Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:6]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH:15]([O:17][CH2:18][CH3:19])=[CH2:16]>C(OCC)C.P(=O)(O)(O)O>[CH2:15]([O:17][CH:18]([O:8][C:7](=[O:9])[CH:6]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH3:19])[CH3:16]
Reactant: C=COCC
Reactant: C=CCCCC(CCCC=C)C(=O)O
Agent: O=P(O)(O)O
Solvent: CCOCC
Product: C=CCCCC(CCCC=C)C(=O)OC(C)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-pentenyl)-6-hepteneoic acid (1 eq.) in diethyl ether (20 mL) was slowly added via a Pasteur pipette to a precooled (0° C.) solution of ethyl vinyl ether (excess, usually >4 eq.) and phosphoric acid (cat., 1 drop from capillary pipette) in diethyl ether (10 mL). The solution was stirred cold for 30 minutes under argon, and then warmed to room temperature for 3 days. Basic alumina (˜1 g) was added to the reaction mixture and stirred for five minutes. After filtration and solvent removal, 1-ethoxyethyl-2-(pent-4-enyl)hept-6-enoate was isolated as 7.3 g (99.0% yield) of colorless oil with no further purification required. 1H NMR (CDCl3): δ (ppm) 1.22 (t, 3H) 1.30-1.55 (br, 9H), 1.62 (m, 2H), 2.05 (q, 4H), 2.36 (m, 1H), 3.53 (d, 1H), 3.71 (m, 1H), 4.97 (m, 4H), 5.82 (m, 2H), 5.94 (q, 1H); 13C NMR (CDCl3): δ (ppm) 15.24, 21.14, 26.86, 26.89, 31.91, 32.10, 33.76, 45.98, 64.77, 96.33, 114.92, 138.56, 176.17. In like manner 1,2-(7-octenyl)-9-deceneoic acid was converted into 1-ethoxyethyl-2-(oct-7-enyl)dec-9-enoate (99.1% yield). 1H NMR (CDCl3): δ (ppm) 1.16-1.53 (br, 24H), 1.61 (m, 2H), 2.04 (q, 4H), 2.34 (m, 1H), 3.53 (m, 1H), 3.71 (m, 1H), 4.97 (m, 4H), 5.81 (m, 2H), 5.95 (q, 1H); 13C NMR (CDCl3): δ (ppm) 15.24, 21.13, 27.59, 27.65, 29.03, 29.15, 29.58, 32.52, 32.71, 33.94, 46.30, 64.72, 96.22, 114.41, 139.27, 176.42. In like manner to Example 1, 2-(10-undecenyl)-12-trideceneoic acid was converted into 1-ethoxyethyl-2-(undec-10-enyl)tridec-12-enoate (98.4% yield). 1H NMR (CDCl3): δ (ppm) 1.16-1.53 (br, 36H), 1.60 (m, 2H), 2.04 (q, 4H), 2.33 (m, 1H), 3.54 (m, 1H), 3.71 (m, 1H), 4.97 (m, 4H), 5.81 (m, 2H), 5.95 (q, 1H); 13C NMR (CDCl3): δ (ppm) 15.24, 21.13, 27.59, 27.65, 29.03, 29.15, 29.58, 32.52, 32.71, 33.94, 46.30, 64.72, 96.22, 114.41, 139.27, 176.42.
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[CH2:22][C@H:21]4[N:17]([CH2:18][CH2:19][CH2:20]4)[C:16]4[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:15]=4[C:14]3=[O:29])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:28][S:27][C:24]1[N:25]=[CH:26][C:15]2[C:14](=[O:29])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]4[O:6][C:2]([S:1][CH3:30])=[N:3][N:4]=4)[CH:8]=3)[CH2:22][C@H:21]3[N:17]([CH2:18][CH2:19][CH2:20]3)[C:16]=2[N:23]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(S)o3)c1)C2=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(SC)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
(S)-5-[3-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (37 mg, 0.09 mmol) obtained in Step 1 was dissolved in DMF (1.0 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (36 mg, 0.26 mmol) and methyl iodide (0.012 mL, 0.19 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (23 mg, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[O:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C@@H:13]([OH:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@@H](CBr)c1ccc(OCc2ccccc2)cc1
Temperature: -25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A solution of 23 g of (+)-diisopinocamphenylchloroborane dissolved in 30 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 12 g of 4-benzyloxyphenacyl bromide. The resulting mixture was stirred for 4 hours at -20° to -15° C. The reaction mixture was added to a mixture of 150 ml of diethyl ether and 100 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: hexane:toluene=1:2) to obtain 6.8 g of (R)-1-(4-benzyloxyphenyl)-2bromoethanol.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:26])=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[ClH:26].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 4-nitrobenzoyl chloride. Mp. >280° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35](Br)[CH:36]=[CH2:37]>>[CH2:37]([O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH:36]=[CH2:35]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: C=CCBr
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 9.53 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 3.42 ml of allylbromide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.03.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: COc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: COc1cccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)c1
Yield: 81 %

Procedure:
The title compound was prepared from (R)-(−)-N-boc-3-pyrrolidinol and 3-methoxyphenol, using the same method as that described for preparation 3, as a gum in 81% yield.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A solution of ethyl 3-(5-{(1R)-4-cyclohexyl-1 -[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3- yl)propanoate (Example 54) (58 mg, 0.15 mmol) in 1,4-dioxan (2 ml) and water (1 ml) was treated with lithium hydroxide monohydrate (13 mg, 0.31 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with diethylether (×2). The aqueous layer was acidified with hydrochloric acid (2M) (2 ml) and washed with ethyl acetate (×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 90:10:1 (dichloromethane:methanol:acetic acid) to afford the title compound as an orange gum (36 mg).
Reaction SMILES: O[C@@]1(C)C=C[C@H]2[C@H]3[C@H]([C@@H]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=5)=[CH:22][CH:21]=4)C[C@]12C)[C@@H]1C(=CC(=O)CC1)CC3.Cl.CCCCCC.C(OCC)(=O)C>CC(C)=O>[C:26]1([C:23]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=2)[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=1
Reactant: C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](c3ccc(-c4ccc(C#N)cc4)cc3)C[C@@]21C
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccccc2)cc1

Procedure:
260 mg of 4'-[3,3-[1,2-ethanediylbis(oxy)]-17β-methoxy-17α-methyloestra-5,15-dien-11β-yl][1,1'-biphenyl]-4-carbonitrile are reacted with 0.7 ml of 4 normal aqueous hydrochloric acid in 14 ml of acetone in the manner described in Example 1 r). Column chromatography on silica gel with a mixture of hexane/ethyl acetate yields 218 mg of 4'-17β-methoxy-17α-methyl-3-oxo-oestra-4,15-dien-11β-yl][1,1'-biphenyl]-4-carbonitrile in the form of a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](OCC)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.BrC1N=C(OC)[C:17]([O:22]CC)=[CH:16]C=1.[Li]CCCC.CN([CH:33]=[O:34])C.[Cl-].[NH4+]>C1COCC1>[CH2:17]([O:22][C:7]1[C:2]([CH:33]=[O:34])=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[N:6]=1)[CH3:16]
Reactant: CN(C)C=O
Reactant: CCOc1cc(Br)cnc1OC
Reactant: CCOc1ccc(Br)nc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1nc(OC)ccc1C=O
Reaction time: 1 h

Procedure:
To a 3:2 mixture of 5-bromo-3-ethoxy-2-methoxy-pyridine and 6-bromo-3-ethoxy-2-methoxy-pyridine (1.0 g, 4.31 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added at −78° C. under Ar a solution of n-BuLi (3.23 mL, 5.17 mmol, 1.2 equiv, 1.6 M solution in hexane). After stirring for 1 h, anhydrous DMF (0.7 mL, 9.05 mmol, 2.1 equiv) was added and the reaction mixture stirred for an additional 30 min. A sat. solution of ammonium chloride (20 mL) was added and the solution extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified by twice recrystallization from isopropanol yielding 0.35 g (75%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 3H), 4.11 (s, 3H), 4.15 (q, J=7.0 Hz, 2H), 7.46 (d, J=1.9 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 9.93 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.44, 54.67, 64.59, 113.72, 127.59, 144.29, 144.31, 158.80, 189.66. MS (ISP): 181.8 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([OH:20])[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1.C1(C)C=CC=CC=1.O[CH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[C:32]([CH3:38])[CH:31]=1>O.C(OCC)(=O)C>[OH:20][C:12]1[CH:13]=[C:14]([CH3:19])[C:15]([CH3:18])=[CH:16][C:17]=1[CH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[C:32]([CH3:38])[CH:31]=1
Reactant: Cc1cc(CO)c(C)cc1O
Reactant: Cc1ccc(O)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(O)c(Cc2cc(C)c(O)cc2C)cc1C
Temperature: 20 °C
Yield: 68.8 %

