Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
To a stirred mixture of 4-amino-1-benzylpiperidine (1.53 mL, 7.5 mmol), K2CO3 (2.28 g, 16.5 mmol) and DMF (15 mL) heated at 50° C. was added dropwise over 60 min bis(2-bromoethyl)ether (0.96 mL, 7.65 mmol). After stirring for 6 hours at 80° C., the solvent was removed by blowing with a stream of nitrogen over 2 hours. The residue was purified on a silica gel column to give 1.7 g (87%) of 4-(1-benzyl-piperidin-4-yl)-morpholine as a waxy solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCC1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2nc3ccccc3s2)CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
To a solution of 2 mL (18.3 mmol) of benzothiazole in 20 mL of tetrahydrofuran was added 11.4 mL (18.2 mmol) of 1.6 M n-BuLi at −78° C. After 45 min, 1.6 mL (18.1 mmol) of cyclopentanone was added at the same temperature. The reaction was let warm to room temperature over 1 h. Water was added to quench the reaction and the mixture was extracted with ether (3×). The ether layer was washed with brine (3×) and dried over magnesium sulfate. After removal of solvent, purification by silica gel column chromatography eluting with hexane:ethyl acetate (4:1) gave 2.8 g (71%) of 1-(1,3-benzothiazol-2-yl)cyclopentanol as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 2.25 (m, 4H), 2.00 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][NH:28][N:29]=[C:23]2[N:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:21]1=[O:34].O>CC(C)=O>[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][N:28]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[N:29]=[C:23]2[N:22]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:21]1=[O:34]
Reactant: ClCc1cccc2ccccc12
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Yield: 89.3 %

Procedure:
In accordance with the teaching of German Patent No. 63,381, 1-(chloromethyl)-naphthalene (2.2 g), potassium carbonate (1.6 g) and 5-methyl-7-(2-methylpropyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2.5 g) were combined in acetone (40 ml) and heated under reflux for 3 hours and then cooled to ambient temperature. Water (200 ml) was added and the precipitated solid was collected by filtration. The solid was triturated with isohexane and then dried in vacuo to give the title compound (3.64 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:6][C:5]([SH:12])=[C:4]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:3]=1.Br[C:18]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:18][S:12][C:5]1[CH:6]=[C:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[CH:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1cc(Br)c(C(C)CC)cc1S
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Product: CCC(C)c1cc(SC)c(C(C)CC)cc1Br

Procedure:
4-Bromo-2,5-di-sec-butylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-bromo-2,5-di-sec-butylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 126°C at 0.3 mm Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([CH:15](C1N=C(C(O)=O)C=C(OC)C=1)[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([CH:15]([C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: COC(=O)c1cc(C)cc(Cl)n1
Reactant: CCC(CC)c1cc(OC)cc(C(=O)O)n1
Product: CCC(CC)c1cc(C)cc(C(=O)O)n1

Procedure:
Methyl 6-chloro-4-methyl-pyridine-2-carboxylate (500 mg, 2.69 mmol) is treated with 1-ethyl-propyl zinkbromide and saponified as described for 6-(1-ethyl-propyl)-4-methoxy-pyridine-2-carboxylic acid to give the title compound (220 mg) as a pale yellow oil; LC-MS**: tR=0.37 min, [M+1]+=208.29; 1H NMR (CDCl3): δ 0.80 (t, J=7.3 Hz, 6H), 1.69-1.81 (m, 4H), 2.48 (s, 3H), 2.58-2.67 (m, 1H), 7.21 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
4-(Hydroxyethyl)phenol (2.7 g, 20.0 mmol) was dissolved in N,N-dimethylformamide (50 mL) and thereto were added potassium carbonate (6.90 g, 50.0 mmol) and 1,2-dibromoethane (15.03 g, 80.0 mmol). After stirring at 80° C. for 6 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 2-[4-(2-bromoethoxy)phenyl]-1-ethanol (750.0 mg).
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[Na+].[S:7]([CH2:11][CH2:12][OH:13])([O-:10])(=[O:9])=[O:8]>>[CH3:3][Si:2]1([CH3:4])[O:10][S:7](=[O:9])(=[O:8])[CH2:11][CH2:12][O:13]1
Reactant: O=S(=O)([O-])CCO
Reactant: C[Si](C)(Cl)Cl
Agent: [Na+]
Product: C[Si]1(C)OCCS(=O)(=O)O1
Reaction time: 20 h
Yield: 67 %

Procedure:
To 25 mL of dichlorodimethylsilane in a 100 mL r.b. flask was added 10 g of isethionic acid sodium salt and the mixture was heated to reflux with stirring for 20 hrs. The excess dichlorodimethylsilane was distilled and the residue transferred to a short-path distillation tube with a CH2Cl2 rinse. The residue was distilled at 145-175° C., 0.2 mm pressure, to give 8.25 g (67%) of a viscous liquid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1>CO>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:1][C:2](=[O:3])[C:4]=2[CH:9]=1
Reactant: O=C1CCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCCC2)Oc2ccc(Br)cc21

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (31.6 g, 0.1477 mol), cyclopentanone (26 mL, 0.2939 mol) and pyrrolidine (24 mL, 0.288 mol) in methanol (600 mL) was stirred at 25° C. overnight. The mixture was then concentrated to a red oil. Water was added and the solution was adjusted to pH 1 with concentrated hydrochloric acid. The product was extracted with diethylether. The organic layer was evaporated under reduced pressure. The residue was then dissolved in a small volume of methanol. The solution was treated with charcoal, filtered and water was added to the filtrate. The residue was extracted with diethylether. The organic layer was dried over magnesium sulfate and diethylether was evaporated under reduced pressure. The product was used directly in the next step (77%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([O:19][CH3:20])[N:3]=1.[S-2:21].[Na+].[Na+]>CN(C=O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([SH:21])[N:3]=[C:4]([O:19][CH3:20])[C:5]=2[C:17]#[N:18])=[CH:11][CH:12]=1
Reactant: [S-2]
Reactant: COc1nc(Cl)c(C#N)c(-c2ccc(O)cc2)c1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(S)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (4.550 mmol) of 2-chloro-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 10 ml of DMF, 426 mg (5.460 mmol) of sodium sulphide are added and the mixture is stirred at room temperature overnight. The reaction mixture is reacted further without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH2:15])[CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH:15][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(-c2ncco2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10.3 g (47.2 mmol) of 3-amino-5-oxazol-2-yl-benzoic acid methyl ester, 25 g of anhydrous sodium carbonate and 7.69 ml (51.9 mmol) of benzyl chloroformate is stirred for 16 h at rt and filtered. The filtrate is concentrated, and the residue is chromatographed on silica gel (EtOAc/hexane 1:2) to yield the product in the form of colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]1([CH2:4][O:5][N:26]2[C:27](=[O:36])[C:28]3=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]3[C:30]2=[O:31])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Reaction time: 15 h
Yield: 86.4 %

Procedure:
To a suspension of cyclopropyl methanol (562 μl, 6.93 mmol), triphenylphosphine (2.02 g, 7.63 mmol) and N-hydroxyphthalimide (1.28 g, 7.63 mmol) in THF (10 mL) at 0° C. was added dropwise diethylazodicarboxylate (1.20 mL, 7.63 mmol) in THF (10 mL). The reaction mixture was allowed to stir for 15 h after which the solvent was removed under vacuum to dryness. Et2O (15 mL) was added to triturate the triphenylphosphine oxide and diethylhydrazinedicarboxylate, which was filtered off and washed with a little Et2O. The ethereal solution was concentrated under vacuum to give a residue which was filtered through a pad of silica (eluting with EtOAc/PE, 3:7). Removal of the solvent under reduced pressure afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-(cyclopropylmethoxy)phthalimide (1.30 g, 86%), as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.Cl[C:16]1[N:17]=[N:18]C(C2C=CC(Cl)=CC=2)=CC=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:16]=[N:17][N:18]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Product: Clc1cccc(-c2ccc3nncn3n2)c1

Procedure:
The procedure of Example 15 is repeated substituting an equimolecular amount of 3-chloro-6-(m-chlorophenyl)pyridazine for the 3-chloro-6-(p-chlorophenyl)pyridazine employed in that example. There is thus obtained the title compound in equally good yield; m.p. 175°-177° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH3:23])[CH:14]=1)=[O:12].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][C:15]=1[NH:22][CH3:23]
Reactant: CNc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Add an aqueous solution of sodium hydrosulfite (17.4 g, 100 mmol in 80 mL of water) to methyl-3-(methylamino)-4-nitrobenzene carboxylate (855 mg, 4.75 mmol) in tetrahydrofuran (70 mL) and ethanol (30 mL) at 0° C. The orange solution turned to an orange suspension upon addition. Stir the mixture at room temperature for 2 hours. The orange suspension turned to a yellow suspension over this time. Add saturated sodium bicarbonate (100 mL) then the yellow suspension turned colorless. Extract the mixture with ethyl acetate (2×100 mL). Wash the combined organics with brine (30 mL). Dry over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield methyl 4-amino-3-(methylamino)benzoate (586 mg, 68%) as a yellow oil. The resulting oil began to crystallize upon standing after 10 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (s, 3H), 3.37-3.81 (m, 2H), 3.85 (s, 3H), 6.67 (d, J=8.01 Hz, 1H), 7.33 (d, J=1.37 Hz, 1H), 7.44 (dd, J=8.11, 1.66 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]1[N:12]([CH3:13])[N:11]=[N:10][N:9]=1)=[O:7].[CH3:14][N:15]1[C:19]([SH:20])=[N:18][N:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]1[C:19]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]2[N:12]([CH3:13])[N:11]=[N:10][N:9]=2)=[O:7])=[N:18][N:17]=[N:16]1
Reactant: Cn1nnnc1S(=O)CCCCBr
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCS(=O)c1nnnn1C
Yield: 49.1 %

Procedure:
1-Methyl-1,2,3,4-tetrazol-5-yl 4-bromobutyl sulfoxide (2.7 g) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.4 g) are dissolved in acetone (50 ml), and thereto is added potassium carbonate (1.4 g), and the mixture is refluxed for 2 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Kieselgel 60), eluting with chloroform-methanol (100:1) to give 1-methyl-1,2,3,4-tetrazol-5-yl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyl sulfoxide (1.5 g), as colorless liquid, nD19 =1.5660.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31][O:30]1>>[C:36]([O:35][CH2:34][C@@H:32]1[CH2:31][O:30][C:29](=[O:28])[N:33]1[C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:5]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:8]([CH:10]4[CH2:11][CH2:12]4)=[CH:7][N:6]=3)[CH2:14][CH2:15]2)=[O:20])=[CH:22][CH:23]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: O=C(OC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1)c1ccccc1
Yield: 90 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (1.42 g) described in Preparation Example 95 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (664 mg), the title compound (1.53 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:4][N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:22])=[CH:15][CH:16]=3)[N:21]=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)CC(=O)c1ccnc(Cl)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C)cc2-c2ccnc(Cl)c2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of 1-(2-chloro-4-pyridinyl)-1,3-butanedione (7 g, 35.25 mmol), paratolylhydrazine.HCl (6.13 g, 38.78 mmol) and triethylamine (5.41 mL, 38.78 mmol) in methanol (100 mL) was heated to reflux overnight. The resulting dark colored solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. After filtration, the solution was concentrated to give a brown solid. The solid was purified by column chromatography (silica gel, 2:8 EtOAc/hexane) to yield the titled product (3.6 g, 52%) as a crystalline light brown solid. MP: 100.07° C. Anal. Calc'd for C16H14N3Cl: C, 67.72, H, 4.97, N, 14.81. Found: C 67.40, H, 4.89, N, 14.59.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9]O)[CH2:5][CH2:4]1.C(N(S(F)(F)[F:33])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9][F:33])[CH2:5][CH2:4]1
Reactant: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(CF)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one dimethyl ketal (0.37 g, 1.02 mmol) in methylene chloride (5 mL) was added dropwise to a solution of diethylaminosulfur trifluoride (0.14 mL, 1.02 mmol) at -78° C. under an argon atmosphere. The mixture was allowed to warm to room temperature and after 0.75 h, 5% aqueous sodium carbonate was added. The mixture was extracted with chloroform, the organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo to provide a yellow oil (0.3 g, 80%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-])=O)=[CH:29][CH:28]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[N:9]2[CH2:10][CH2:11][C:6]3([C:4](=[O:5])[NH:33][CH2:32][CH:31]3[C:30]3[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:7][CH2:8]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CCOC(=O)C1CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC1
Product: COc1ccc(C2CNC(=O)C23CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC3)cc1
Yield: 52 %

