Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: C1CCOC1
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Succinic acid (1.18 g, dissolved in 35 ml of acetone and 5 ml of water) is slowly added to a solution of Donepezil (3.79 g) in tetrahydrofuran (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 168.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[Br:13]Br.C(N(CC)CC)C>>[CH2:1]([O:3][C:4](=[O:12])/[C:5](/[Br:13])=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)/C=C/C1CCCC1
Reactant: BrBr
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(Br)=C/C1CCCC1
Yield: 65 %

Procedure:
Following the method of example 54b, reaction of (E)-3-cyclopentyl-acrylic acid ethyl ester (87 g, 520 mmol) with bromine (29.3 ml, 572 mmol) and triethylamine (90 ml, 650 mmol) affords the title product as an oil (83.5 g) GC-MS (m/e): 247 (M+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:44]1([CH:50]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[OH:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CCOCC.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:55]2[CH2:56][CH2:57][CH:52]([CH:50]([OH:51])[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:53][CH2:54]2)=[O:17])=[CH:19][CH:20]=1
Reactant: OC(c1ccccc1)C1CCNCC1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(C(O)c2ccccc2)CC1
Yield: 34.2 %

Procedure:
The following was added sequentially to anhydrous DMF (5 mL): 1-(4-fluorobenzyl)-1H-indole-2-carboxylic acid (0.119 g, 0.443 mmol), Hunig's Base (0.232 ml, 1.329 mmol), EDC (0.093 g, 0.487 mmol), HOBT (0.075 g, 0.487 mmol), and phenyl(piperidin-4-yl)methanol (0.085 g, 0.443 mmol). The solution was stirred at room temperature for 30 h, at which time a 1:1 solution of EtOAc:Et2O was added and washed with 10% aq. Na2CO3. The organic solution was dried with MgSO4 and concentrated in vacuo to give a residue that was purified by silica gel chromatography (45 g silica, 80% EtOAc/Hexanes) to give 67 mg of the title compound.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:3]2[CH2:2][CH:1]3[N:8]([CH2:10][CH2:11][C:12]4[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=4)[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: C1CC2CNCC1N2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CC3CCC(C2)N3CCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3,8-diazabicyclo[3.2.1]octane (55 mg, 0.49 mmol), 1-(2-bromoethyl)-4-nitrobenzene (340 mg, 1.5 mmol), tetrabutylammonium iodide (18 mg, 0.049 mmol), and K2CO3 (270 mg, 2.0 mmol) in DMF (2 mL) was heated to 80° C. for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 411 [M+1]+. (0.19 μM)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=O)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:11][O:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COC(=O)CCCCC(=O)Nc1ccccc1
Product: COC(=O)CCCCc1nc2ccccc2n1-c1ccccc1
Yield: 88.2 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 5-phenylcarbamoyl-pentanoic acid methyl ester (141 mg, 0.6 mmol) yielded the title compound as brown oil (136 mg, 88%). 1H NMR (DMSO) δ 1.50-1.74 (m, 4H), 2.27 (d, J=7.2Hz, 2H), 2.89 (d, J=7.5Hz, 2H), 3.52 (s, 3H), 7.22 (d, J=8.1Hz, 1H), 7.38 (apparent t, J=7.6Hz, 1H), 7.46 (apparent t, J=7.6Hz, 1H), 7.52-7.72 (m, 5H), 7.79 (d, J=7.8 Hz, 1H); 13C NMR δ 23.3, 25.3, 25.4, 32.2, 50.9, 111.3, 115.6, 124.3, 124.4, 126.8, 130.0, 132.4, 133.2, 133.4, 153.9, 172.3. HRMS (FAB): cal. for C19H21N2O2 [M+H+]: 309.1603; found: 309.1595.
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][S:19][C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]4=[N:22][N:21]=3)[CH2:13][CH2:12]2)(=O)=O)=CC=1.[OH-].[Na+]>Cl>[N:14]1([CH2:17][CH2:18][S:19][C:20]2[N:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]3=[N:22][N:21]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(CCSc3nnc4ccccn34)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccn2c(SCCN3CCNCC3)nnc2c1
Yield: 81.2 %