Procedure:
Into a 1 liter of four-necked flask were charged 1.90 g of para-toluene sulfonic acid, 24.43 g of 3,4-xylenol and 48.87 g of toluene. Further, keeping the temperature at 30° C., 7.61 g of 4-hydroxymethyl-2,5-dimethylphenol was added in ten portions over 1 hour. The mixture was stirred at the same temperature for 2 more hours. After completion of the reaction, 50 g of toluene and 50 g of ethyl acetate was added. Thereafter, 50 g of deionized water was added and the resulting mixture was stirred and a phase separation was carried out. Then, metal content was removed by adding 50 g of 1% aqueous oxalic acid solution, followed by stirring the mixture and by carrying out a phase separation. Thereafter, washing with 50 g of deionized water was repeated four times, and the oil phase was concentrated. To the concentrated mass, 100 g of toluene was added and the resulting solution was cooled to 20° C. and filtered. The filter cake was rinsed with 200 g of toluene and dissolved in 50 g of ethyl acetate. After adding 200 g of toluene thereto,the resulting mixture was concentrated. To the concentrated mass, 100 g of toluene was added and the resulting mass was cooled to 20° C. and filtered. The filter cake was rinsed with 100 g of toluene and dried a whole day and night under reduced pressure at 45 ° C. to obtain 8.82 g of 4-(2-hydroxy-4,5-dimethylbenzyl)-2,5-dimethylphenol.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1>ClCCl.FC(F)(F)C(O)=O>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3cccnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)ccc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of 0.26 g of tert-butyl (1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 4 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water and diethyl ether was added to the resultant residue, and the aqueous layer was separated and washed with diethyl ether, and then, thereto was added a 20% aqueous sodium hydroxide solution and the reaction mixture was adjusted to pH 13 to 14. Thereto were added dichloromethane and sodium chloride, the organic layer was separated, and the aqueous layer was extracted with chloroform while being salted out. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.15 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:13]=12.[O:20]1[CH2:25][C:24](=O)[CH2:23][C:22](=[O:27])[CH2:21]1>C(O)C>[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([CH:18]3[C:23]4[C:22](=[O:27])[CH2:21][O:20][CH2:25][C:24]=4[NH:1][C:2]4[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]3=4)[CH:15]=[CH:14][C:13]=12
Reactant: Cn1oc(=O)cc1N
Reactant: O=Cc1ccc2nonc2c1
Reactant: O=C1COCC(=O)C1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc2nonc2c1
Temperature: 25 °C

