Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH:19]=[CH:20][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[NH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:19]=[CH:20][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1cccc2[nH]cc(CCCN(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]cc(CCCN(C)C)c12
Reaction time: 2 h

Procedure:
A solution of EXAMPLE 339F (484 mg) in dichloromethane (22 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (11 mL) was added. The reaction was stirred for 2 hours, concentrated and the crude product was chromatographed on silica gel with 7N-methanolic ammonia in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]>>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:24])[C:17]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([CH2:9][CH2:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Reactant: Fc1cccc(F)c1Br
Product: CCCc1c(OC)cc(C=Cc2c(F)cccc2F)cc1OC

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)-ethene and 1-bromo-2,6-difluorobenzene quantitatively in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8-7.2 (m, 4H), 7.41 (d, J=16.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14](OCC)=[O:15]>OS(O)(=O)=O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:14](=[O:15])[CH2:13][CH:12]2[CH2:11][Cl:10]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(Br)c(O)c1
Agent: O=S(=O)(O)O
Product: O=C1CC(CCl)c2cc(Br)c(O)cc2O1
Yield: 52 %

Procedure:
4-Bromoresorcinol (15.12 g, 80 mmol) and ethyl 4-chloroacetoacetate (16.2 mL, 0.12 mmol) were stirred in 80 mL of conc. H2SO4 for six days. The reaction mixture was poured into crushed ice with stirring and the slurry stirred for 30 min. The crude product was then filtered and washed with cold water. It was then dissolved in ethyl acetate and washed with water, 5% aqueous sodium bicarbonate solution, water and saturated brine solution and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated to about 15 mL and the slurry cooled for 30 min and filtered to get the product (52%). The characterization data were consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]O)[CH3:22]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:13][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][CH2:12][CH3:11])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([O:10][CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:9])([O-:3])=[O:2]
Reactant: CCCCC(CC)CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OCC(CC)CCCC
Temperature: 120 °C
Yield: 65.5 %

Procedure:
4-Nitrophthalic acid (2.0 g, 9.5 mmol) was dissolved in 30 ml of 2-ethylhexanol, and then 0.3 ml of sulfuric acid was added. The mixture was heated at 120° C. for 24 hours, and the solvent was evaporated under reduced pressure. Excess 2-ethyihexanol was removed from the oily residue by distillation. The oily residue was dissolved in diethyl ether and washed three times with water and once with 10%Na2CO3 solution. The ether solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =30:1) to give 2.3 g (65.5%) of bis(2-ethylhexyl) 4-nitrophthalate (compound 411.)
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[CH3:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.O>[CH3:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)COc1cccc(C)c1

