Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH:38]CC2C=CC(OC)=CC=2)[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.O>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:14]([O:13][C:11]([NH:10][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH2:38])[N:27]=1)=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c3cc(OC)ccc3n2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Reaction time: 9 h
Yield: 66.2 %

Procedure:
A solution of 1.76 g of (1R,2S)-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-methoxybenzylamino)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 80 mL of methylene chloride was combined with 3.17 g of N-methylmorpholine-N-oxide and 95 mg of tetrapropylammonium perruthenate, and stirred for 9 hours. The reaction solution was combined with water, extracted with methylene chloride, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 10:1) to obtain 0.95 g of the desirable compound.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=2)/[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)=[N:12][N:11]=[C:9]12)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCn1/c(=N/NC(=O)CCCc2nc(-c3ccccc3)no2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
The mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanohydrazide (2.78 g, 6.17 mmol) in toluene (100 ml) was refluxed for 2 hours. After cooling to room temperature, the solid was filtered, washed with ethyl acetate/Hexane (1:9) and dried to give the desired product (1.97 g, 74% yield). LCMS calculated for C22H25N8O2 (M+H): 433.2. found: 433.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1cc(Cl)ccc1F
Temperature: 0 °C
Yield: 71 %

Procedure:
To a solution of 5-chloro-2-fluorobenzaldehyde (1 g, 6.3 mmol) in diethyl ether (20 mL) cooled at −78° C. was added a solution of 3.0M ethylmagnesium bromide in ether (4.2 mL, 13 mmol) dropwise over 5 minutes. The reaction mixture was warmed to 0° C. and after 30 minutes was quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (850 mg, 71%), which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[C:15]([CH3:21])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=2)=[O:13])[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:20][C:18]1[CH:17]=[N:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[C:12]([NH:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(Cl)cnc2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trans-4-[(5-Chloro-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester (step 2) (2.20 g, 7.08 mmol) is placed in a flask with dry THF (100 mL). This is cooled to 0° C. and lithium aluminum hydride (0.537 g, 14.16 mmol) is added. The reaction mixture is stirred at r.t. for 2 hours and then quenched with water (0.5 mL), 2M NaOH (0.5 mL) and then water again (1.5 mL). The solids are filtered off through Celite® (filter material) and the filtrate is partitioned between EtOAc and water. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.38 *1H, d), 7.79 (1H, d), 4.40 (1H, t), 3.66 (1H, m), 3.21 (2H, t), 2.47 (3H, s), 1.92 (2H, m), 1.78 (2H, m), 1.31 (1H, m), 1.22 (2H, m), 0.98 (2H, m). [MH]+ 283.30.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:15][C:14]=1[OH:27])=[O:12]>CC(C)=O>[CH2:7]([O:27][C:14]1[CH:15]=[C:16]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:17]=[CH:18][C:13]=1[CH:11]=[O:12])[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Reaction time: 2 h
Yield: 73.5 %

Procedure:
Potassium carbonate (1.6 g, 11.5 mmol) and allyl bromide (1 ml, 11.5 mmol) were added to a solution of trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester (1.55 g, 5.7 mmol) in acetone (50 ml). The reaction mixture was stirred at 55 C for 2 h, filtered and evaporated in vacuo. The residue was chromatographed (silica gel, EA:Hex, 1:20) to give 1.3 g (73%) of trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([CH:15]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:25](=[O:37])[C:24]2=[O:38])[CH2:16][CH2:17][CH:18]([F:20])[F:19])=[O:14])[CH3:11]>O1CCCC1>[C:33]([O:32][C:30]([NH:26][C:27]1[CH:28]=[CH:29][C:21]([CH:15]([CH2:16][CH2:17][CH:18]([F:19])[F:20])[C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:22][C:23]=1[C:24](=[O:38])[C:25]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:37])=[O:31])([CH3:35])([CH3:34])[CH3:36]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)C(CCC(F)F)c1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(F)F)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
1.53 g of isoindoline are added to 5.29 g of 5-(1-ethoxycarbonyl-4,4-difluorobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline in 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 1.7 g (25%) of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-5,5-difluoropentanoate; LC-MS retention time: 2.62 min (“nonpolar” gradient).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1[O:31][C:30]2[C:25](=[CH:26][CH:27]=[C-:28][CH:29]=2)[O:24]1.[Mg+2].[Br-].C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([CH:21]([OH:22])[CH2:20][C:10]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([Cl:19])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Reactant: [c-]1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.380 mmol) in tetrahydrofuran (4 mL) at −78° C. was dropwise added a 1M solution of 3,4-(methylenedioxy)phenylmagnesium bromide in 1:1 toluene/tetrahydrofuran (0.380 mmol, 1.0 eq.) and stirring at −78° C. was continued for 10 min. The reaction mixture was then allowed to warm to room temperature and was stirred 1 h then quenched with saturated aqueous sodium bicarbonate solution (2 mL). After stirring 15 min the reaction mixture was extracted with ethyl acetate (3×5 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give a brown oil that was purified by column chromatography using 30% ethyl acetate/hexanes to give the final product as a white foam (0.126 mmol, 33%). MS (ESI) m/z 434.2; HRMS: calcd for C25H20ClNO4+H+, 434.11536; found (ESI, [M+H]+ Obs'd), 434.1150.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](Cl)=[O:8]>O.[OH-].[Na+]>[Cl:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([NH:2][OH:3])=[O:8]
Reactant: NO
Reactant: CC(C)(CCl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CCl)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydroxylamine hydrochloride (50.0 g, 0.7195 mol) in 150 mL of water, 50% aqueous sodium hydroxide solution is added dropwise until a pH of 7.0-7.2 is obtained. The solution is cooled to 20°-25° C. and 3-chloropivaloyl chloride (100.0 g, 0.6426 mol) is added dropwise maintaining a pH of 7.0-7.2 with 50% aqueous sodium hydroxide solution and a reaction pot temperature <30° C. The total addition time is 1 hour. This yellow slurry is stirred at room temperature overnight then diluted with water (200 mL). The hydroxamic acid is extracted with ethyl acetate (2×200 mL) and washed with water (200 mL). The organic layer is dried over magnesium sulfate and concentrated to 46.3 g of the title compound as a yellow solid and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:18][CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:20]=2)=[CH:24][CH:23]=1
Reactant: CCC1(c2cccs2)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1ccc(Br)cc1
Product: CCC1(c2cccs2)OC(=O)N(C)c2ccc(Nc3ccc(Br)cc3)cc21