Procedure:
73 g of 3-[2-(4-(4-methylphenylsulfonyl)piperazin-1-yl)ethylmercapto]-1,2,4-triazolo(4,3-a)pyridine, prepared in Example 78, are dissolved in 360 ml of a concentrated solution of hydrochloric acid and the resulting solution is heated under reflux for 8 hours. After cooling, it is neutralized with sodium hydroxide and extracted with chloroform. The chloroform phase is dried over magnesium sulfate and concentrated in vacuo to give 37.4 g of 3-[2-(piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine in the form of an oil which crystallizes from acetone. M.p.=104° C.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[CH2:12][C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[F:19][C:13]1([F:18])[CH2:12][C:11]2[C:10]3[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)CC(F)(F)C3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: FC1(F)Cc2ccc3c(c2C1)CCNCC3
Temperature: 60 °C
Yield: 57.6 %

Procedure:
To a stirred solution of the product from step (c) (20 mg, 0.07 mmol) in chloroform (2 ml) was added TMSI (0.092 ml, 0.7 mmol). The reaction mixture was heated to 60° C. for 6 hours after which LCMS indicated no starting material. The reaction mixture was cooled to RT and the volatiles were removed in vacuo. The residue was dissolved in 1N HCl (10 ml) and washed with diethyl ether (3×). The aqueous layer pH was then adjusted to 12 by addition of 2M NaOH. The aqueous mixture was then extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the titled compound as a colorless oil (9 mg). 1H NMR (300 MHz, CDCl3) δ 6.99 (d, J=7.8 Hz, 1H); 6.96 (d, 7.8 Hz, 1H); 3.47-3.34 (m, 4H); 2.98-2.82 (m, 8H); 2.09 (bs, 1H); MS: ESI (positive): 224 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[NH:17]1[C:25](=[O:26])[C:23](=[O:24])[C:21](=[O:22])[NH:20][C:18]1=[O:19].Cl>CCCCCC.O1CCCC1>[OH:24][C:23]1([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[C:21](=[O:22])[NH:20][C:18](=[O:19])[NH:17][C:25]1=[O:26]
Reactant: c1ccc(-c2ccco2)cc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NC(=O)C(O)(c2ccc(-c3ccccc3)o2)C(=O)N1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
2-Phenylfuran (5.76 g., 40 mmoles) was combined with 100 ml. of tetrahydrofuran and cooled to -30° C. Butyl lithium in hexane (2.3 M, 19.1 ml.) was added dropwise over 5 minutes, keeping the temperature between -20° and -30° C. The reaction mixture was allowed to warm to room temperature and then recooled to -30° C. Sublimed alloxan (5.96 g., 42 mmoles) in 40 ml. of tetrahydrofuran was added over 5 minutes, again keeping the temperature -20° to -30° C. The reaction mixture was again allowed to warm to room temperature, then recooled to 0° C. and 50 ml. of 1 N hydrochloric acid added portionwise over 2-3 minutes. The quenched reaction mixture was extracted with 100 ml. of ethyl acetate. The extract was filtered through a bed of anhydrous magnesium sulfate, and evaporated to yield 5-hydroxy-5-(5 -phenyl-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione [9.4 g., gummy solid, Rf 0.75 (1:1 hexane ethyl acetate/5% acetic acid)] contaminated with starting material (Rf 0.45).
Reaction SMILES: [Li][CH3:2].[CH:3]12[O:8][CH:7]1[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:4]2>CCOCC.[Cu]I>[OH:8][C@H:7]1[C@H:3]([CH3:2])[CH2:4][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of CuI (10.2 g, 54 mmol) in ether (120 mL) at −10° C. was added dropwise MeLi (73 mL, 109 mmol, 1.5 M in ether) ensuring that the temperature remained below −5° C. The resulting solution was stirred at −10° C. for 20 min and a solution of phenylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (Example 113) (5 g, 23 mmol) in ether (50 mL) was added, maintaining the temperature below −2° C. The reaction was stirred at −10° C. for 1 hour after which time it was quenched with water and partitioned with DCM. A standard work up yielded phenylmethyl (trans)-3-hydroxy-4-methyl-1-pyrrolidinecarboxylate, which was purified and subjected to chiral chromatography, producing two enantiopure compounds of undetermined absolute stereochemistry. (Yield of E1=1.55 g, yield of E2=1.58 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Br.[NH:17]([C:19]1[S:20][CH2:21][CH2:22][N:23]=1)[NH2:18].C([O-])(=O)C.[Na+]>C(O)C>[S:20]1[CH2:21][CH2:22][NH:23][C:19]1=[N:17][N:18]=[C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[NH:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: NNC1=NCCS1
Reactant: Clc1c2ccccc2nc2ccccc12
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2c(=NN=C3NCCS3)c3ccccc3[nH]c2c1