Procedure:
A mixture of chloroacetone (43.75 g.) and finely-powdered potassium iodide (1 g.) in ethyl methyl ketone (50 ml.) was added dropwise, over 25 minutes, to a stirred, refluxing mixture of 3-methylphenol (54 g.) and dry potassium carbonate (82 g.) in ethyl methyl ketone (100 ml). Stirring and refluxing were continued for a total of 5 hours and the mixture was cooled, poured into water (cs. 500 ml.) and extracted with ether. The ether extract was washed exhaustively with 5N-sodium hydroxide, dried over anhydrous sodium sulphate and evaporated. The residue was distilled to give a fraction b.p. 126°-134°/13 mm. Redistillation gave 1-(3-methylphenoxy)-propan-2-one, b.p. 124°-126°/13 mm.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH2:26][CH2:27]O)=[CH:24][C:23]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)=[O:30])=[C:22]2[CH3:42])=[C:17]([CH3:43])[CH:16]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH2:26][CH2:27][F:11])=[CH:24][C:23]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)=[O:30])=[C:22]2[CH3:42])=[C:17]([CH3:43])[CH:16]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1cc(Cl)ccc1-n1c(CCO)cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1-n1c(CCF)cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of bis(2-methoxyethyl)aminosulfur trifluoride (11 ml, 61 mmol) in dichloromethane (200 ml), a solution of the above 1-(4-chloro-2-methylphenyl)-5-(2-hydroxyethyl)-2-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (6.8 g, 15 mmol) in dichloromethane (200 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to a saturated aqueous sodium hydrogencarbonate solution cooled to 0° C., and the mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated brine, and after it was dried with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=4:1) to give the title compound (3.8 g, 56%) as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[CH2:18][CH3:19])[C:6](OCC)=[O:7])C.[BH4-].[Na+].O>CO>[Br:17][C:13]1[C:12]([CH2:18][CH3:19])=[C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Br)c1CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1c(Br)cccc1C(CO)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a solution of 2-(3-bromo-2-ethyl-phenyl)-malonic acid diethyl ester (D127) (13 g, 37.88 mmol) in methanol (130 mL) was added sodium borohydride (14.33 g, 378.78 mmol), the reaction mixture was stirred for 12 hr at room temperature. Then water was added and extracted with CH2Cl2. The organic layers were separated, dried over Na2SO4, and concentrated in vacuo to afford 2-(3-bromo-2-ethyl-phenyl)-propane-1,3-diol (D128) (8 g). MS (ES): C11H15BrO2 requires 258.0. found 223.0 (M+H+-36).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:11][C@H:12]([OH:27])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:37](=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([N:10]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:11][C@H:12]([O:27][CH3:37])[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (333 mg, 8.30 mmol) was dissolved in 50 mL of tetrahydrofuran, added dropwise with a solution of tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, 8.30 mmol) in tetrahydrofuran in an ice-water bath. The reaction solution was stirred for 10 minutes and warmed up to room temperature. The reaction solution was stirred for 1 hour and cooled down to 0° C. followed by the addition of methyl iodide (1.18 g, 8.30 mmol). The reaction solution was stirred for 12 hours. The resulting solution was added with 10 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (2.10 g, yield: 56.0%) as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[Br:6][CH:7]([CH3:11])[C:8](Br)=[O:9].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:8](=[O:9])[CH:7]([Br:6])[CH3:11]
Reactant: CC(Br)C(=O)Br
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCCBr
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
3-Bromopropanol (10.75 g, 0.075 mol) is added over 20 minutes to a solution of 2-bromopropionylbromide (17.9 g, 0.079 mol) in toluene (75 ml) while keeping the temperature between 15-20° C. The mixture is stirred for 6 h at room temperature and is then poured under vigorous stirring into 1M solution of Na2CO3 (80 ml). The organic layer is separated, washed with water (3×50 ml), dried over MgSO4 and evaporated to afford 19.75 g of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:31][C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:44][C:19]([F:18])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[O:31][C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 96 were used as the starting compounds. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-xanthen-9-yl]butyl]-piperazin-1-yl]benzoate was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[N:8]=1.O.[CH3:22]O>>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:17][CH3:22])=[O:16])[N:8]=1
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)no1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(-c2noc(C)n2)c1

Procedure:
7.83 ml (147 mmol) of concentrated sulfuric acid are added to a suspension of 30.0 g (147 mmol) of 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid in 150 ml of methanol, and the mixture is heated at the boil for 18 hours. The reaction mixture is cooled in an ice bath, water is added, the mixture is filtered off with suction and washed well with water: methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate as colourless crystals; m.p. 81° C., ESI 219 (M+H), HPLC: Rt.=2.65 min (method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:22]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:21]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:20]3)=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:82](=[O:87])([O:84][CH2:85][CH3:86])[NH2:83].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:85]([O:84][C:82](=[O:87])[NH:83][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:22]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:21]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:20]2)=[CH:15][CH:16]=1)[CH3:86]
Reactant: CCOC(N)=O
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(O)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(NC(=O)OCC)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To (4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methanol (110 mg, 97.2 μmol) were added toluene (2 mL), ethyl carbamate (17.8 mg, 200 μmol), and methanesulfonic acid (1 μL, 15 μmol) and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was cooled to room temperature, sodium carbonate (5 mg, 47 μmol) was added and the solvent was evaporated. The residue was crystallized from methanol (5 mL) to give ethyl{(4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methyl}-carbamate (127 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>C(O)CC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CN(C)CCN
Solvent: CCCO
Product: CN(C)CCNc1ccccc1[N+](=O)[O-]
Yield: 91.7 %

Procedure:
To a solution of 2-bromonitrobenzene (10.23 g) in 1-propanol (100 ml) was added N,N-dimethylethylenediamine (13.41 g) and the mixture was refluxed for 3 days. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=50:1) to give 9.72 g of N-(2-nitrophenyl)-N',N'-dimethylethylenediamine.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[C:31]([CH:35]([N:39]2[CH:43]=[C:42]([C:44]3[C:45]4[CH:52]=[CH:51][N:50]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:46]=4[N:47]=[CH:48][N:49]=3)[CH:41]=[N:40]2)[CH2:36][CH:37]=O)[CH:32]=[CH:33][CH:34]=1>C1COCC1>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]([N:39]2[CH:43]=[C:42]([C:44]3[C:45]4[CH:52]=[CH:51][N:50]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:58])[CH3:59])[C:46]=4[N:47]=[CH:48][N:49]=3)[CH:41]=[N:40]2)[CH2:36][CH:37]=[CH2:1])[CH:32]=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC(c1cccc(Br)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium tert-butoxide in THF (1M, 200 μL) was added to a solution of methyltriphenylphosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) at 0° C. The reaction was stirred at room temperature for 1 h and then cooled to −78° C. The 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (90 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was allowed to warm to room temperature gradually. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc:Hexane, (1:1) to give 4-{1-[1-(3-bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl}-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (35 mg, 40%) as an oil. m/z=524, 526 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:10][C:8](=[O:9])[C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[N:5][CH:6]=3)[CH:19]=1
Reactant: COC(=O)COCCc1cccc(C)c1
Reactant: NC(=O)c1cncnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOCc2nc3ncncc3c(=O)[nH]2)c1

Procedure:
In analogy to example 3.3, 4-amino-5-pyrimidinecarboxamide and (2-m-tolyl-ethoxy)-acetic acid methyl ester (prepared from 2-m-tolyl-ethanol [1875-89-4] in analogy to example 3.1-3.2) reacted in the presence of LiHMDS in THF to yield the title compound (after purification of the crude product with column chromatography (silica gel, EtOAc/MeOH) and crystallization from TBME) as white solid. MS: m/e=295.5 [M−H−].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
To 10 mL of a methylene chloride solution containing 280 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 150 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde, 0.05 mL of acetic acid was added, and stirred at room temperature for 1.5 hours. To the reaction mixture, 280 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 233 mg of 7-methoxy-1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(OC(C)C)(C)C>C(O)C>[N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)CCl)cc1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 40.5 %

Procedure:
A mixture of 47 g of ethyl 2-[4-(chloroacetyl)phenyl]propionate, 100 ml of ethanol and 30 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated to give a reddish brown oil. To the oil is added isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from isopropyl ether to give 22 g of ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionate as colorless scales melting at 110°-112°C.
Reaction SMILES: [CH2:1]([CH:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[NH:6]1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[C:28]3[NH:38][N:37]=[N:36][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCC1Nc2ccc(C)cc2C(=O)N1Cc1ccc(-c2ccncc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2ccncc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 2-butyl-6-methyl-3-[[4-(3-cyanopyridin-4-yl)phenyl]methyl]quinazolin-4(1H)-one (1.0 eq.) and trimethylstannylazide (3 eq.) in toluene is heated to reflux for 4 days. The mixture is cooled to rt, concentrated, then purified by flash chromatography on SiO2 to give the titled compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3][CH:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100 mmol, 1.00 equiv) in ether (60 mL)-30° C. was added dropwise a solution of BF3.Et2O (16.0 mL, 1.30 equiv) in ether (20 mL). After stirring 30 min at −30° C., a solution of ethyl 2-diazoacetate (16.0 g, 140 mmol, 1.30 equiv) in ether (20 mL) was added dropwise to the reaction at −30° C. The resulting solution was stirred for 1 h at −30° C., then warmed to 25° C. and stirred for 2 h. The reaction was then quenched with 100 mL of 30% aqueous potassium carbonate. The resulting mixture was extracted with 2×250 mL of ethyl acetate, and the combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/10) as eluent to furnish 19.0 g (66%) of the title compound as a light yellow oil.