Procedure:
Prepared 6-amino-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in Example 1. MS (ESI) m/z 443/445 ([M+H]+); MS (ESI) m/z 441/443 ([M−H]−); Anal. calcd for C21H19BrN2O2S: C, 56.89; H 4.32; N 6.32. Found: C, 56.65; H, 4.09; N, 6.18.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:24](Br)[CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:24][CH2:25][OH:26]
Reactant: Cc1c(SCCCN)ccnc1CSc1nc2ccccc2[nH]1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(SCCCNCCO)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
2-((3-Methyl-4-(3-aminopropylthio)-2-pyridyl)methylthio)1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (20 ml) and thereto were added ethylene bromohydrin (0.83 g) and potassium carbonate (1.25 g). The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The residue was subjected to column chromatography and extracted with chloroform-methanol to give 2-((3-methyl-4-(3-(2-hydroxyethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH2:9][CH3:10])[NH:4][N:3]=1.CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O>C(O)(=O)C>[CH2:9]([C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:3]2[N:4]=1)[CH3:10]
Reactant: CCc1[nH]nc(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: CCc1nn2c(-c3cccnc3)ccnc2c1C#N

Procedure:
As for Example 2, 2.72 g. of 3-amino-5-ethylpyrazole-4-carbonitrile is heated at reflux temperature for 16 hours with 3.52 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 2.65 g. of the product of the example as colorless crystals, m.p. 170°-172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:26]1[CH2:30][CH:29]=[N:28][C:27]1=[O:31]>>[C:7]([C:6]1[CH:9]=[C:2]([N:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: O=C1N=CCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C#N)CC2)c(C)c1
Yield: 80.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 193 and oxazolin-2-one (104 mg), the title compound (327 mg) was obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:33]([F:36])([F:35])[F:34])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([C:33]([F:34])([F:35])[F:36])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.25 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as a white solid (0.13 g, 26%). MS (ISN) 495.2 [(M−H)−]; mp 290° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O.C1(C)C=CC=CC=1>[C:17]1([CH2:16][O:15][C:13]([NH:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer and internal thermometer, sodium hydroxide (61.65 g, 1.541 mol) was dissolved in distilled water (1000 ml). To this solution, L-methionine (100.0 g, 0.670 mol) was added at room temperature. The solution was cooled in an ice bath (internal temperature 30° C.) and benzyl chloroformate (110 ml, 0.737 mol) was added over 10 minutes. After a 15 minute induction period, the internal temperature rose from 3° C. to 12° C. over 30 minutes and then dropped to 0° C. over 15 minutes. The reaction was stirred at 0° C. for 2 hours, during which time the initially cloudy reaction mixture became homogeneous. The ice bath was removed, and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was transferred into a separatory funnel and washed with hexane (2×300 ml). The aqueous layer was acidified with 6N hydrochloric acid to pH 5 and diluted with ethyl acetate (600 ml). The mixture was further acidified to pH 2. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×600 ml). The organic extracts were combined and washed with brine (750 ml), dried (magnesium sulfate), filtered and concentrated in vacuo to produce a light yellow oil. The crude product (oil) was dissolved in toluene (1500 ml), and the solution was concentrated to half of its volume. A second portion of toluene (750 ml) was added, and concentrated again such that 630 ml of toluene remained. This solution was stored at 5° C. overnight, during which time some of the product crystallized from solution. The solid was redissolved by warming to room temperature. Toluene (134 ml) was then added (a few seed crystals remained). With mechanical stirring, heptane (500 ml) was added in 30 ml portions at 10 minute intervals (approximately 3 hours total addition time). At this point, the product started to crystallize from solution. An additional portion of heptane (1020 ml) was added over 1.5 hours, and the resulting slurry was stirred for 2 hours. The product was collected by vacuum filtration, washed with 1:2 toluene:heptane (3×150 ml) and heptane (3×500 ml) and air-dried to give 158.6 g of title product as a white solid; m.p. 66° C.; [α]D =-1.5° (c=1, 95% ethanol). TLC (ethanol:water, 3:1) Rf =0.78.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1.[H-].[Na+].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C)C=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([N:4]3[C:5]([CH3:7])=[CH:6][C:2]([O:1][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3]3)=[CH:9]2)=[CH:14][CH:13]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc2ccc(-n3nc(O)cc3C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(-n3nc(OCCN4CCOCC4)cc3C)cc2c1
Temperature: 60 °C
Yield: 81.3 %

