Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([O-])([O-])=O.[K+].[K+].[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:19]OS(C)(=O)=O)[O:17][CH:18]=1)=[O:13])[CH3:10].[Br:25][C:26]1[CH:27]=[N:28][NH:29][CH:30]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CC(C)=O>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:19][N:28]2[CH:27]=[C:26]([Br:25])[CH:30]=[N:29]2)[O:17][CH:18]=1)=[O:13])[CH3:10]
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)c1coc(COS(C)(=O)=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(Cn2cc(Br)cn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), K2CO3 (356 mg, 2.55 mmol) was added at rt to a solution of 2-methanesulfonyloxymethyl-oxazole-4-carboxylic acid ethyl ester (127 mg, 0.51 mmol), TBAB (33 mg, 0.10 mmol) and 4-bromo-1H-pyrazole (76 mg, 0.51 mmol) in acetone (5.0 mL). After stirring at rt for 2 h, the solvent was removed under reduced pressure. The residue was partitioned between water and EA, the two layers were separated and the aq. layer was extracted twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as an orange solid. TLC: rf (1:1 hept-EA)=0.27. LC-MS-conditions 01: tR=0.84 min, [M+H]+=299.96.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:51])=[C:29]([N:35]2[CH2:40][CH2:39][CH:38]3[N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43][CH:37]3[CH2:36]2)[CH:30]=[C:31]([C:33]#[N:34])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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.[Fe+2]>[Cl:51][C:28]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:19][CH2:20]3)[CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[CH:32][C:31]([C:33]#[N:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][CH:38]2[N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43][CH:37]2[CH2:36]1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2CN(c3cc(C#N)cc(N)c3Cl)CCC21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5C(CCN5C(=O)OC(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 73.3 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (263 mg, 0.741 mmol), tert-butyl 5-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (266 mg, 0.706 mmol), palladium(ii) acetate (42.0 mg, 0.187 mmol), xantphos (40.8 mg, 0.071 mmol), DPPF (39.1 mg, 0.071 mmol) and cesium carbonate (598 mg, 1.835 mmol) in dioxane (10 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 10 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-40% ethyl acetate/hexanes) to give tert-butyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (360 mg) as a foaming solid.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].[O-]CC.[Na+]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C

Procedure:
In a manner similar to Examples 15 and 16, to a solution of 2.86 g. (50 mmoles) of N-methylsaccharin and 10.8 ml. (100 mmoles) of methyl chloroacetate in 17 ml. of dimethylsulfoxide was added 11.56 g. (170 mmoles) of sodium ethoxide in 63 ml. of dimethylsulfoxide over a period of 2.5 hours.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[C:10]([CH3:17])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:15][CH:11]1[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9][C:10]1([CH3:17])[CH3:16]
Reactant: CC1CN(Cc2ccccc2)CC(C)(C)C1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)(C)C1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3,3,5-trimethylpiperidine (1.9 g, 8.15 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3,3,5-trimethylpiperidine as oil. Yield 1.0 g (87%), C9H17NO, m/z 144 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]1[CH:22]2[CH:13]([C:14](=[O:23])[NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=32)[CH2:12][CH2:11]1>ClCCl>[N+:1]([C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:23])[CH:13]3[CH2:12][CH2:11][CH2:10][CH:22]3[C:21]=2[CH:20]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccccc2C2CCCC12
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C2CCCC12
Reaction time: 1 h
Yield: 53 %

Procedure:
65% Nitric acid (0.33 ml) is mixed at 0° C. with 96% sulfuric acid (0.44 ml). To this end, a solution of 1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (1.9 g, 5.3 mmol) in dichloromethane (5 ml) is added in drops. After 1 hour at room temperature, the batch is poured onto ice water, the solid is filtered off and washed with water. Column-chromatographic purification (SiO2) of the filter residue with ethyl acetate-hexane yields 0.65 g (53%) of product.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:27][CH:23]5[CH2:24][NH:25][CH2:26][CH:22]5[CH2:21]4)[C:16]([CH3:28])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:27][CH:23]5[CH2:24][N:25]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:26][CH:22]5[CH2:21]4)[C:16]([CH3:28])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CNCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CN(C(=O)CC#N)CC2C1
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (86.9 mg, 0.23 mmol) and 2-cyanoacetic acid (31.3 mg, 0.37 mmol) in a mixture of DCM (8 mL) and DMF (2 mL) were added HOAT (65.5 mg, 0.48 mmol) and EDCI (77.6 mg, 0.40 mmol). After addition, the reaction mixture was stirred at 45° C. for 1 h, and then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (69.8 mg, 68.2%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.C([Li])CCC.[C:24]([CH2:26][CH2:27][N:28]=[C:29]=[O:30])#[N:25].[Cl-].[NH4+]>COC(C)(C)C>[C:24]([CH2:26][CH2:27][NH:28][C:29](=[O:30])[C:14]#[C:13][C:10]([CH2:11][F:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][F:16])#[N:25]
Reactant: N#CCCN=C=O
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: N#CCCNC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
An amount (61 mg) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69 M n-butyllithium (0.148 ml) was added at −70° C. under a nitrogen atmosphere and the mixture was stirred for 10 minutes. To the reaction mixture, 2-cyanoethyl isocyanate (28 mg) was added and the resulting mixture was stirred at −70° C. for 10 minutes. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane/ethyl acetate (1/1); the resulting organic layers were washed with a 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried with anhydrous sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=3/2) to give the titled compound (45 mg) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:27]C=O)[CH2:6][CH:5]1[CH2:30][CH3:31])(=[O:3])[CH3:2].Cl>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH2:30][CH3:31])(=[O:3])[CH3:2]
Reactant: CCC1CC(NC=O)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Agent: Cl
Solvent: CCO
Product: CC[C@H]1C[C@@H](N)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Temperature: 85 °C

