Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]([CH2:32][S:33][C:34]4[S:35][CH:36]=[CH:37][N:38]=4)[O:21][C:20]3=[O:39])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-:40].[Li+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:40])[CH2:32][S:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[C:20]([OH:21])=[O:39])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3C(=O)OC(CSc4nccs4)C3OCc3ccccc3)cc2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)O)C(OCc3ccccc3)C(O)CSc3nccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-4-phenylmethoxy-5-[[(2-thiazolyl)thio]methyl]-tetrahydrofuran 63f, 154 mg, 0.258 mmol) is dissolved in THF/water (2 mL/2 mL) and lithium hydroxide (108 mg, 2.58 mmol) is added and the reaction is stirred for two hours at room temperature. The reaction is concentrated to remove the solvent, diluted with water and extracted (2 times) with ether. The aqueous layer is neutralized with 1N HCl to pH6 and extracted with ethyl acetate (3 times). The combined organic layer is washed with brine, dried over magnesium sulfate, and the solvent removed in vacuo. The crude material is adsorbed onto silica gel and purified over a short silica column eluting with hexane/ethyl acetate (1/1) followed with ethyl acetate and ethyl acetate/methanol (8/2). Product fractions are combined and dried to give the desired product as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][C:22]2[S:23][CH:24]=[N:25][N:26]=2)=[O:20])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[S:23]1[CH:24]=[N:25][N:26]=[C:22]1[NH:21][C:19]([C:18]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:4][CH:3]=2)[C:15]([CH3:14])=[CH:28][CH:27]=1)=[O:20]
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Reactant: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(C(=O)Nc4nncs4)ccc3C)cc2)n1

Procedure:
Example 27 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and 4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-([1,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23) using DMF as the solvent.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH:13]([CH2:15][CH3:16])[CH2:12][NH:11][CH2:10][C:9]=2[CH:17]=1)([O-])=O>CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH:13]([CH2:15][CH3:16])[CH2:12][NH:11][CH2:10][C:9]=2[CH:17]=1
Reactant: CCC1CNCc2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Solvent: CO
Product: CCC1CNCc2cc(N)ccc2O1

Procedure:
7-Nitro-2-ethyl-2,3,4,5-tetrahydro-1,4-benzoxazapine hydrochloride (3.4 g, 13.1 mmol) was dissolved in methanol (100 ml) and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd--C. After 1 h the mixture was filtered through glass and evaporated to an oil which was used immediately in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:14])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[N+:1]([C:4]1[CH:13]=[C:12]2[CH2:11][CH2:10][CH2:9][C:8]3=[N:15][NH:14][C:6]([CH:5]=1)=[C:7]23)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc2c1CCCC2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2c3c(n[nH]c3c1)CCC2
Reaction time: 20 h
Yield: 60.3 %

Procedure:
To a solution of 3-nitro-5,6,7,8-tetrahydro-naphthalen-1-ylamine (5.9 g, 31.0 mmol) prepared in Step A in glacial acetic acid (100 mL) was added a solution of sodium nitrite (2.13 g, 31.0 mmol) in water (5.0 mL) at 0° C., and the resultant dark solution was stirred at this temperature for 20 h. The volatiles were evaporated and the residue was basified with a saturated solution of sodium bicarbonate (100 mL). The aqueous was extracted with ethyl acetate (4×200 mL) and the combined extracts were washed with brine, dried (MgSO4) and evaporated to a residue that was purified by column chromatography (silica, 20% to 30% gradient of ethyl acetate in hexane) to give an oil (3.8 g, 60%): MS (ES) m/z 204 (M+); 1H NMR (CDCl3) δ 8.22 (1H,s), 7.77 (1H, s), 3.06 (4H, m), 2.26 (2H, m).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([O-])=O)=[CH:5][CH:4]=1.[Na+].[Cl-].[Na+].[C-]#[N:18].[Na+].O>CN(C)C=O.C(O)=O>[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][C:8]#[N:18])=[CH:5][CH:4]=1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(O)cc1
Temperature: 135 °C

Procedure:
A stirred suspension of sodium p-hydroxymandelate monohydrate (50 g. of 77% w/w material, the impurity being sodium chloride) and sodium cyanide (12.5 g.) in N,N-dimethylformamide (67.5 ml.) is heated at 135° C. for 2 hours and then cooled. Water (200 ml.) and formic acid (20 ml.) are added and the mixture is extracted twice with methyl isobutyl ketone (200 ml. and 100 ml.). The combined extracts are washed twice with water (50 ml. each time) and are then concentrated by evaporation. There is thus obtained a solution of p-hydroxybenzyl cyanide in methyl isobutyl ketone which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
A 5 liter round bottom flask, fitted with a reflux condensor, dropping funnel and mechanical stirrer, was charged with p-hydroxymethylbenzyl chloride (255 g, 1.91 moles) in dichloromethane (2 liters). The flask was charged with 2-methoxyethoxymethyl chloride (300 g, 2.41 moles) and stirred at 20°-25° C. while N,N-diisopropylethylamine (500 mL, 2.86 moles) was slowly added. The reaction became exothermic and caused the dichloromethane solvent to reflux vigorously for 20 minutes. The contents were then stirred for 24 hours at room temperature. The dichloromethane extract was washed with water and brine. The remaining organics were dried over anhydrous magnesium sulfate. After removal of the solvent by rotary evaporation, the residue was passed through a plug of silica gel to provide 310 g (67% yield) of the desired product. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.35 (m, 4H), 4.80 (s, 2H), 4.62 (s, 2H), 4.58 (s, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.4 (s, 3H).
Reaction SMILES: S(CO[CH:7]1[C:15]2[CH:14]=[CH:13][C:12]3[C:16]4[C:21]([CH:22]=[CH:23][C:11]=3[C:10]=2[NH:9][CH2:8]1)=CC=CC=4)(O)(=O)=O.C1CS(=O)(=O)[O:26][CH2:25]1>>[CH:25]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]3[CH:16]=[CH:21][CH:22]=[CH:23][C:11]3=2)[CH2:7][CH2:8]1)=[O:26]
Reactant: O=S1(=O)CCCO1
Reactant: O=S(=O)(O)COC1CNc2c1ccc1c2ccc2ccccc21
Product: O=CN1CCc2ccc3ccccc3c21

Procedure:
N-propylsulfonate naphthoindoline 102 (FIG. 19) was prepared by alkylation of 93 (FIG. 17) with 1,3-propane sultone with heating. Formyl-benzoindoline derivative 108 (FIG. 20) was prepared by formylation of 101 (FIG. 101) by the procedures of Example 17.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]Cl>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: CN(C)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Product: CN(C)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
When 3-(4-hydroxybenzoyl)-2-phenylbenzofuran is reacted with 3-dimethylaminopropyl chloride by the procedure described in Example 1, 3-[4-(3-dimethylaminopropoxy)benzoyl]-2-phenylbenzofuran is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][CH3:15])=[N:4][CH:5]=[C:6]([N+:11]([O-])=O)[C:7]=1[CH2:8][CH2:9][OH:10]>C(O)(=O)C.O.[Fe]>[NH2:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([Cl:1])[C:3]([S:14][CH3:15])=[N:4][CH:5]=1
Reactant: CSc1ncc([N+](=O)[O-])c(CCO)c1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ncc(N)c(CCO)c1Cl
Reaction time: 0.5 h

Procedure:
3-Chloro-4-(2-hydroxyethyl)-2-methylthio-5-nitropyridine (0.430 g, 1.73 mmol) was dissolved in a mixture of glacial acetic acid (30 ml) and water (15 ml), and was treated with iron powder (3.78 g, 0.068 mol) with stirring. After 0.5 h, the mixture was filtered through kieselguhr and the resultant yellow solution was evaporated under reduced pressure. The residue was partitioned between sodium bicarbonate solution and ethyl acetate. The biphasic suspension was filtered through kieselguhr, and the organic layer was dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a yellow solid, which was dried in vacuo (0.275 g, 73%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[CH2:20][CH:6]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][S:18][CH:19]=2)=[CH:11][CH:10]=1>C(O)(C)C>[CH:1]([NH:4][CH2:20][CH:6]([OH:5])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][S:18][CH:19]=2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: c1cc(-c2csnn2)ccc1OCC1CO1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(C)NCC(O)COc1ccc(-c2csnn2)cc1
Reaction time: 6 h

Procedure:
A mixture of 10 g. of isopropylamine, 2 g. of 4-[4(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole and 10 ml. of isopropanol is refluxed under stirring for 6 hours. The isopropanol and unreacted isopropylamine are then removed by distillation under vacuo. Crystallization of the residue from methanol-ether produces the pure 4-[4(3-isopropylamino-2hydroxypropoxy)phenyl]-1,2,3-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[Cl:14][C:15]1[S:19][C:18]([NH:20][S:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([C:33]#[N:34])[CH:25]=2)(=[O:23])=[O:22])=[N:17][CH:16]=1>>[Cl:14][C:15]1[S:19][C:18]([NH:20][S:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:2]([F:1])[CH:3]=3)=[O:29])=[C:26]([C:33]#[N:34])[CH:25]=2)(=[O:23])=[O:22])=[N:17][CH:16]=1
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)NCc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-fluoro-4-(trifluoromethyl)benzylamine and 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}-2-cyanobenzoic acid of Preparation 22, following Method O described for Example 344. The reaction mixture was stirred at room temperature for 18 hours.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][CH:2]([C:4]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(Br)c1nc2ccccc2c(=O)n1C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1nc2ccccc2c(=O)n1C
Temperature: 65 °C

Procedure:
A mixture of 2-(1-bromo-ethyl)-3-methyl-3H-quinazolin-4-one (801 mg, 3 mmol), 4-amino-1-N-Boc piperidine (661 mg, 3.3 mmol), potassium iodide (498 mg, 3 mmol) and potassium carbonate (622 mg, 4.5 mmol) in acetonitrile (12 mL) was heated at 65° C. for 3 days. The reaction mixture was then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium thiosulphate solution and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 4-[1-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester (HPLC ret. time 2.20, 10-99% CH3CN, 5 min run, ESI-MS m/z 387.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[Li]CCCC.CCCCCC.[Cl:23][C:24]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:25]=1[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:39]([O-:41])=[O:40])=[C:31]([CH:38]=1)[O:32][CH:33]([CH3:37])[C:34](Cl)=[O:35].Cl>O1CCCC1>[Cl:23][C:24]1[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][C:25]=1[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:39]([O-:41])=[O:40])=[C:31]([CH:38]=1)[O:32][CH:33]([CH3:37])[C:34](=[O:35])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:10]#[N:11]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.93 g of 2,4-dichlorophenylacetonitrile in 30 ml of anhydrous tetrahydrofuran (hereinafter abbreviated as "THF") was cooled to -78° C. To this solution was added 3.5 ml of a 1.6Mn BuLi-hexane solution. Then, a THF solution of 2.12 g of 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]propionic acid chloride was added thereto dropwise. The mixed solution was stirred for 30 minutes, then acidified with a 10% hydrochloric acid aqueous solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:3]=1.[F-:14].[Cs+].CS(C)=O>CCOC(C)=O>[F:14][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:3]=1
Reactant: Cc1cc(Cl)cc(-c2cncs2)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)cc(-c2cncs2)n1
Reaction time: 16 h

Procedure:
To a 2 dram vial equipped with a stir bar and charged with the entirety of 5-(4-chloro-6-methylpyridin-2-yl)thiazole from step 1 was added CsF (200 mg, 1.32 mmol) and DMSO (0.7 mL). The vial was capped and then placed in a 140° C. heating block with stirring for 16 h. The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with EtOAc (50 mL). The solution was twice washed with brine:water (25 mL:25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford an amber solid residue. This material was subjected to silica gel chromatography (hexanes:EtOAc) to afford 5-(4-fluoro-6-methylpyridin-2-yl)thiazole as a colorless solid (7.1 mg, 21% over two steps). 1H-NMR (500 MHz, CDCl3) 8.84 (d, J=0.3 Hz, 1H), 8.32 (d, J=0.3 Hz, 1H), 7.22 (dd, J=9.3, 1.7 Hz, 1H), 6.82 (dd, J=9.2, 2.0 Hz, 1H), 2.59 (s, 3H); MS: MS m/z 195.2 (M++1).
Reaction SMILES: [C:1]1([C:12]2[CH2:22]CCC[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)CCCCCCCCNN=1.[CH3:23][C:24]1(C)C2C=CC=CC=2[Se:26][NH:25]1>BrCC>[CH3:22][C:12]1([CH3:1])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[Se:26][N:25]1[CH2:24][CH3:23]
Reactant: CC1(C)N[Se]c2ccccc21
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCBr
Product: CCN1[Se]c2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 53 %

Procedure:
Diazabicycloundecene (380 mg; 2.5 mmole) was added to a solution of derivative 3,3-dimethyl-benzisoselenazoline (107 mg; 0.5 mmole) obtained above in bromoethane (1.5 ml). The mixture was stirred at room temperature for 10 h, then the same quantity of diazabicycloundecene was added again. After 14 h at room temperature, the bromoethane was evaporated off under reduced pressure. The desired product was obtained in the form of a very viscous yellow oil after purification by liquid chromatography on a silica column (eluent: cyclohexane-ethyl acetate, 6/1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21](O)=[C:16]2[CH:15]=[N:14]1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[CH3:6])[N:14]=[CH:15][C:16]=12
Reactant: Cc1ccncc1-n1ncc2c(O)ncnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccncc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Phosphorus oxychloride (5.10 ml, 54.75 mmol) was added to 1-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.622 g, 2.74 mmol). The resulting solution was stirred at 100° C. for 2 hours. The reaction mixture was evaporated. Toluene was added to the residue and the reaction mixture was concentrated. This was repeated to remove excess POCl3. The residue was dissolved in DMF (15 mL) and MP carbonate was added (˜3 g) and allowed to stir overnight. The DMF was evaporated in vacuo to afford crude product which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.1 (3H, s), 7.60 (1H, d), 8.65 (1H, d), 8.68 (1H, s), 8.82 (1H, s), 8.91 (1H, s); m/z (ES+) (M+H)+=246; HPLC tR=1.69 min.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[O:14]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[B:21]([OH:24])[OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1COc1ccccc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1COc1ccccc1
Reaction time: 2 h