Procedure:
The product from Example 45A (0.11 g, 1 mmol), 2,1,3-benzoxadiazole-5-carboxaldehyde(0.15 g, 1 mmol), prepared as described in (Gasco, A. M., Ermondi, G. Eur. J. Med. Chem., (1996) 31, 3) and 2H-pyran-3,5(4H,6H)-dione (0.11 g, 1 mmol) were heated in 2 mL of ethanol for 2 days. The resulting mixture was allowed to cool to ambient temperature and filtered to provide the title compound as the filter cake (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 4.08 (s, 2H), 4.6 (q, 2H), 4.92 (s, 1H), 7.62 (dd, 1H), 7.76 (s, 1H), 8.0 (dd, 1H), 10.8 (s, 1H); MS (ESI) m/z 339 (M−H)−; Anal. Calcd for C16H12N4O5; C, 56.47; H, 3.52; N, 16.47. Found: C, 56.03; H, 3.97; N, 15.57.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[BrH:30].O1CCOCC1>O>[BrH:30].[BrH:30].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]-acetyl]phenoxy]isobutyrate (50 mg), 48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heated at 95° C. for 4 hours. The solution was cooled, diluted with water and freeze-dried to give the title compound, 40 mg, as a pale yellow solid: m.p. 163°-167° C.; NMR (D2O) δ 8.40 (2H, d), 8.16 (2H, d), 7.40 (2H, d), 7.21 (2H, d), 5.21 (2H, s), 4.32 (4H, b), 3.89 (4H, bt), 1.86 (6H, s); m/e 384 (M+H)+ ; calculated for C21H25N3. 2HBr.2H2O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22]CN(C(C)C)C(C)C.[Cl-].[CH2:32]1C[O:35][CH2:34][CH2:33]1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[C:33]([CH3:32])=[CH2:22]
Reactant: C1CCOC1
Reactant: COC(=O)c1c[nH]c2ncnc(-c3ccc(F)c(N)c3)c12
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Product: C=C(C)C(=O)Nc1cc(-c2ncnc3[nH]cc(C(=O)OC)c23)ccc1F
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(3-amino-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.349 mmol) and DIPEA (183 μL, 1.05 mmol) in THF (1.7 mL) at room temperature was added methacyloyl chloride (36.5 mg, 0.349 mmol) and the solution was stirred for 1 hour. The desired product was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with 2 M aqueous potassium carbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give methyl 4-{4-fluoro-3-[(2-methylacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C18H16FN4O3 [M+H]+, 355; found 355. 1H NMR (600 MHz, DMSO-D6) δ 13.0 (s, 1H), 9.69 (s, 1H), 8.91 (s, 1H), 8.35 (s, 1H), 7.88 (d, 1H, J=7.04 Hz), 7.42 (m, 1H), 7.35 (t, 1H, J=9.39 Hz), 5.89 (s, 1H), 5.54 (s, 1H), 3.44 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]1[C:9]2=[C:10]([S:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:11]3[C:12]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:10]2[C:11]3[C:12]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][C:16]=3[N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:33])=[O:2])[C:9]=23)=[CH:27][CH:28]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(OC(C)C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(S(C)(=O)=O)c2c(Sc3ccc(Cl)cc3)c3n(c2c1)CCC3CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of the ester of Step 2 (70 mg) in THF/MeOH (3:1) mixture at r.t. was added 1 M LiOH aqueous solution (1 mL). The reaction mixture was stirred at r.t. for 1 hour. Then AcOH was added. The aqueous layer was extracted with EtOAC and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with 1% AcOH in EtOAc to give 60 mg of the title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]OS(C)(=O)=O.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K].O>CN(C=O)C>[F:1][CH2:2][CH2:3][CH2:4][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: CS(=O)(=O)OCCCF
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCF
Yield: 99.1 %

Procedure:
A solution of methanesulfonic acid 3-fluoro-propyl ester (34.5 g, 221 mmol) in 250 mL of anhydrous DMF was treated with solid potassium phthalimide (49 g, 265 mmol, 1.2 equiv) at 25° C. The resulting suspension was warmed to 70–80° C. for 2 hours. When 1H NMR showed that the reaction was complete, the reaction mixture was treated with H2O (200 mL). The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired 2-(3-fluoro-propyl)-isoindole-1,3-dione (45.4 g, 45.5 g theoretical, 99.7% yield) as a white powder.
Reaction SMILES: Cl.C[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([N:16](C(C)C)CC)(C)C.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH2:11]([O:10][C:8]([C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[NH:16][CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:9])[CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCOC(=O)C(=CNc1cc[nH]c1C(=O)OCC)C(=O)OCC
Temperature: 100 °C

Procedure:
Equimolar ratios of ethyl 3-methyl-1H-pyrrole-2-carboxylate hydrochloride, diisopropylethylamine and diethyl ethoxymethylenemalonate were mixed in a sealed tube and heated at 100° C. for 15 hours. After cooling to room temperature, column chromatography afforded the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:33]([C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:36])([F:37])[F:26])=[CH:30][CH:31]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.445 g) and 4-(trifluormethoxy)aniline (0.3 g) was dissolved in toluene (20 ml) under an argon atmosphere at RT, dimethylaluminium chloride in heptane (0.9 molar, 3.8 ml) was added and the mixture was refluxed for 3 hours. It was then cooled to RT, water (1 ml) was added and the reaction mixture was then stirred for 10 min. The solvent was evaporated off, the residue absorbed on silica gel and purified by flash chromatography (AcOEt/heptane, gradient from 0 to 25%) to give 8-(2-chloro-benzenesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one as a white solid. MS (ESI): 489.08 (MH+).