Procedure:
1.0 g of 9-chloroacridine, 0.926 g of 2-hydrazino-2-thiazoline hydrobromide and 0.767 g of anhydrous sodium acetate are dissolved in 100 ml of dry ethanol, heated to boiling under reflux for 2 hours and the red solution is then evaporated in vacuo. The residue is treated with water and the crystalline mass is filtered under suction. After recrystallization from ethanol, there is obtained 9-acridanone (2-thiazolidinylidene)hydrazone of melting point 212°-216° (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[N:4]=1.[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:10]=2)[N:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CN(CC(=O)OC(C)(C)C)c1nccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(CC(=O)OC(C)(C)C)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 47.6 %

Procedure:
tert-Butyl [methyl(6-cyano-2-pyrimidinyl)amino]acetate (1.63 g, 6.56 mmol) and methyl thiosalicylate (3.31 g, 19.7 mmol) were dissolved in toluene (50 ml), and triethylamine (2.76 ml, 19.7 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.20 g, 39%) as pale yellow crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:8]2[CH:16]=[N:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:26])=O.CN(C)C=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:8]2[CH:16]=[N:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:26])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccncc1N(C(=O)C(F)(F)F)C1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccncc1N(C(=O)C(F)(F)F)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinic acid (350 mg, 1.1 mmol) in dry dichloromethane (15 mL) and oxalyl chloride (0.65 mL, 6.6 mmol, 6 eq) a drop of N,N-dimethylformamide was added. The mixture was stirred at room temperature for 1 h and then evaporated to dryness affording the crude title compound that was used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][O-].[Na+].C(O)(=O)C>O>[Cl:18][C:7]1[C:6]([OH:9])=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1
Reactant: [O-]Cl
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 188.8 %

Procedure:
A solution of 6-(trifluoromethyl)pyridine-3-ol (7 g, 40 mmol) and sodium carbonate (4.5 g, 4.2 mmol) in water (200 mL) was cooled in an ice bath. 0.7N Sodium hypochlorite solution (63.9 mL, 4.29 mmol) was added portionwise over 30 minutes, and the reaction stirred at 0° C. for 2 hours. The reaction mixture was acidified using acetic acid, and extracted into EtOAc (3×50 mL). The combined organics were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated. The product was purified by flash chromatography (0 to 25% EtOAc in hexanes) giving the title compound (1.6 g, 20%) as a solid. 1H NMR (400 MHz; CDCl3) δ 7.61 (1H, d), 7.45 (1H, d), 5.83 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1C=O

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (1.2 g, 4.5 mmol) was treated with 4-methylmorpholine N-oxide (0.786 g, 6.7 mmol) and tetrapropylammonium perruthenate (catalytic) in CH2Cl2. Standard workup procedure afforded the title compound.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].C1(C)C=CC=CC=1.[ClH:43]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O>[Cl:43][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 7 h