Procedure:
As described for example 1b, cis-rac-1-[2-(4-fluoro-phenyl)-cyclohexyl]-piperidine-4-carboxylic acid ethyl ester (800 mg, 2.4 mmol) (using 4-methoxy-beta-nitrostyrene instead of trans-beta-nitrostyrene) was converted to the title compound (642 mg) 52%) which was obtained as a light yellow foam. MS: m/e=513.4 (M+H).
Reaction SMILES: C[O:2][C:3]1([O:12][CH3:13])[CH2:8][CH:7]([CH3:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]1.[CH3:14][C:15]([O:20]O)([CH3:19])[CH2:16][CH2:17][CH3:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>[CH3:13][O:12][C:3]1([O:2][O:20][C:15]([CH3:19])([CH3:14])[CH2:16][CH2:17][CH3:18])[CH2:8][CH:7]([CH3:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]1
Reactant: CCCC(C)(C)OO
Reactant: COC1(OC)CC(C)CC(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: CCCC(C)(C)OOC1(OC)CC(C)CC(C)(C)C1
Yield: 92.2 %

Procedure:
A mixed solution consisting of 20.7 g of dimethyl sulfoxide and 1.6 g of p-toluenesulfonic acid was kept at 20° C., to which was added dropwise another mixed solution consisting of 37.3 g of 3,3,5-trimethyl-cylcohexanone-dimethylacetal and 23.8 g of 1,1-dimethylbutyl hydroperoxide. The resulting solution had an acid concentration of 0.1 mol/kg of the solution. The solution was treated in the same manner as described in Example 1 to obtain 50.3 g (yield: 68%) of crude 1-methoxy-1-(1,1-dimethylbutylperoxy)-3,3,5-trimethylcyclohexane having a purity of 75%. The resulting crude peroxyketal was distilled at 68°-72° C. under a vacuum of 0.005 mmHg to obtain a purified peroxyketal having a purity of 96%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@@H:21]([C:26]3[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[CH2:22][N:23]=[N+]=[N-])=[O:19])=[C:16]([F:36])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:23][CH2:22][C@@H:21]([NH:20][C:18](=[O:19])[C:17]1[CH:34]=[CH:35][C:14]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:4]=2)=[CH:15][C:16]=1[F:36])[C:26]1[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([F:33])[CH:27]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(I)c1
Temperature: 70 °C

Procedure:
The crude (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-fluoro-5-iodophenyl)ethyl)-2-fluorobenzamide was dissolved in THF (5 mL), and triphenylphosphine (polymer bound, 3 mmol/g) (0.97 g, 3.70 mmol) was added dropwise. The mixture was heated at 70° C. for 3 h. LCMS indicated absence of starting material (at this stage, the phosphorylimine intermediate is likely present in solid phase). Water (4.5 mL) and THF (5 mL) were added, and the mixture was heated at 80° C. for 3 h and then filtered. The filter cake was washed with DCM and then filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to afford the residue which was purified by flash chromatography (0-60% DCM/10% MeOH in EtOAc containing 0.5% NH4OH), and the product fractions were collected and concentrated. The residue was dissolved in acetonitrile and water, and lyophillized to obtain 101.2 mg of (S)—N-(2-amino-1-(3-fluoro-5-iodophenyl)ethyl)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamide as the desired product. LCMS (m/z): 580.1 (MH+), 0.70 min. 1H NMR (CD3OD) δ (ppm): 7.92 (s, 1H), 7.85-7.79 (m, 1H), 7.73 (dd, J=8.0, 1.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.50-7.43 (m, 1H), 7.23 (d, J=9.5 Hz, 1H), 5.12 (t, J=6.9 Hz, 1H), 4.07 (dd, J=11.2, 3.3 Hz, 2H), 3.60 (td, J=11.7, 2.0 Hz, 2H), 3.09-2.83 (m, 3H), 2.02-1.76 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH2:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C.N1C=CC=CC=1>[Cl:19][CH2:20][C:21]([NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:17][C:21](=[O:22])[CH2:20][Cl:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Dissolve 1,8-diaminoanthraquinone (0.476 g, 2.0 mmol) in 20 ml DMF. Add pyridine (0.5 ml) as catalyst in an ice bath. Then add chloroacetyl chloride (0.5 ml, 6 mmol) into the solution, remove the ice bath, introduce nitrogen, protect from light, and stir the solution at room temperature for 24 hours. The reacted solution is poured into ice water (50 ml), filtered to get precipitate. At last, the precipitate is recrystallized to get yellow compound 3.