Procedure:
To a solution of 3-hydroxy-5-methyl-1-(7-methoxynaphthalen-2-yl)-1H-pyrazol (1.51 g, 5.96 mmol) in dimethylformamide (40 ml), cooled down to 0° C., a dispersion in mineral oil at 60% of NaH (0.36 g, 8.94 mmol) was added, the cooling bath was removed, and was left to stirring until it recovered the room temperature (1.5 hrs). Subsequently, 2-chloroethylmorpholine (1.02 g, 6.85 mmol) dissolved in DMF (10 ml) was added dropwise, and the resulting mixture was heated at 60° C. during 20 hrs. Water-ice was added and it was evaporated to dryness in a rotavapor. The resulting slurry was divided between water and ethyl ether. The aqueous phase was newly extracted with a solvent, and the collection of organic phases was washed with water, dried over sodium sulfate, filtered, and evaporated yielding 2.19 g of a crude product, which was purified by crystallization of its chlorhydrate (prepared by dissolving in HCl-saturated dioxane) in isopropyl alcohol-ethyl ether. 1.78 g (74%) of the 4-{2-[1-(7-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine chlorhydrate were obtained as a solid with a m.p.=143-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[C:7]([Cl:9])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1cc(Br)c(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromopyridin-2-amine (500 mg, 2.89 mmol) in N,N-dimethylformamide (5 mL) was added N-chlorosuccinimide (463 mg, 3.47 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was filtered through diatomaceous earth and concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude title compound. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]Cl)[O:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:18]=[N+]=[N-].[Na+]>CN(C)C=O>[Si:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][NH2:18])[O:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Oc1coc(CCl)cc1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1coc(CN)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved (5-tert-butyldimethylsilyloxy-4-oxo-4H-pyran-2-yl)methyl chloride (2.00 g). Sodium azide (1.00 g) was added to the resulting solution and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, followed by washing once with water and then once with saturated aqueous NaCl solution. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in methanol (100 ml), followed by the addition of 10% palladium-carbon (50% wet w/w, 800 mg). The resulting mixture was stirred overnight under a hydrogen gas stream of normal pressure. The reaction mixture was subjected to Celite filtration, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column (methylene chloride methanol=100:3), whereby the title compound (290 mg) was obtained as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=1[OH:18])[CH2:8]2.[CH3:19]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=1[O:18][CH3:19])[CH2:9]2
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(I)ccc1C1C2CC3CC(C2)CC1C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(I)ccc1C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 2-adamantyl-5-iodophenol (7.70 g, 21.7 mmol) in acetone (100 mL) was treated with dimethylsulfate (4.11 g, 32.6 mmol) and potassium carbonate (4.50 g, 32.6 mmol). The reaction mixture was stirred at reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The crude product was partitioned between methylene chloride and water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide 6.5 g (81%) of 2-adamantyl-5-iodoanisole; 1H NMR (300 MHz, CDCl3) δ 7.22 (dd, J=2, 8 Hz, 1H, ArH), 7.10 (d, J=2 Hz, 1H, ArH), 6.89 (d, J=8 Hz, 1H, ArH), 3.79 (s, 3H, OCH3), 2.02 (s, 9H, adamantyl), and 1.73 (s, 6H, adamantyl); 13C NMR (75 MHz, CDCl3) δ 159.35, 138.43, 129.63, 128.25, 120.75, 91.20, 55.22 (OCH3), 40.35, 37.02, 36.92, and 28.97; MS (DCI) m/e 369 (MH+), 368 (M+), 367 (M--H)+, 135 (C10H15+). Anal. Calcd for C17H21OI: C, 55.45; H, 5.75. Found: C, 55.51; H, 5.81.