Procedure:
To the same three-necked flask were added 5 g of a commercially available D-glucose and two kinds of surface active agent, i.e., 97.6 mg of sodium laurylbenzenesulfonate and 89.6 mg of cetyltrimethylammonium chloride. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for 25 minutes. Stirring was continued at 50° C. for a further 7 hours. The reaction solution was diluted with a little water and filtered through Celite while being washed with toluene. The toluene layer was treated in the same manner to obtain about 1.7 g of 5-chloromethylfurfural.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[C:7]([F:20])=[CH:6][C:4]([NH:5][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=3)=[CH:3][C:2]=2[F:1])[NH:16][CH:17]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nccc(Nc2cc(F)c(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
200 mg (0.67 mmol) of 3,5-difluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 88 mg (0.67 mmol) of 4-chloropyrimidine-2-amine are suspended in 6 ml of water/ethanol 1:1. 69 μl (0.81 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux for 3 h. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: [Br:1][CH:2]1[C:7]2([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][C:4]([CH:17]=[CH:18][O:19][CH3:20])([CH2:5][O:6]2)[CH2:3]1.[Cr](Cl)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[CH3:20][O:19][C:18](=[O:22])[CH2:17][C:4]12[CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)([CH:2]([Br:1])[CH2:3]1)[O:6][CH2:5]2
Reactant: COC=CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a stirred solution of the cis and trans mixtures of 6-bromo-1-(4-chloro-phenyl)-4-(2-methoxy-vinyl)-2-oxa-bicyclo[2.2.2]octane (1.7 g, 4.75 mmol) in dichloromethane (12 ml) and tetrahydrofuran (25 ml) at room temperature, was portionally added pyridinium chlorochromate (3.07 g, 14.26 mmol). The reaction mixture was stirred at room temperature for 2 hours. More pyridinium chlorochromate (2.05 g, 9.51 mmol) was added, and the mixture was stirred for another 60 hours at room temperature. The mixture was filtrated and the filtrate was concentrated, and diluted with ethyl acetate (100 ml). The organic phase was washed with water, brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (heptanes/acetone 2/1) to afford [6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acetic acid methyl ester (1.08 g, 61%) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.79 (m, 1H) 1.87-1.98 (m, 1H) 2.01-2.11 (m, 1H) 2.14 (s, 2H) 2.23-2.30 (m, 1H) 2.52-2.63 (m, 1H) 2.75-2.87 (m, 1H) 3.62 (s, 3H) 3.84 (dd, J=10.11, 2.65 Hz, 2H) 4.19-4.29 (m, 1H) 7.23 (d, J=8.80 Hz, 2H) 7.33 (d, J=8.80 Hz, 2H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:23]=[C:22]([CH3:24])[C:12]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)=[C:11]([CH3:25])[CH:10]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:23]=[C:22]([CH3:24])[C:12]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)=[C:11]([CH3:25])[CH:10]=1
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1OCC1CCCN(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(O)cc(C)c1OCC1CCCN(C)C1
Reaction time: 8 h

Procedure:
To a solution of 3-[4-(tert-butyidimethylsilyloxy)-2,6dimethylphenoxymethyl]-1-methylpiperidine (3.2 g, 8.8 mmol) in tetrahydrofuran (50 mL) containing 20% acetic acid (5.5 mL, 19 mmol) at 0° C. was added 1M tetrabutylammonium fluoride in tetrahydrofuran (17.5 mL). The mixture was stirred from 0° C. to room temperature overnight and concentrated in vacua. The residue was partitioned between water and dichloromethane. The organic layer was dried and concentrated and the residue purified on silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, to give 3-(4-hydroxy-2,6-dimethylphenoxymethyl)-1 -methylpiperidine.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:11]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (207 mg, 0.40 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture stirred for 2 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a white foam (131 mg, 80%). LCMS (method H): RT 1.81 min [M+H]+ 419.4
Reaction SMILES: CO[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])/[CH:5]=[CH:6]\[C:7]([O:9]C)=O.CN(C=O)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:7](=[O:9])[CH:6]=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC=C(/C=C\C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(=O)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 250 mL round-bottomed flask was charged with (Z)-dimethyl 4-(methoxymethylene)pent-2-enedioate (2.70 g, 13.5 mmol) and 50 mL of DMF. 4-fluorobenzenamine (1.43 ml, 14.8 mmol) was added dropwise at rt. After stirring at rt for 15 min, the yellow mixture was heated to reflux overnight. The reaction was then diluted with water (200 mL) and extracted with ether (3×100 mL). The combined extracts were dried with MgSO4 and concentrated to give a solid. Purification by MPLC gave methyl 1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:37])([CH2:29][S:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(N2CC(O)(CSc3ccccc3)N=C2c2ccc(Cl)cc2)cc1

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in acetone (20 mL), 1-bromo-3-phenylthio-2-propanone (1.5 mmol) is added. After heating to reflux for 24 hours, the reaction mixture is filtered, washed with acetone and concentrated in vacuo. The crude product is chromatographed (silica gel, toluene/ethyl acetate) to give 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl) phenyl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole.