Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH2:18][P:19]([N:30]([CH3:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([N:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22])=[S:20])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])=O>O1CCCC1.O>[CH3:38][N:30]([P:19]([CH2:18][NH:5][CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])([N:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22])=[S:20])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCOC(=O)CN(CP(=S)(N(C)Cc1ccccc1)N(C)Cc1ccccc1)C(=O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)CNCP(=S)(N(C)Cc1ccccc1)N(C)Cc1ccccc1
Temperature: 0 °C
Yield: 22.5 %

Procedure:
N-trifluoroacetyl-N-[bis(N-methyl-N-benzylamino)phosphinothioylmethyl]glycine, octyl ester (3.7 g, 6.16 mm), was dissolved in 30 ml of tetrahydrofuran containing 6 ml of water and cooled to 0° C. on an ice bath. The solution was stirred and sodium tetrahydrido boron (234 mg, 6.16 mm) was added portionwise over about 10 minutes. The solution was allowed to warm to room temperature and stirred for an additional 35 minutes. (a) The solvent was removed by evaporation under vacuum and the residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and the insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. A thin layer chromatograph of the residue indicated that the starting material was still present. The remainder of this residue was dissolved in tetrahydrofuran (30 ml), H2O (6 ml) and sodium tetrahydridoboron (234 mg) was added with stirring. The solution was stirred for 2 hours. This solution was then treated as in step (a). The resulting residue from the repeat of step (a) was then chromatographed on silica gel employing ether to yield N-[bis(N-methyl-N-benzylamino)phosphinothioylmethyl]glycine, octyl ester (700 mg) having a refractive index ND25 =1.5404.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])C(C)C.[Cl:21][C:22]([CH2:24]Cl)=[CH2:23]>C1COCC1>[CH2:19]([O:18][C:13](=[O:17])[C:5]([CH3:6])([CH3:7])[CH2:24][C:22]([Cl:21])=[CH2:23])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: C=C(Cl)CCl
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(Cl)CC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisopropylamine (1.25 eq) was added to a reaction flask containing THF (tetrahydrofuran; 10.0-fold, V/W of ethyl isobutyrate) under N2. The mixture was cooled to less than −70° C., and n-butyllithium (2.7M; 1.14 eq) was added to the reaction mixture while the temperature was maintained at less than −65° C. The reaction mixture was slowly warmed to room temperature and then stirred for 2 hours under N2. The reaction mixture was then cooled to less than −70° C., and ethyl isobutyrate (1.0 eq) was added, followed by 2,3-dichloro-1-propene (1.09 eq), while the temperature was maintained at less than −70° C. The reaction was allowed to warm to room temperature and stirred overnight under N2. The reaction was then quenched with ice water (10.0-fold, V/W of starting material), and the pH adjusted to pH 7 with aqueous 6M HCl. The organic layer was separated, washed twice with brine, and dried over Na2SO4. The solvent was removed in vacuo and the product was taken on to the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][C@H:16]([CH3:19])[CH2:17][OH:18].C(N(CC)CC)C.CO>>[OH:18][CH2:17][C@H:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH3:19]
Reactant: C[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 88 °C
Yield: 40 %

Procedure:
A 250 mL round bottom flask was charged with 5-nitro-isochromen-1-one (40 g, 0.2 mol), (2R)-2-Aminopropan-1-ol (18 g, 0.24 mol), triethylamine (100 mL, 0.7 mol) and methanol (500 mL, 10 mol) and the reaction heated at 88° C. for 1.5 hours. The product precipitated out upon cooling the reaction and was filtered to afford the product as a yellow solid. (17.3 g, 40% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH:7]=[O:8])[CH2:4][O:3]1.[CH:10]([Mg]Br)=[CH2:11].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C.O>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH:7]([OH:8])[CH:10]=[CH2:11])[CH2:4][O:3]1
Reactant: C=C[Mg]Br
Reactant: CC1(C)OC[C@H](C=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(O)[C@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
On a stirred solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (11.0 g, 0.063 mol, 75% assay, 94% ee) in THF (40 g) at 0° C. under nitrogen atmosphere, a vinyl magnesium bromide solution (1.0 M in THF, 88.7 ml, 0.0887 mol) was added over a period of 90 min. After 2 h stirring at 0° C., the temperature was raised to 10° C. and a saturated ammonium chloride solution (60 ml) was added dropwise in 30 min. The quenched reaction mixture at 20° C. was then diluted with ethyl acetate (100 ml) and demi water (50 ml) and the layers separated. The organic phase was further washed with demi water (50 ml). The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to furnish 11.7 g of 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol as a light yellow oil. Spectroscopic data are conform to literature.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](I)[CH3:16].O>CN(C=O)C>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: Oc1ccc(I)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification.
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[O:46][C:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[C:44](I)[C:43]2=[O:55].CC1(C)C(C)(C)OB([C:64]2[CH:69]=[CH:68][C:67]([C:70]3([NH:74][S:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH2:73][O:72][CH2:71]3)=[CH:66][CH:65]=2)O1>>[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[O:46][C:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[C:44]([C:64]1[CH:65]=[CH:66][C:67]([C:70]3([NH:74][S:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH2:73][O:72][CH2:71]3)=[CH:68][CH:69]=1)[C:43]2=[O:55]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(Br)cccc12
Reactant: CC(C)(C)S(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)COC1
Yield: 55 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-bromo-3-iodo-2-phenyl-chromen-4-one and 2-methyl-propane-2-sulfinic acid {3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-oxetan-3-yl}-amide were reacted to give the title compound as a tan solid (59 mg, 55%). LCMS (Method B): RT=5.02 min, [M+H]+=552/554.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.O.CCN(CC)CC>C1COCC1>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
In a 100 mL, 2-necked round bottom flask, to a mixture of 1-[(4-{[(tert-butoxycarbonyl) amino]methyl}piperidin-1-yl)methyl]cyclopentanecarboxylic acid (5 g, 14.7 mmol, Step 7) in THF (25 mL), a solution of p-TsOH H2O (8.4 g, 44 mmol) in THF (25 mL) was added at room temperature. The resulting mixture was stirred at 70° C. for 3 h under N2 and it was cooled down to room temperature. To this solution, Et3N (6 mL, 44 mmol) was added dropwise slowly. The white precipitate was formed during the addition of Et3N and the resulting mixture was stirred at room temperature for 14 h. The suspension was filtered and the obtained solid was washed with THF (10 mL), dried at 50° C. for 5 h to give 5.9 g (97%) of the titled compound as a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][O:55][CH2:56][CH2:57][CH2:58]O>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:58][CH2:57][CH2:56][O:55][CH3:54])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: COCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
Diethyl azodicarboxylate (123 μl, 0.88 mmol) was added portionwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.8 mmol), (prepared as described for the starting material in Example 4), triphenylphosphine (228 mg, 0.96 mmol) and 3-methoxy-1-propanol (71 mg, 0.8 mmol) in methylene chloride (20 ml) cooled at 0° C. The mixture was then allowed to warn to ambient temperature and stirred for 18 hours. The resulting precipitate was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/concentrated aqueous ammonia (100/8/1). The purified oil was treated with ethereal hydrogen chloride and the volatiles were then removed by evaporation. The residue was triturated with ether and the solid collected by filtration to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methoxypropoxy)quinazoline hydrochloride (100 mg, 32%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[I-:36].[Na+].I.C(=O)(O)[O-].[Na+]>CC(C)C(=O)C.COC(C)(C)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([I:36])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: [I-]
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A mixture of 250 mg (0.467 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 24), 250 mg (1.64 mmol) sodium iodide and 0.12 ml (0.99 mmol) hydroiodic acid (57% in water) in 5 ml 3-methyl-2-butanone was heated at 80° C. for 5 h in a sealed tube. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated. Flash column chromatography gave 218 mg (48%) of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([N:7]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:8](=[O:21])[NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH2:1]([N:7]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]=2[CH:23]=1)[C:8](=[O:21])[NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 45 °C
Yield: 82.7 %

Procedure:
A solution of ethyl 4-[3-hexyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (19) (296 mg, 0.62 mmole) in 8 mL ethanol was treated with 694 mg of potassium hydroxide in 3 mL water. THF (2 mL) was added and the mixture was heated to 45° C. for two hours. The reaction mixture was diluted with 10 mL water and the pH adjusted to 2 with concentrated HCl and then extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide a pale yellow solid. The product was purified by trituration in pentane and 231 mg (83%) of 4-[3-hexyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (13) were obtained as a pale yellow solid. M.P.: 176.6-177.1° C.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](CNC)=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.O.[CH:47]([N:50](C(C)C)[CH2:51]C)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:50]([CH2:51][C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26]3)[CH3:47])=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cn(Cc2ccccc2)c2ccccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(C=CC(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(ccn2Cc2ccccc2)c1)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
EDC (0.42 g, 2.20 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.36 g, 2.20 mmole), 1-benzyl-3-(methylaminomethyl)-1H-indole (0.50 g, 2.00 mmole), HOBt.H2O (0.30 g, 2.20 mmole) and diisopropylethylamine (0.70 mL, 4.00 mmole) in DMF (30 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.48 g, 60%) as a light yellow solid: MS (ES) m/e 397 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][Cl:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 56.5 %

Procedure:
A mixture of 1-benzhydrylpiperazin (4.13 g), 1-bromo-3-chloropropane (5.18 g) and anhydrous potassium carbonate (2.26 g) in anhydrous acetone (82 ml) was refluxed for 10 hours under stirring. The insoluble materials were filtered off and the filtrate was evaporated to dryness. The residue was subjected to column chromatography on alumina (50 g) using benzene as an eluent. The fractions containing the object compound were collected and evaporated to give oil of 1-benzhydryl-4-(3-chloropropyl)piperazine (3.04 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.OO.NC(N)=[O:14].CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2CO1.O>ClCCl.O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:7][O:14]2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: NC(N)=O
Agent: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: OO
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1ccc(C2CO2)cc1
Yield: 66 %

Procedure:
Fifth recycle 4-Hydroxy styrene: 1 g, 8.3 mmol, urea hydrogen peroxide: 3 g, 32 mmol, Immobilized lipase: 87 mg, 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate: 0.3 g, 1.03 mmol, dry dichloromethane:tetrahydrofuran (4:1): 15 mL. Same procedure was followed as described in example ‘1’. Reaction time: 20 hours, Yield: 66%.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[OH:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([O:24][CH3:25])[C:18]([CH3:27])([CH3:26])[CH2:17]1.[OH:28][CH:29]1[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([OH:37])[C:31]([CH3:39])([CH3:38])[CH2:30]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:15][CH:16]1[CH2:21][C:20]([CH3:22])([CH3:23])[N:19]([O:24][CH3:25])[C:18]([CH3:27])([CH3:26])[CH2:17]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:28][CH:29]1[CH2:34][C:33]([CH3:35])([CH3:36])[N:32]([OH:37])[C:31]([CH3:39])([CH3:38])[CH2:30]1)=[O:11]
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC1(C)C

Procedure:
Sebacoyl chloride is added to a mixture of 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine, 4-hydroxyl-1-oxyl-2,2,6,6-tetramethylpiperidine, triethylamine and methylene chloride. The reaction mixture is worked up in the usual manner and purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:5]1[CH:6]=[C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:14])[CH:3]=[N:4]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cnn(-c2ccccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4bromo-1H-pyrazol-1-yl)pyridine (0.446 g, 2.0 mmol), 3-cyanophenylboronic acid (0.302 g, 2.0 mmol), potassium carbonate (0.552 g, 4.0 mmol) in a mixture of ethylene glycol dimethyl ether (20 mL) and water (4 mL) was degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degassing continued a further 15 min. The resulting solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from EtOAc/Hexane give 3-(1-pyridin-2-yl-1H-pyrazol-4-yl)benzonitrile as a white solid. MP=160-161° C. 1H NMR (CD3Cl, 300 MHz) δ 8.88 (s, 1H), 8.45 (d, 1H), 8.03 (s, 1H), 8.01 (d, 1H), 7.87 (d, 1H), 7.86 (s, 1H), 7.81 (d, 1H), 7.57˜7.48 (m, 2H), 7.25 (dd, 1H). MS (ESI) 247.1 (M++H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.O[C:37]1[CH:38]=[CH:39][C:40]([N+:47]([O-:49])=[O:48])=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)[Cl:70].C(O)(C(F)(F)F)=O.O>C1COCC1>[ClH:70].[N+:47]([C:40]1[CH:39]=[CH:38][C:37]([O:35][CH2:34][CH2:33][O:32][C:27]2[C:26]([N:23]3[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]3)=[N:31][CH:30]=[CH:29][N:28]=2)=[C:46]2[C:41]=1[CH:42]=[CH:43][CH:44]=[N:45]2)([O-:49])=[O:48]
Reactant: O=[N+]([O-])c1ccc(O)c2ncccc12
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: O=[N+]([O-])c1ccc(OCCOc2nccnc2N2CCNCC2)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
DEAD (0.485 mL, 3.08 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 8-hydroxy-5-nitroquinoline (0.589 g, 3.08 mmol) and PPh3 (0.85 g, 3 24 mmol) in THF (10 mL). The mixture was stirred at room temperature for 2 h, and concentrated. The residue was passed through a silica column using toluene/EtOAc (1.1) as eluent The N-Boc protected intermediate obtained was treated with CH2Cl2/TFA/H2O (50:45:5, 15 mL) for 30 min at room temperature and concentrated. The residue was dissolved in 0 1 M aqueous HCl and washed with toluene The water phase was concentrated to give 0.206 g (15%) of the title product. Pos-EI-MS shows M= and 7 ions supporting the stated structure: HRMS m/z calcd for C19H20N6O4 (M)+396.1546, found 396.1557.
Reaction SMILES: [C:1]([N:8](C)[C@H:9](C=O)[CH3:10])(OC(C)(C)C)=O.C([Cl:17])(=O)C.[CH:18](OC)([O:21][CH3:22])[O:19][CH3:20]>CO>[ClH:17].[CH3:20][O:19][CH:18]([O:21][CH3:22])[C@@H:9]([NH:8][CH3:1])[CH3:10]
Reactant: C[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Reactant: COC(OC)OC
Solvent: CO
Product: CN[C@@H](C)C(OC)OC
Product: Cl
Temperature: 15 °C
Reaction time: 1 h

Procedure:
13.1 g Crude Boc-N-methyl-alaninal (70 mmol) were dissolved in 100 ml methanol and cooled to ˜15° C. A solution of 11 g (140 mmol) acetyl chloride in 30 ml methanol was added all at once and the yellowish solution was stirred at RT for 1 h (gas evolution). 67.52 g Trimethyl orthoformate (630 mmol) were now added and the reaction mixture was stirred at RT over night (18 h). The solvent and the excess of the orthoester were removed by rotary evaporation (40° C./≧10 mbar) and the resulting 11.9 (100%) beige, crystalline residue was crystallized from 120 ml hot isopropyl acetate yielding after stirring at −20° C. for 17 h 8.4 g (71%) beige product, [α]D=10.8 (CHCl3; c=1). 1H-NMR: