Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=1[CH2:29]Br>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=1[CH2:29][N:11]1[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]1=[O:14]
Reactant: CS(=O)(=O)Oc1ccc(Br)c(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc(OS(C)(=O)=O)ccc2Br)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino)-2-oxopyrrolidine, as described above in Step A, (1.00 g, 4.99 mmol) in THF (10 mL) was added sodium hydride (230 mg of a 60% dispersion in oil, 5.75 mmol) in THF (5 mL), dropwise. The resulting mixture was stirred for 30 min at ambient temperature, then a solution of methanesulfonic acid 4-bromo-3-bromomethylphenyl ester, as described above in Step C, (1.96 g, 5.70 mmol) in THF (6 mL) was added dropwise and stirring was continued for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (3 mL), then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated and the organic extract was washed with H2O, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2—5% MeOH, to yield the titled product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[CH:8]=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C#Cc1cncc(S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1cncc(S(C)(=O)=O)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 80 %

Procedure:
The title compound was synthesized from (5-methanesulfonyl-pyridin-3-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 80% yield. Mass Spectrum (LCMS, ESI) calculated for C29H31N4O5S: 547.2 (M-Boc+H); found 547.3 (-Boc).
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1>C(OC(OCC)(OCC)C)C>[F:20][C:19]1[C:2]2[N:1]=[C:23]([CH3:24])[O:22][C:3]=2[C:4]2[NH:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:5]=2[C:18]=1[F:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(I)cc2F)c1O
Agent: CCOC(C)(OCC)OCC
Product: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(I)cc3F)c2o1
Yield: 535.7 %

Procedure:
Intermediate I-18a was prepared from 5-amino-6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-13a: 550 mg, 1.3 mmol) in 1,1,1-triethoxy-ethane (5 mL) and p-toluene sulfonic acid (20 mg, 0.13 mmol) using procedures analogous to those described above for Intermediate I-16a to afford 310 mg of the product (53.6% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.39 (s, 1H), 7.96 (dd, 1H), 7.78 (d, 1H), 7.48 (t, 1H), 2.67 (s, 3H). LCMS: 92.6%, m/z=445.9 (M+1).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)(O)[CH2:6][CH2:5]2)[O:3]C1.O>C(O)(C(F)(F)F)=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CC=C(c2ccc(F)cc2)CC1
Yield: 103.9 %

Procedure:
Compound 4-(4-Fluoro-phenyl)-4-hydroxy-cyclohexanone ethylene ketal (8.23 g, 32.6 mmol) from Step 1 was stirred in TFA (25 mL) for 15 minutes. The reaction mixture was poured into H2O (100 mL) and then extracted with CHCl3 (2×75 mL). The organic solution was washed with saturated bicarbonate, dried (Na2SO4), filtered and concentrated under reduced pressure to afford crude 1-(4-fluorophenyl)-cyclohexen-4-one (6.44 g): 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, J=8, 8 Hz, 2H), 7.04 (dd, J=8, 8 Hz, 2H), 6.05 (m, 1H), 3.05 (m, 2H), 2.87 (m, 2H), 2.65 (dd, J=7, 7 Hz, 2H).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([OH:22])(=O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC)(=O)C.P(Cl)(Cl)([Cl:31])=O.[Cl-].[Na+]>O.CN(C)C=O>[CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([Cl:31])(=[O:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)Cl
Reaction time: 0.17 h

Procedure:
To a solution composed of 32.7 g (0.1 mol) of dodecylbenzenesulfonic acid, 80 ml of ethyl acetate, and 12 ml of dimethylformamide (DMF) was added dropwise 12.4 ml (0.15 mol) of phosphorus oxychloride with stirring over a period of 10 minutes and then while heating the mixture so as to maintain the temperature thereof at 40° C., the reaction was performed for 60 minutes. After the reaction was over, the reaction mixture was cooled to 5° to 10° C. and then a solution composed of 16 g of sodium chloride and 160 ml of water was added dropwise to the reaction mixture over a period of 15 minutes. After removing an aqueous layer, an ethyl acetate layer thus formed was washed once with 100 ml of an aqueous 10% sodium chloride solution. The ethyl acetate solution of dodecylbenzenesulfonyl chloride obtained was used for the subsequent reaction as it was.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C(=O)N([Cl:20])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:20][C:3]1[C:4]2=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1ccc2[nH]ccc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2[nH]cc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (517.0 mg, 3.23 mmol) in anhydrous DMF (5.0 mL) at 0° C. was added a solution of NCS (462.0 mg, 3.39 mmol) dissolved in anhydrous DMF (10 mL). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 18 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with sat'd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with EtOAc/heptane. Recovered product was crystallized from DCM to afford 600 mg (95.5%) of 1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H), 8.01 (d, J=2.9 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 2.71 (s, 3H); MS (ESI) m/z: 195.2 [M+1]+.
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3](=[O:2])[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 98.7 %

Procedure:
A solution of 36.12 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 hours at room temperature with 2.76 g of para-toluenesulfonic acid. Then, it is concentrated by evaporation in a vacuum to 1/3 of the volume, taken up with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 31.7 g of 3-hydroxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one is obtained as crystals with a melting point of 194-196° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.OS(O)(=O)=O>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([B:16]([OH:21])[OH:17])=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Butyl lithium (BuLi) (5.6 mL, 1.40 equiv) was added dropwise to a solution of 5-bromobenzo[d][1,3]dioxole (2 g, 9.95 mmol, 1.00 equiv) and triisopropyl borate (1.96 g, 14.00 mmol, 1.40 equiv) in THF (20 mL) at −78° C. in a 100-mL 3-necked round-bottom flask under an inert atmosphere of nitrogen. The mixture was stirred at room temperature for 4 hr, quenched with water (10 mL), and acidified with H2SO4 (4.9 g, 50.00 mmol, 5.00 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux. The solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting solid material was washed with 3×3 mL of ethyl acetate. This resulted in 0.5 g (30%) of benzo[d][1,3]dioxol-5-ylboronic acid as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[CH2:23]Cl)[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[CH2:23][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.9 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(3,4-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 58 mg (41%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.41 (m, 2H), 7.55 (t, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.25 (d, J=6 Hz, 1H), 10.08 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][C:13]=1[C:25](O)=[O:26]>>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:25]([C:13]3[CH:14]=[CH:15][C:16]4[C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:23][C:24]=4[CH:12]=3)=[O:26])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (50 mg, 0.35 mmol) and 9H -fluorene-2-carboxylic acid (D71) (83 mg, 0.38 mmol) as an off-white solid. MS(ES): MH+ 337, M-H+ 335.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:14][CH3:15])([CH3:13])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1>>[CH2:14]([C:10]([CH3:13])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1)[CH3:15]
Reactant: CCC(C)(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1cc2ncnn2nc1Cl
Product: CCC(C)(COc1nn2ncnc2cc1C)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 189°-190° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]([CH3:28])[CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:29]/[C:30](/[CH3:38])=[CH:31]\[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33].[N+:39]([C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH:45]=O)([O-:41])=[O:40]>CC(O)C>[CH3:5][C:3]1[NH:29][C:30]([CH3:38])=[C:31]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH:45]([C:44]2[CH:47]=[CH:48][CH:49]=[C:42]([N+:39]([O-:41])=[O:40])[CH:43]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][N:10]([CH3:28])[CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:6]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN(C)C/C(C)=C/c1ccc(Cc2cccnc2)cc1
Reactant: C/C(N)=C/C(=O)OC(C)C
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCN(C)C/C(C)=C/c2ccc(Cc3cccnc3)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Yield: 71.5 %