Procedure:
{1-acetyl-2-ethyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinyl}formamide (for a preparation see Intermediate 6) (1.00 g, 2.026 mmol) was dissolved in Ethanol (20 ml), mixed with 5M hydrochloric acid (1.216 ml, 6.08 mmol) and stirred under reflux at 85° C. for 24 hours. The mixture was loaded onto a 5 g SCX-column, eluting with MeOH (70 mL), followed by 2M MeOH/NH3 (70 mL). Product-containing fractions were evaporated to dryness to give a yellow solid (1.242 g). The residue was purified on a 40+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 19:1). Product-containing fractions were evaporated to dryness to give a pale yellow solid (0.782 g). LCMS (Method C): Rt 0.57, MH+=392
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Na+].O.C1(P(C2CCCCC2)C2(OC)C(S([O-])(=O)=O)C=CC(OC)=C2C2C=CC=CC=2)CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:20]=[C:19]([F:21])[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)C(S(=O)(=O)[O-])C=C1
Solvent: O
Product: O=C(O)c1cc(F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A 2 dram vial was charged with (3-fluorophenyl)boronic acid (168 mg, 1.2 mmol), 3-chloro-5-fluorobenzoic acid (175 mg, 1.0 mmol), potassium carbonate (345 mg, 2.5 mmol), palladium acetate (1.1 mg, 0.005 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxy-3-sulfonato-1,1′-biphenyl hydrate sodium salt (5 mg, 0.01 mmol). The vial was fitted with a septum cap, degassed water (1.5 mL) was added and the mixture was purged with nitrogen and stirred at room temperature. After stirring for 4 d, the mixture was diluted with water (30 mL), acidified to pH 4 with 1.0 N aqueous HCl and extracted with EtOAc (3×25 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 235 mg (quant.) of 3′,5-difluoro-[1,1′-biphenyl]-3-carboxylic acid which was used without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:35][C:36]([CH3:38])=[O:37].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[OH:37][C:36]([CH3:38])([CH3:35])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:15][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CN3CCOCC3)cc2)c(OC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccc(CN2CCOCC2)cc1)S(N)(=O)=O
Reaction time: 0.08 h

Procedure:
Under inert gas, 0.410 g of N-(2,4-dimethoxybenzyl)-C-(4-morpholin-4-ylmethylphenyl)methanesulfonamide was initially charged in 5 ml of THF and then, at −78° C., 1.34 ml of a 1.6 N butyllithium solution in hexane were added dropwise. The reaction mixture was stirred for 5 minutes and then 0.29 ml of acetone was added dropwise. The mixture was stirred at constant temperature for 5 minutes, 0.22 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 2 ml of trifluoroacetic acid were added. After stirring at room temperature for 16 h, 20 ml of 1M HCl were added and the aqueous phase was removed and concentrated. This gave the crude product with a molecular weight of 364.9 g/mol (C15H25N2O4S), which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)=[CH:3][CH:2]=1.[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH2:28])=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH:28][C:11]2[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:13][N:12]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCSCc1ncccc1Br
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1ccncc1

