxn was diluted with EtOAc and washed with ice cold 1N HCl, brine and then dried (MgSO4). Isolated crude product was purified by Biotage 25M column to afford tert-butyl isoxazolidin-2-ylsulfonylcarbamate as a beige solid (0.82 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (9 H, s), 2.38 (2 H, quin, J=7.37 Hz), 3.81 (2 H, m), 4.19 (2 H, t, J=7.30 Hz). To a cold (0-5° C.) solution of tert-butyl isoxazolidin-2-ylsulfonylcarbamate (0.82 g, 3.25 mmol) in DCM (2 mL) was added TFA (2 mL, 35.1 mmol) and the reaction mixture was stirred for 2 h at r.t and removed the solvent to afford isoxazolidine-2-sulfonamide (0.229 g, 46%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.40 (2 H, quin, J=7.32 Hz), 3.65 (2 H, m), 4.20 (2 H, t, J=7.32 Hz), 4.83 (2 H, brs).
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:30])[CH:11]=[C:12]([C:28]#[N:29])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)=[O:8])[CH3:5].[H][H]>[OH-].[OH-].[Pd+2].C1COCC1>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:30])[CH:11]=[C:12]([C:28]#[N:29])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)cn1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)cn1C
Reaction time: 18 h

Procedure:
Add a 1:2 ethanol:THF mixture to 20% palladium hydroxide on carbon (catalytic, 29.4 g) followed by 3-(4-benzyloxy-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (97.93 g, 0.271 mol, prepared in examples E-6a or E-6b). Subject the reaction to 344.74 kPa (50 psi) of hydrogen gas. After 18 hours, filter and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 271.1 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[N:35]=[CH:34][C:33]5=[CH:36][CH:37]=[C:38]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=6[O:45][CH3:46])[N:32]5[N:31]=4)=[C:25]([O:47][CH3:48])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.CC(O)=O>>[CH3:46][O:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:38]1[N:32]2[C:33]([CH:34]=[N:35][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:20]4[CH2:21][CH2:22][CH:17]([N:14]5[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]5)[CH2:18][CH2:19]4)=[CH:24][C:25]=3[O:47][CH3:48])=[N:31]2)=[CH:36][CH:37]=1
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
A mixture of 4-(1-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-piperazine-1-carboxylic acid benzyl ester (0.027 g, 0.042 mmol) and 33% wt. HBr in HOAc (4 mL, 40 mmol) was stirred at room temperature for 5 hours. The reaction was evaporated under vacuum. Water (5 mL) was added and the solution filtered. The filtrate was basified, extracted with ethyl acetate, washed dried and evaporated to give a tan solid (0.009 g, 40%). MP; 65-67° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 8.88 (s, 1H), 7.84-7.81 (d, 2H, J=8.84 Hz), 7.48 (s, 1H), 7.43-7.41 (t, 1H, J=7.58 Hz), 7.21-7.19 (d, 1H, J=8.20 Hz), 7.10-7.06 (t, 1H, J=7.24 Hz), 6.95-6.89 (q, 2H, J=4.60 Hz), 6.63 (s, 1H), 6.38-6.36 (d, 1H, J=8.60 Hz), 3.83 (s, 3H), 3.78 (s, 3H), 3.69-3.62 (br, 2H), 2.76 (br, 3H) 2.67-2.57 (m, 3H), 2.35-2.25 (br, 2H), 1.90 (s, 1H), 1.89-1.78 (br, 2H), 1.53 (br, 3H), 1.23 (m, 4H), 1.19-1.18 (d, 2H, J=5.36 Hz) 1.13-1.08 (q, 4H, J=7.00 Hz), 0.95-0.83 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5]([CH:15]=[O:16])=[CH:4][C:3]=1[O:17][CH3:18].[H-].[Na+].[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[O:16])[C:6]2[C:11]([C:2]=1[O:1][CH2:21][O:22][CH3:23])=[C:10]([CH2:12][CH2:13][CH3:14])[CH:9]=[CH:8][CH:7]=2
Reactant: COCCl
Reactant: CCCc1cccc2c(C=O)cc(OC)c(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
322 g of 4-hydroxy-3-methoxy-5-propyl-1-naphthalenecarbaldehyde was dissolved in 1.3 liters of N,N-dimethylformamide and cooled to 10° C. 63.3 g of 60% sodium hydride was added to the solution at 30° C. or below and agitated for 20 minutes. The reaction solution was cooled to 5° C., to which 190 ml of chloromethyl methyl ether was added. After agitation at room temperature for 2 hours, the solution was poured into iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, after which it was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 294.5 g of the captioned compound as a brown oily substance.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][CH2:24][C:25]1([OH:35])[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[Br:20][CH2:23][CH2:24][C:25]1([OH:35])[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1
Reactant: OCCC1(O)CCc2ccccc2C1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC1(CCBr)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a 0° C. solution of triphenylphosphine (1.03 g, 3.93 mmol), in CH2Cl2 (15 ml) was added slowly a solution of bromine (0.192 ml, 3.74 mmol) in CH2Cl2. After 1 hour stirring at room temperature, the reaction mixture was cooled to 0° C. and treated slowly with a solution of (RS)-2-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol (0.72 g, 3.74 mmol) in CH2Cl2 (15 ml). After 1.5 hour stirring at room temperature, the reaction mixture was again cooled to 0° C., treated slowly with triethylamine (0.52 ml, 3.74 mmol), washed successively with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (RS)-2-(2-bromo-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol (0.58 g, 61%) as a colorless oil, MS: m/e=255.1 (M).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]Cl)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
1-Aminopropan-2-ol (60.0 g, 799 mmol) was charged to a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, and heated to 120° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at 120-125° C. On completion of the addition, stirring was continued at 115-120° C. for 2.5 h. NaOH (50%, 12.78 g, 160 mmol) was added followed by water (25 mL) and the mixture was stirred at 70 to 75° C. for 15 min. The organic phase was separated and washed with water (4×25 mL) at 70 to 75° C. The combined aqueous phases were extracted with toluene (38 mL) for 15 min at 70 to 75° C. Then, the combined organic phases were concentrated under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 104 mL and the golden solution was stirred overnight at 50° C. (bath) under nitrogen. Karl Fischer titration showed 0.052% water.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH2:26][CH3:27]
Reactant: CCCOC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCCOC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and propyl chloroformate, there is obtained ethyl N-propoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 352 (8), 323 (14), 293 (14), 263 (78), 194 (100).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[CH:7][C:6]=1[F:32].CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:32][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:24]=[CH:25][C:26]([CH2:29][O:30][CH3:31])=[CH:27][N:28]=3)[CH2:19][CH2:18]2)[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:33])=[O:2]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl{2-fluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetate (1.50 g, 3.28 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. Lithium hydroxide (0.393 g, 16.4 mmol) was added to the mixture, and stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed in vacuo, and the remaining aqueous layer extracted with dichloromethane (3×30 ml). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 444.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])=[CH:17][CH:18]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(N)cc1)OCC
Yield: 56.1 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of diethyl 4-nitrobenzylphosphonate (5 g, 18.32 mmol, 1.00 equiv) in ethanol (50 mL) and a solution of NH4Cl (2.9 g, 54.72 mmol, 2.99 equiv) in water (50 mL) was added. This was followed by the addition of Fe (4.1 g, 73.21 mmol, 4.00 equiv), while the temperature was maintained at reflux. The resulting solution was heated to reflux for 1 hr. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). This resulted in 2.5 g (56%) of the title compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@H:4]([CH2:36][CH2:37][S:38][CH3:39])[NH:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[C@@H:15]2[CH2:19][CH:18]([OH:20])[CH2:17][N:16]2C(OC(C)(C)C)=O)=[CH:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Li+].[OH-].Cl>CO>[OH:20][CH:18]1[CH2:17][NH:16][C@H:15]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:40])=[O:2])[CH2:36][CH2:37][S:38][CH3:39])=[O:35])=[C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:9]=2)=[O:28])[CH2:19]1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CC(O)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(NC(=O)[C@@H]2CC(O)CN2)cc1-c1ccccc1)C(=O)O
Reaction time: 4 h
Yield: 111.7 %

Procedure:
To a solution of 358 mg (0.62 mmol) of [4-(N-Boc-4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 169C, in 6 ml of methanol was added 1 ml (1 mmol) of 1 N LiOH in an ice bath and the reaction mixture was stirred for 4 hours. The reaction mixture was adjusted to pH 2-3 with 1 N HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned between chloroform and water and extracted 3 times with chloroform. The combined organic solution was washed with 1 N HCl and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 317 mg (92%) of [4-(4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine as a white solid. To a 5 ml of 1:1 solution of TFA and dichloromethane was added 306 mg (0.54 mmol) of the acid. After 3 hours, the reaction mixture was thoroughly evaporated under high vacuum to give an oily residue. The residue was triturated with anhydrous ether and the white solid was collected by filtration to give 254 mg (72%) of [4-(4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine trifluoroacetate: HPLC 90% (purity); mp 127 (sub.), 154-157° C. (dec.);
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[C:13]([CH3:16])[N:12]=[C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[N:10]=1)=[O:8])C.[OH-].[Na+]>CO.O1CCCC1>[OH:15][C:14]1[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:38])=[O:3])=[O:8])=[N:10][C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[N:12][C:13]=1[CH3:16]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Ethyl({[5-hydroxy-2-({1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.22 g, 0.42 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and an aqueous sodium hydroxide solution (1 M, 5.0 mL) was added, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and hydrochloric acid (1 M, 5.0 mL) was added to the resulting residue, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (0.17 g, 0.35 mmol) as a pale yellowish white solid (yield 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCN(Cc2cccnc2OC)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(Cc2cccnc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 g of ethyl 2-[1-[(2-methoxy-3-pyridyl)methyl)hexahydro-4-pyridinylidene]acetate and 380 mg of 10% palladium-carbon powder (water-containing product) were suspended in 20 ml of ethyl acetate. After replacing the atmosphere of a container with hydrogen, the mixture was stirred at room temperature under normal pressure for one hour. The reaction solution was filtered, and the filtrate was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.O.[NH2:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH:11]([C:3]1[C:2]([C:20]2[CH:21]=[C:16]([NH2:15])[CH:17]=[CH:18][CH:19]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nn2ccccc2c1I
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a 20 ml microwave reaction vial was added 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine (690 mg, 2.41 mmol), 3-aminophenylboronic acid monohydrate (411 mg, 2.65 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (197 mg, 0.24 mmol), acetonitrile (8 ml), and 1 M aqueous Na2CO3 solution (5 ml). The mixture was placed in a microwave reactor for 2 hours at 140° C. The reaction mixture was concentrated in vacuo, and the crude material partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 30% ethyl acetate in hexanes) to give 205 mg (34%) of 3-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine. 1H-NMR (250 MHz, DMSO-d6) δ 8.40 (d, J=7.0 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.25-7.18 (m, 1H), 7.03-6.97 (m, 1H), 6.81 (d, J=7.3 Hz, 1H), 6.71 (s, 1H), 6.67-6.62 (m, 2H), 3.65 (broad s, 2H), 3.35 (sept, J=6.9 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H). LC/MS 252.3 m/z (M+H+). Compound 1100.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CCO>C(Cl)Cl>[C:23]([C:21]1[N:22]=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:39])=[O:5])=[CH:10][C:11]=2[C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)=[O:17])[NH:19][CH:20]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C=CC(=O)O)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 3-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-acrylic acid tert-butyl ester (30 mg, 0.055 mmol)(as prepared in the previous step) in 1.0 mL of DCM was added 0.30 mL of TFA, 0.026 mL of EtOH and stirred at RT for 2 h. The mixture was concentrated and the residue triturated with MeOH to give 19 mg (95%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.39 (br s, 1H), 9.83 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.9 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.56 (d, J=16.0 Hz, 1H), 6.53 (d, J=16.0 Hz, 1H), 5.83 (m, 1H), 2.31-2.14 (m, 4H), 1.81-1.65 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H18N4O3, 363.1 (M+H). found 363.0.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][CH:24]=[CH2:25])=[C:17]([CH3:26])[CH:16]=2)=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C(OCC)C>[CH2:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14]2[O:11][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[N:12][N:13]=2)=[CH:16][C:17]=1[CH3:26])[CH:24]=[CH2:25]
Reactant: C=CCOc1c(C)cc(C(=O)NNC(=O)c2ccc(CC(C)C)s2)cc1C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOc1c(C)cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc1C
Yield: 76.5 %

Procedure:
A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N′-(5-isobutyl-thiophene-2-carbonyl)-hydrazide (1.40 g, 3.62 mmol) and Burgess reagent (1.12 g, 4.71 mmol) in THF (15 mL) is stirred at 110° C. for 3 min under microwave irradiation. The mixture is diluted with diethyl ether, washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazole (1.02 g) as a colourless oil; LC-MS: tR=1.21 min, [M+1]+=369.15.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:10][CH2:8][OH:9]
Reactant: NCCO
Reactant: Clc1ncccn1
Solvent: O
Product: OCCNc1ncccn1

Procedure:
2-Chloropyrimidine (5 g) and ethanolamine (15 ml) were stirred for 2 hours at 140° C. After cooling, the mixture was added to water (200 ml) and continuously extracted with ethyl acetate (500 ml) for 16 hours. The organic extract was dried (MgSO4) filtered and evaporated to dryness. The title compound was obtained as a solid (m.p. 66° C.), following chromatography on silica-gel in 3% methanol in dichloromethane.