Procedure:
90 ml of n-butyllithium (1.6 M) in solution in hexane are added dropwise at −70° C. to 36 g of 1-bromo-2-(phenoxymethyl)benzene, obtained in step 1.1, in solution in 150 ml of tetrahydrofuran. After 2 hours at −70° C., 16 ml of trimethyl borate are introduced dropwise. The temperature of the reaction medium is allowed to rise to −30° C. The medium is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulfate. After evaporation, 33 g of a white solid are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[C:16]([NH:19]N=NC)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:3]=1>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:3]=1
Reactant: CN=NNc1ccc2ncnc(Nc3cccc(C)c3)c2c1
Solvent: CS(C)=O
Product: Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Reaction time: 24 h

Procedure:
SMA41 (1 mg) was dissolved in DMSO (500 μL), added to RPMI with 10% fetal bovine serum (2 mL) and incubated for 24 h at 37° C. Thereafter, proteins were precipitated by the addition of acetonitrile (3.5 ml) and the supernatant collected by centrifugation. The concentration of SMA52 derived from the degradation of SMA41 was calculated using a standard curve obtained from the serial dilution of independently synthesized SMA52 incubated in serum-containing medium under identical conditions. HPLC analyses were performed on a Hewlett-Packard 1090 liquid chromatograph using a Deltapak C4 15 μm 300×3.9 mm column (reverse phase) to characterize and quantitate the products resulting from the degradation of SMA41. The operating mode was isocratic and two solutions, “A” (50% acetonitrile) and “B” (50% water), were used with a 0.5 ml/min flow rate and a 5 μL injection volume. Under these conditions, independently synthesized SMA52 and SMA41 showed retention times of 11 and 15 min, respectively. For the rapid quantitation of metabolite, a less polar acetonitrile-water (70:30) eluent was used. Under these conditions SMA52 showed a retention time of 7.49 min. For LC-MS analysis of the degradation of SMA41, the column was placed on a Spectra System P1500 HPLC coupled with a Finnigan LCQDUO mass spectrometer.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](OC)=[O:14])[C:7]([CH3:17])=[CH:6]2)#[N:2].[Li+].[BH4-]>C1COCC1>[OH:14][CH2:13][CH2:12][N:8]1[C:9]2[C:5](=[C:4]([C:18]([F:21])([F:19])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[CH3:17]
Reactant: COC(=O)Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCO
Reaction time: 2 h
Yield: 7.6 %

Procedure:
A solution of methyl [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetate (0.200 g, 6.76 mmol) in THF (5 mL) was cooled to 0° C. and treated with LiBH4 (0.51 mL, 2M in THF). After 2 h, the reaction was partitioned between Et2O and water. Drying (Na2SO4), filtration, and concentration was followed by column chromatography (SiO2, hexanes/EtOAc) to afford the title compound (0.137 g): MS (ES) m/z 269 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][N:3]1[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].O.[OH-].[Li+].O.CO>O1CCCC1>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]1[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: COC(=O)c1ccn([C@H](C)c2ccccc2)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)n1ccc(C(=O)O)cc1=O
Temperature: 20 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
A mixture of (R)-methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate (451 mg, 1.75 mmol), lithium hydroxide monohydrate (369 mg, 8.77 mmol), water (4 mL) and methanol (4 mL) in tetrahydrofuran (12 mL) was stirred at 20° C. for 12 hours. The reaction mixture was concentrated. The residue was acidified with concentrated hydrochloride solution to pH=2. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:2) to give (R)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid as a white solid (336 mg, 80%). LRMS (M+H+) m/z: calcd 243.13. found 243.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:10][C:3]2[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=2[NH2:1])[CH:15]=1
Reactant: Nc1cc(Cl)c(Cl)cc1O
Reactant: Fc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(Cl)cc1Oc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of 2-amino-4,5-dichlorophenol (1.5 g, 8.47 mmol) in THF (20 mL) at 0° C., NaH (60% dispersed in oil, 373 mg, 9.33 mmol) was added and the resulting mixture was stirred for 20 min. To this mixture, 4-chloro-2-fluoropyridine (1.67 g, 12.7 mmol) was added and the resulting mixture was stirred at reflux under argon for 15 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to 10:1) to afford the desired product (1.1 g, 45% yield). ESI-MS m/z: 287.0 [M−H]−.