Procedure:
5-(4-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.1 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.15 g) according to the procedure of Example 2. The reaction mixture was triturated under hot water to give 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. This product was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue crystallised from ethanol to give the title compound m.p. 211°-215° (decomp).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.CC(CCCCCCCCCCCCC(O)=O)C.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56]CC2)CCCCC1>O1CCCC1>[CH3:1][N:50]([C:51]1[CH:56]=[CH:57][CH:58]=[CH:53][N:52]=1)[CH3:44]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)CCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 878 mg of isopalmitic acid, 20 ml of dry tetrahydrofuran, 848 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 1.12 g of the title compound were obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a mixture of 4-iodopyrazole (Aldrich, Buchs, Switzerland, 10 g, 51.6 mmol) and Cs2CO3 (20.16 g 61.9 mmol) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (Aldrich, Buchs, Switzerland, 9.74 ml, 61.9 mmol). The RM was stirred at 70° C. for 17 h. Then the RM was quenched with water (100 ml) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (hexane/EtOAc 0% to 30%). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC: tR 3.12 min (Method A); M+H=323 MS-ES)
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][C@@H:9]([C:21]([NH:23][C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:25][O:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])=[O:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:32][O:31][CH:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][C@@H:24]([C:33]([O:35][CH3:36])=[O:34])[NH:23][C:21](=[O:22])[C@H:9]([CH2:8][CH2:7][OH:6])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of N-[O-[(1,1-dimethylethyl)dimethylsilyl]-N-[(phenylmethoxy)carbonyl]-L-homoseryl]-O-(2,2-dimethoxyethyl)-L-serine, methyl ester [5.56 g, 10 mmol, prepared as described in Example 10(h)] in methanol (65 ml) was cooled to 0° C. (ice salt bath), treated with p-toluenesulfonic acid monohydrate (386 mg, 2.0 mmol) and stirred at 0° C. for 1.5 hours. The reaction was quenched with sodium bicarbonate solution (198 mg. in 20 ml water), stirred for 5 minutes then evaporated to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×200 ml) and the combined organic extract was washed with water (110 ml), 5% sodium bicarbonate (80 ml) and brine (80 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on silica gel column (Merck), eluting the column with ethyl acetate:hexane (2:1) and ethyl acetate:methanol (98:2) to give 3.975 g of title product as a syrup. TLC (ethyl acetate:hexane, 4:1) Rf =0.17.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:16]([F:27])[CH:15]=2)[N:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:16]([F:27])[CH:15]=2)[N:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OCC(C)C)c(Cn3nc(C)cc3C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(Cc2cc(COc3ccc(CCC(=O)O)c(F)c3)ccc2OCC(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a mixed solution of ethyl 3-[4-({3-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-4-isobutoxybenzyl}oxy)-2-fluorophenyl]propanoate (0.37 g, 0.77 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (0.25 g, yield 56%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.CN(C)C=[O:34].C(OO)(C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:19])[F:20])=[C:16]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][C:6]2=[O:34]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)(C)OO
Solvent: CC#N
Product: COc1ccc2c(c1)C(=O)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 50 °C
Yield: 36 %

Procedure:
To a stirred solution of 7-methoxy-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 66A, 0.103 g, 0.250 mmol) and cuprous iodide (0.476 mg, 0.0025 mmol) in acetonitrile (2.0 mL) at room temperature [note: the reactant was sparingly soluble in acetonitrile, so dimethyl formamide (0.5 ml) was added to solubilize the reactant] was added t-butyl hydroperoxide (0.250 mL, 1.50 mmoL). The reaction mixture was heated at 50° C. overnight. An additional aliquot of t-butyl hydroperoxide (0.250 mL, 1.50 mmol) was added, and the reaction was heated at 50° C. overnight. A small change in the amount of product was noted, so an additional aliquot of t-butyl hydroperoxide (0.250 mL, 1.50 mmol) was added. The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo, and the crude mixture was chromatographed using reverse-phase preparative HPLC to give the product [39 mg, 0.094 mmol, 36% yield] as a tan solid. The product had an HPLC ret. time=3.90 min. (condition B). LC/MS M+1=427.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].II.[CH2:13]([O:20][C:21]1[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[CH:24]=[C:23]([CH3:30])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:20][C:21]1[C:26]([CH:27]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:28])=[C:25]([CH3:29])[CH:24]=[C:23]([CH3:30])[N:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(C)cc(C)nc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A Grignard reagent (0.5 mol/L solution in tetrahydrofuran) was prepared in the usual way from 4-bromoanisole, magnesium, a catalytic amount of iodine and tetrahydrofuran. The obtained Grignard reagent (0.41 mL) was added to a solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.019 g) in tetrahydrofuran (0.8 mL), and the mixture was stirred for 80 minutes at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=4/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-Methoxyphenyl methanol (0.014 g) To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-methoxyphenyl methanol (0.014 g) in ethanol (1 mL) was added a catalytic amount of 10% palladium carbon powder, and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=10/1) to give 3-(4-methoxybenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.010 g).