Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].Cl.[Br:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[OH:19]>O.C(OCC)C>[Br:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]=1[OH:19]
Reactant: COc1cc(Br)c(O)cc1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C
Reaction time: 7 h

Procedure:
Sodium nitrate (361 mg, 4.25 mmol) was dissolved in water (4 mL) and LaNO3 *6H2O (18 mg, 0.04 mmol) and HCl (12M, 4 mL) were added. The solution was cooled to 0° C. and a slurry of 4-bromo-3-hydroxy-6-methoxybenzoic acid in diethyl ether (20 mL) was added to the reaction mixture in portions during 10 min. After slowly raising the temperature to room temperature the mixture was stirred for 7 h. Extraction between H2O (20 mL) and CH2Cl2 (3×30 mL), drying the organic phase with MgSO4, filtration and evaporation under reduced pressure gave a mixture of products. Purification by silica gel chromatography (HOAc-EtOAc-toluene 1:2:8) gave the title compound (0.6 g). 1H NMR (CD3OD): δ7.57 (s, 1H), 3.85 (s, 3H). MS (EI, 70 eV): m/z (rel. int.) 291/293 (M+, 21/19).
Reaction SMILES: [C:1]([NH:8][S:9]([C:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:8][S:9]([C:12]1([CH:15]=[O:16])[CH2:13][CH2:14]1)(=[O:10])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a stirred solution of compound 79 (100 mg, 0.39 mmol) in DCM (2 mL) was added pyridinium chlorochromate (130 mg, 0.60 mmol). The mixture was stirred at room temperature for 16 hrs and was filtered through a silica gel column with DCM, and the organic solution was concentrated under reduced pressure to yield compound 80 in 66% yield.
Reaction SMILES: [CH2:1](/[C:3](/[C:13]1[S:17][CH:16]=[C:15]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:30](OC)=[O:31])[C:23](=[CH:28][CH:29]=2)[C:24](OC)=[O:25])[CH:14]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:11][CH3:12])([OH:10])[CH2:8][CH3:9])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[OH:31][CH2:30][C:22]1[CH:21]=[C:20]([CH:29]=[CH:28][C:23]=1[CH2:24][OH:25])[O:19][CH2:18][C:15]1[CH:14]=[C:13](/[C:3](/[CH2:1][CH3:2])=[CH:4]/[CH2:5][CH2:6][C:7]([CH2:11][CH3:12])([OH:10])[CH2:8][CH3:9])[S:17][CH:16]=1
Reactant: CC/C(=C\CCC(O)(CC)CC)c1cc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC/C(=C\CCC(O)(CC)CC)c1cc(COc2ccc(CO)c(CO)c2)cs1
Reaction time: 0.25 h

Procedure:
480 mg (1.1 mmol) of dimethyl 4-[5-((E)-1,5-diethyl-5-hydroxyhept-1-enyl)-3-thienylmethoxy]phthalate are dissolved in 10 mL of ethyl ether. This solution is added to a suspension of 130 mg (3.4 mmol) of lithium aluminium hydride and the reaction medium is stirred for 15 minutes. The reaction medium is then treated by successive addition of 130 μL of water, 130 μL of 15% sodium hydroxide and 400 μL of water. After filtration and chromatography on silica gel (eluent: 2 heptane/8 ethyl acetate), the desired product is obtained in the form of white crystals (m.p.=63-64° C.; m=380 mg; Y=90%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:13]([N+:30]([O-])=O)[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[NH4+].[Cl-].C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:13]([NH2:30])[CH:12]=2)=[O:10])=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2N)c(Cl)c1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-chlorophenyl)acetate (110 mg, 0.219 mmol) was diluted with THF (1 mL) followed by the addition of Zn dust (14.3 mg, 0.219 mmol) and saturated NH4Cl (1 mL). After stirring for 1 hour, the reaction was diluted DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-chlorophenyl)acetate (102 mg, 98.6% yield).
Reaction SMILES: [CH3:1]N(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)=[CH:9][CH:8]=1.[H-].[Na+].CI>C1(C)C=CC=CC=1.O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH3:1])[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1c[nH]c(-c2ccc(F)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])cc1-c1ccc(F)cc1

Procedure:
To an N,N-dimethylformamide solution (0.50 mL) of 2-(4-fluorophenyl)-4-nitro-1H-pyrrole (10.0 mg, 0.0485 mmol) synthesized in Reference Synthesis Example 245, sodium hydride (2.50 mg, 0.0582 mmol) was added at 0° C. and the resultant mixture was stirred for 1 hour. Thereafter, methyl iodide (18.8 μL, 0.0582 mmol) was added to the reaction solution and the resultant mixture was stirred at room temperature for 7 hours and 30 minutes. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with toluene was performed. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH2:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH:25][C:32]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[O:33])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CN)c3)cnc21
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CCOCC4)c3)cnc21
Reaction time: 16 h

Procedure:
6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), tetrahydro-pyran-4-carboxylic acid (57 mg, 0.44 mmol) and triethyl amine (0.12 mL, 0.88 mmol) are mixed in acetonitrile (3.0 mL). Then TBTU (113 mg, 0.35 mmol) is added and the mixture is stirred for 16 hrs. All the solvent is removed in vacuo and to the residue are added saturated NaHCO3 aqueous solution (5 mL), water (15 mL) and EtOAc (20 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×15 mL). The organic layers are combined and concentrated to give the crude 6-(5-{[(Tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester which is used in the next step directly.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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.C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(Br)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cnc(-c2ccc(Br)cc2)cn1
Temperature: 50 °C

Procedure:
5-Bromopyrazin-2-amine (173 mg, 0.99 mmol) and (4-bromophenyl)boronic acid (100 mg, 0.490 mmol) were placed in a sealable vial followed by toluene (1.5 mL), ethanol (1.5 mL), and K2CO3 (0.7 mL, 2 M). The resultant mixture was then sparged with argon for 10 minutes before adding tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.15 mmol), and heating at 50° Celsius. Reaction progress was monitored by LCMS. Once the reaction was complete, the reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and the resultant filtrate concentrated to dryness. The crude product was purified by FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.52-8.31 (d, J=1.5, 1H), 8.08-7.95 (d, J=1.6, 1H), 7.86-7.71 (d, J=8.4, 2H), 7.63-7.49 (d, J=8.6, 2H), 4.81-4.61 (s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7](C1C=C(F)C=CC=1F)([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])(O)=O.[Na+]>C(OCC)C.C(OCC)(=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][C:5]([C:18]([F:19])([F:20])[F:21])([OH:22])[CH2:4][OH:3]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)CC(O)(CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.4 g (15.5 mmol) of 4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (WO 02/10143) is dissolved at 0° C. in diethyl ether and mixed within 20 minutes with 1.76 g (46.5 mmol) of lithium aluminum hydride. It is allowed to stir at room temperature for 4 hours, and then enough saturated NaHCO3 solution is carefully added until no more gas generation can be observed. The mixture is diluted with ethyl acetate, stirred for 15 more minutes, and then the formed precipitate is filtered off. It is concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (50%). 2.45 g of 2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is obtained as a weakly yellowish crystallizing oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])C.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:4]([C:6]2[C:22]3[C:10](=[C:11]([CH3:25])[C:12]4[N:13]([CH3:24])[C:14]5[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=5[C:20]=4[CH:21]=3)[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:31][CH2:32]1
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Reactant: NCCCN1CCOCC1
Product: Cc1c2ccnc(C(=O)NCCCN3CCOCC3)c2cc2c3cc(O)ccc3n(C)c12
Temperature: 120 °C

Procedure:
0.36 g (1. 078 mmol) of the ester obtained in Step A of Example 11 are dissolved in 10 ml of 4-(3-aminopropyl) morpholine under an argon atmosphere. The mixture is heated at 120° C. for 19 hours.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH2:16][NH:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CNCC2CCCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A solution of 1-Boc-2-aminomethylpiperidine (429 mg, 2 mmol) and methyl 4-formylbenzoate (329 mg, 2 mmol) in dichloroethane (10 mL) was stirred as acetic acid (180 mg, 3 mmol) and sodium triacetoxyborohydride (487 mg, 2.3 mmol) were added sequentially. The reaction was stirred at ambient temperature for 17 hours. The reaction was poured into water and extracted with methylene chloride (2×). The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 0.7 g of 1,1-dimethylethyl 2-((4-(methoxycarbonyl)phenylmethylamino)methyl)-1-piperidinecarboxylate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Yield: 70 %

Procedure:
Upon boiling a solution of 8.7 g 2-trifluoromethylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2,6-diamino-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 191°C (ethanol) is obtained. Yield: 70% of theory.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][C:26]([F:28])([F:27])[CH:23]([C:20]1[CH:21]=[CH:22][C:15]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)=[N:18][C:17]=3[C:16]=2[CH:19]=1)[OH:24]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C=O)cc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C(O)C(F)(F)F)cc1-2
Yield: 6 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbaldehyde (0.354 g, 1.04 mmol) was dissolved in THF (7 mL) and treated with (trifluoromethyl)trimethylsilane (0.154 mL, 1.04 mmol) followed by TBAF (1M, 0.02 mL, 0.02 mmol). Stirred the resulting reaction mixture at ambient temperature for 2 h. Concentrated in vacuo and re-dissolved in DMF and purified by reverse phase HPLC to give 25.6 mg (6% yield) of 329. LC/MS (ESI+): m/z 411 (M+H). 1H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.10 (s, 1H), 7.41 (d, J=8.4, 1H), 7.10 (d, J=8.3, 1H), 6.80 (s, 1H), 5.80 (dt, J=13.1, 6.5, 1H), 5.21 (d, J=6.7, 1H), 4.39 (t, J=4.9, 2H), 3.45 (t, J=4.9, 2H), 1.55 (d, J=6.5, 6H)
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=1[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxy-3-methyl-benzaldehyde (3.31 g, 21.8 mmol), benzylbromide (4.09 g, 23.9 mmol), NaHCO3 (5.49 g, 65.4 mmol), 1,4-dioxane (30 mL) and water (12 mL) was stirred at 60° C. for overnight. Then the reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (2×200 mL). The extract was dried over Na2SO4, evaporated. The residue was purified on SiO2 (25 g) column, hexane-EtOAc (0 to 5%). Yield 1.57 g (6.48 mmol, 29%) as off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@H:7]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8][CH2:9][C:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)C(O)=O)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:33]([O:32][C:30]([NH:29][C@H:7]([CH2:8][CH2:9][CH:10]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:37])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(Cc1ccc(O)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 65.3 %

Procedure:
A solution of 237 mg (5R)-6-tert-butoxy-2-(tert-butoxycarbonyl)-5-[(tert-butoxycarbonyl)-amino]-2-(4-hydroxybenzyl)-6-oxohexanoic acid (0.45 mmol) and 94 mg 4-N,N-dimethylaminopyridine (0.77 mmol) in 1,4-dioxane (5 mL) was heated under reflux for 2 hours. The residue was purified by column chromatography on silica gel using an ethyl acetate/hexane gradient to give 141 mg of the title compound (65% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[CH:18]=3)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33].C(Cl)Cl>C1COCC1.CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([N:17]2[CH:18]=[C:14]([C:11]3[CH:10]=[N:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=4)=[N:13][CH:12]=3)[CH:15]=[N:16]2)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(I)c4)nc3)cn2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(C#C[Si](C)(C)C)c4)nc3)cn2)CC1
Yield: 38.9 %

Procedure:
A mixture of tert-butyl 4-{4-[2-(3-iodophenyl)pyrimidin-5-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (intermediate 18, 315 mg; 0.59 mmol; 1.0 eq.), Ethynyl-trimethyl-silane (83 μl; 0.59 mmol; 1.0 eq.), (dppf)PdCl2.CH2Cl2 (26 mg; 0.04 mmol; 0.06 eq.), CuI (7 mg; 0.04 mmol; 0.06 eq.) and TEA (115 μl; 0.89 mmol; 1.5 eq.) in dry THF (3.6 mL) and dry DMF (1 mL) was heated in a sealed vial at 80° C. for 48 h. The reaction mixture was then diluted with EtOAc and washed with sat. NH4Cl and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (heptanes:EtOAC, gradient form 90:10 to 50:50) afforded the title compound as a beige solid (115 mg, 39%). 1H NMR (300 MHz, DMSO-d6) d 9.17 (s, 2H), 8.57 (s, 1H), 8.41-8.38 (m, 1H), 8.15 (s, 2H), 7.61-7.54 (m, 2H), 4.08-4.03 (m, 2H), 2.96 (m, 2H9, 2.08-2.05 (m, 2H), 1.83-1.77 (m, 2H), 1.43 (s, 9H), 0.26 (s, 9H). MS (ESI+): 502.5.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[CH2:46]([NH:48][CH:49]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH3:50])[CH3:47].C1C=CC2N(O)N=NC=2C=1>ClCCl.CO>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:48]([CH2:46][CH3:47])[CH:49]([C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)[CH3:50])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CCNC(C)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)C(C)c1cccnc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 145.3 %

Procedure:
In a 3-neck 50 mL round-bottomed flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in dichloromethane (15 mL) at 0° C. under N2 atmosphere. To this reaction DIPEA (0.088 g, 1.2 eq.), EDC.HCl (0.131 g, 1.2 eq.) and N-ethyl-1-(pyridin-3-yl)ethanamine (0.102 g, 1.2 eq.) was added followed by HOBt (0.104 g, 1.2 eq.). Reaction mixture was stirred at 20° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol: dichloromethane as mobile phase and visualization with UV, SM Rf=0.15 and Product Rf=0.40. Reaction was stirred for 3-4 h and yellow reaction mixture was evaporated on rotary evaporator under reduced pressure to afford 0.4 g of crude compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([CH3:24])[CH2:13][NH:14]C(=O)CC2C=CC=CC=2)[CH2:8][CH2:7]1>Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:12]([CH3:24])[CH2:13][NH2:14])[CH2:10][CH2:11]1
Reactant: CC(CNC(=O)Cc1ccccc1)N1CCC(Oc2ccc(F)c(F)c2)CC1
Agent: Cl
Product: CC(CN)N1CCC(Oc2ccc(F)c(F)c2)CC1
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To the product of Example 10, Step (a) (0.772 g) was added 50% conc HCl/50% MeOH (20 ml) and the reaction heated to 60° C. for 2 days. Evaporation of solvent and purification by flash silica column chromatography using 10% MeOH188.9% CH2Cl2/0.1% aq. NH3 as eluent gave the sub-title compound (0.282 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(=O)[C:12]([Cl:14])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClC=C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:12]([Cl:14])=[O:13])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: BrCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=C(Cl)Cl
Product: O=C(Cl)c1ccc(CCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a cold (ice bath) stirred solution of 50.0 g (0.25 mole) of 1-bromo-3-phenylpropane (Aldrich) and 31.9 g (0.25 mole) of oxalyl chloride in 300 mL of trichloroethylene was added, portionwise, 33.3 g (0.25 mole) of aluminum chloride. The reaction mixture was stirred for 0.5 hr and then poured into ice water. The layers were separated and the aqueous layer was extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed twice with 200 mL portions of water and dried (magnesium sulfate). The solvents were evaporated under reduced pressure to leave 63.6 g (97%) of 4-(3-bromopropyl)benzoyl chloride as an oil. To a solution of the acid chloride in 120 mL of dry benzene was added 60 mL of absolute ethanol and the mixture was heated at reflux for 3 hr. The solvents were evaporated under reduced pressure to give 63.4 g (93.5%) of an oil. The oil was purified by chromatography (3.5×90 cm glass column, 200 g of silica gel, benzene-hexane, 1:1). Fractions containing the desired component were combined and the solvents evaporated under reduced pressure to give 60.6 g (89%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3CC(C[CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([C:28]([OH:30])=[O:29])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])C2.[CH2:31](O)[CH3:32]>>[CH:2]1([NH:11][C:12]([N:14]2[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20]3)[CH2:18][CH2:19]2)=[O:13])[CH2:1][CH2:10][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Reactant: CCO
Product: CCOC(=O)C1CC2(CCN(C(=O)NC3CCCCC3)CC2)c2ccccc21

Procedure:
A procedure analogous to that described Example 4 was followed using 1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]3-carboxylic acid and ethanol. 1H NMR (CD3OD) δ=1.29 (t, 3H), 1.54 (m, 1H), 1.64 (m, 2H), 1.86 (m, 9H), 1.96 (m, 5H), 2.43 (m, 2H), 3.04 (m, 2H), 3.86 (s, 1H), 4.06 (m, 2H), 4.15 (m, 1H), 4.20 (m, 1H), 7.20 (m, 3H), 7.34 (m, 1H); LC-MS (4 min) tR=2.12 min, m/z=437.