Procedure:
In 4 ml of 2-propanol were dissolved 1.01 g of 2-[N-methyl-N-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl]amino]ethyl acetoacetate, 0.38 g of isopropyl 3-aminocrotonate and 0.40 g of 3-nitrobenzaldehyde, and the resulting mixture was subjected to reaction under reflux for 3 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 1.28 g (yield 71.5%) of yellow, oily 3-[2-[N-methyl-N-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl]amino]ethyl] 5-isopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1[NH2:4].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:3]([NH2:4])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1F
Reactant: NCc1ccc(F)cc1
Agent: II
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])cc(F)c(NCc2ccc(F)cc2)c1F
Temperature: 120 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a stirred suspension of compound 2 (0.060 g, 0.31 mmol, 1.0 equiv) in dry DMSO (0.3 mL) was added 4-fluorobenzylamine (0.117 g, 0.940 mmol, 3.00 equiv) followed by Et3N (54.0 μL, 0.370 mmol, 1.20 equiv) and I2 (catalytic, 1.0 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 16 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.064 g, 69%) as yellow solid. TLC: 25% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, J=2.0, 12.8 Hz, 1H), 7.31-7.28 (m, 2H), 7.05 (t, J=6.8 Hz, 2H), 6.05 (br s, 2H, Exc), 4.63 (d, J=6.0 Hz, 2H), 4.53 (br s, 1H, Exc); LC-MS: m/z=296 (M+-1) at RT 3.64 (98.8% purity)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@@H:8]([C:16](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:17])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[OH:32]O>C1COCC1.O>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:16]([OH:17])=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: OO
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-nonanoic acid tert-butyl ester (2.65 g, 6.14 mmol) in 20 mL THF at 0° C. was added a precooled (0° C.) solution of LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt % aqueous soln, 5.0 mL) in 10 mL H2O. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred 90 minutes. The reaction was quenched at 0° C. by addition of 100 mL 10% NaHSO3 (aq), then extracted with Et2O. The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. The titled compound was used without purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1F)[C:25]#[N:26].C(OCC)(=O)C>CS(C)=O.O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[C:10]([C:11]([F:14])([F:12])[F:13])=[N:9]1)[C:25]#[N:26]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: FC(F)(F)c1n[nH]c2nccc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Compound (153a) (0.200 g), cesium carbonate (0.880 g), and 3-chloro-4-fluorobenzonitrile (0.154 g) were suspended in DMSO (50 mL), followed by stirring at 60° C. for 24 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain 3-chloro-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. This 3-chloro-4-{4-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, 4-(1-(hydroxymethyl)-1H-pyrazol-4-yl)-1H-imidazole hydrochloride (0.129 g), potassium carbonate (0.263 g), and copper(II) oxide (nanopowder) (0.020 g) were suspended in DMF (2.5 mL), followed by stirring at 120° C. for 24 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The solvent of the filtrate was distilled away, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (188) (0.012 g, 3%).
Reaction SMILES: Br/[CH:2]=[CH:3]/[C@H:4]([OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(NCC)C.[CH:20](/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:21]\[CH:22]=[CH:23]\[C:24]#[CH:25]>C1COCC1.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.[Cu]I>[OH:14][C@H:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)/[CH:3]=[CH:2]/[C:25]#[C:24]/[CH:23]=[CH:22]/[CH:21]=[CH:20]/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)OC
Reactant: O[C@@H](/C=C/Br)COc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
In a flame dried flask, a solution of (1E,3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene (0.84 g, 3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.2 mmol) and copper(I) iodide (60 mg, 0.3 mmol) in THF (50 mL) and diethylamine (5 mL, 48 mmol) was carefully deoxygenated by bubbling in argon gas for 45 minutes. The reaction was stirred as a solution of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (0.9 g, 3.2 mmol) in THF (50 mL), which had been deoxygenated by bubbling in argon for 45 minutes, was added. After about 4 hours, the reaction was complete. The reaction mixture was diluted with hexane and filtered through a pad of silica gel and the silica gel was eluted with ether. The combined filtrates were concentrated to give an oil. Purification by chromatography using a 20-75% gradient of ether in hexane gave 1.1 g of 2-[[(4S,5R)-5-[(1E,3E,7E,9S)-9-hydroxy-10-(4-fluorophenoxy)-1,3,7-decatrien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (EE), as an oil; 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.5 (s, 3H), 3.52 (m, 2H), 3.75 (s, 3H), 3.83 (m, 2H), 4.13 (m, 2H), 4.44 (m, 1H), 5.74 (m, 1H), 5.76 (m, 2H), 6.05 (m, 1H), 6.17 (m, 1H), 6.29 (m, 1H), 6.58 (dd, 1H), 6.88 (m, 4H) ppm.
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C=CC=CC=1.C(OC(=O)[NH:23][C@@H:24]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[C:40]3[O:39]C(C(C)(C)C)=[N:37][C:36]=3[CH:35]=[CH:34][C:33]=2[Cl:45])(=[O:31])=[O:30])[CH2:25]1)(C)(C)C.OS(O)(=O)=O>O1CCOCC1.O>[NH2:37][C:36]1[C:40]([OH:39])=[C:32]([S:29]([N:26]2[CH2:27][CH2:28][C@@H:24]([NH2:23])[CH2:25]2)(=[O:31])=[O:30])[C:33]([Cl:45])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)C1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Solvent: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CC[C@@H](N)C2)c1O
Yield: 95.4 %

Procedure:
Following the general procedure for the hydrolysis of the benzooxazole to the desired aniline outlined in example 51, [(R)-1-(2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (2.0 g, 4.31 mmol), water (3.6 mL), and H2SO4 (3.6 mL) in 1,4-dioxane (60 mL) were reacted to afford the title compound (1.2 g, 94%). LCMS m/z 292(M−H)+.
Reaction SMILES: ClC1(Cl)C(=O)[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C.CC[O:27][CH2:28][CH3:29]>C(O)(=O)C.[Zn]>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]12[CH2:29][C:28](=[O:27])[CH2:8][CH:7]1[CH2:3][CH2:4][CH2:5]2
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC1CCC2C1CC(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC2CCCC2(CCCCCO)C1
Temperature: 70 °C

Procedure:
The starting material, 6,6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichloro-4-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]hexahydro-2(1H)-pentalenone} (12.1 g, 0.30 moles) is dissolved in glacial acetic acid (85 ml) and the solution is stirred while zinc (25 g) is slowly added. The reaction is heated at 70° C. for 1 hour, after which time ether (100 ml) is added and the solution filtered. The filtrate is washed with brine and then neutralized with saturated sodium bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (0.72 g, 3.4 mmoles).