Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available (25)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
A solution of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.44 mmol), K2CO3 (124 mg, 1.89 mmol) in DMF (5 mL) was stirred at RT and CH3I (182 mg, 1.32 mmol) was added dropwise. The reaction was stirred at RT for 3 h. The reaction was concentrated, washed with H2O and filtered to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 73%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 5.88 (s, 1H), 3.34 (s, 3H), 3.10 (s, 3H), 3.05 (d, J=5.2 Hz, 3H). MS (M+H)+: 462/464.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O>O1CCCC1>[Br:28][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH:12]=1
Reactant: CC(C)(C)c1cc2ccc3ccc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Temperature: 30 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
Then, to a mixed solution of 100.6 g of 7-t-butyl-1-(4-chlorophenyl)pyrene, and 1638 ml of tetrahydrofuran was added 53.5 g of N-bromosuccinimide under a nitrogen stream. This mixed solution was stirred at 30° C. for about 5 hours, and concentrated, 984 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. To the resulting solid was added 539 ml of hexane, and the mixture was heated and stirred for about 1 hour, and filtered. After the resultant was vacuum dried, 112.0 g of 1-bromo-7-t-butyl-3-(4-chlorophenyl)pyrene was obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[C:15]1[CH:19]=[C:18]([SH:20])[N:17]([CH3:21])[N:16]=1.[F:22][C:23](I)([F:25])[F:24]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:7]=[C:6]([Cl:14])[C:5]=1[C:15]1[CH:19]=[C:18]([S:20][C:23]([F:25])([F:24])[F:22])[N:17]([CH3:21])[N:16]=1
Reactant: FC(F)(F)I
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.13 g of 60% oily sodium hydride in 10 ml of anhydrous tetrahydrofuran was added dropwise 0.7 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-mercaptopyrazole (2) in 2.0 ml of anhydrous tetrahydrofuran at 0° C., and the mixture was stirred at room temperature for 1 hour. Subsequently, with addition of an excess of trifluoromethyl iodide, the mixture was stirred for 4 hours as contained in a sealed container. Ice water was added to the reaction mixture, the mixture was thereafter extracted with ethyl acetate, and the extracts were combined together, washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5), giving 0.6 g of the desired compound in the form of a colorless oil (yield 48.6%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[CH2:16][CH2:17][CH3:18]>C(Cl)Cl.CCOC(C)=O>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(CO)nc2ccccn12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(CCl)nc2ccccn12
Reaction time: 1 h

Procedure:
Thionyl chloride (125 mg, 1.06 mmol) is added to a solution of 2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine (100 mg, 0.53 mmol) in CH2Cl2 (3 mL) at 0° C. under nitrogen with magnetic stirring. After 1 hour, the reaction is diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The solution is then dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain 2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine as a colorless oil. TLC (10% MeOH/CH2Cl2) Rf=0.60. Step 5. Preparation of 3-{1-[(3-propylimidazo[1,2-a]pyridin-2-yl)methyl]-1H-imidazol-2-yl}benzonitrile
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:19]([OH:21])=O)[CH3:3].C1N=C[N:24](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].C(OCC)(=O)C>C1COCC1>[CH3:1][CH:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:19]([NH2:24])=[O:21])[CH3:3]
Reactant: CC(C)Oc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2ccc(C(N)=O)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a room temperature solution of 1,7-bis-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 mg, 0.69 mmol) in 10 mL of THF is added N,N-carbonyldiimidazole (135 mg, 0.83 mmol). The solution is heated at reflux for 1 hour and cooled to room temperature. Aqueous NH4OH (4 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes, then poured into ethyl acetate, and washed with aqueous NaHCO3 and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is recrystallized from methanol and water to provide 1,7-bis-(1-methylethoxy)-2-naphthalenecarboxamide in 40% yield; mp 145°-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+].[CH3:22][C:23](CC(C)C)=[O:24].O.ClCC(Cl)=O>C(Cl)(Cl)Cl>[CH2:13]([N:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[NH:1][CH2:22][C:23]1=[O:24])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNc1cc(C(=O)OC)ccc1N
Reactant: CC(=O)CC(C)C
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCN1C(=O)CNc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of methyl 4-amino-3-(butylamino)benzoate (950 mg) and sodium bicarbonate (862 mg) in 1:1 isobutyl methyl ketone/water (20 mL) was added chloroacetyl chloride (0.41 mL), and the mixture was stirred for 1 h. The mixture was warmed to room temperature and refluxed for 14 h. The mixture was cooled to room temperature, diluted with chloroform, and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 850 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.89, 7.72, 6.80, 3.97, 3.88, 3.30-3.25, 1.68-1.58, 1.47-1.35, 0.94-0.88.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[H-].[Na+].BrC[CH2:20][CH2:21][CH2:22][C:23]#[N:24].CCOCC>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1ccc2c3c(cccc13)C(=O)N2CCCC#N
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2.15 g of 6-(methylthio)-benz-[cd]indol-2(1H)-one (Example 2), 0.6 g of 60% sodium hydride in 70 ml of N,N-dimethylformamide is heated at 50° C. for 30 minutes then cooled. A solution of 2.22 g of 1-bromo-4-cyano-butane in 25 ml of N,N-dimethylformamide is added dropwise to the reaction mixture and stirring continued for 3 hours. The reaction mixture is quenched in 400 ml of ice water and extracted with (2×300 ml) of ethyl acetate. The organic layer is dried with magnesium sulfate and evaporated to afford a solid which is stirred with ether, filtered and dried to yield 2.5 g of the desired product as a solid, m.p. 120°-122° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH3:46][C:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:53][S:50]([C:47]6([CH3:46])[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: CC1(S(N)(=O)=O)CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (58) and 1-methylcyclopropylsulfonamide following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl]-(cyclopropyl)sulfonamide 11: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-1.01 (m, 1H), 1.05-1.15 (m, 1H), 1.15-1.45 (m, 4H), 1.45 (d, J=6.9 Hz, 6H), 1.4-1.5 (m, 3H), 1.55 (s, 3H), 1.6-1.8 (m, 2H), 2.85-2.95 (m, 1H), 2.15-2.25 (m, 2H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 1H), 2.6-2.7 (m, 1H), 2.65 (s, 3H), 2.9-3.0 (m, 1H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.85 (d, J=10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J=11.3 Hz, J=3.6 Hz, 1H), 4.6 (t, J=8.0 Hz, 1H), 5.0 (t, J=10.6 Hz, 1H), 5.5 (t, J=3.3 Hz, 1H), 5.60-5.70 (m, 1H), 6.75 (s, 1H), 7.02 (s, 1H), 7.2 (d, J=9.2 Hz, 1H), 7.5 (s, 1H), 7.9 (d, J=9.2 Hz, 1H), 11 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[C-:32]#[N:33].[Na+].O>CN(C)C=O>[C:32]([C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:15])([F:16])[F:14])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])#[N:33]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitro-benzamide (2.008 g, 4.4 mmol) (prepared according to WO 05/073165) in N,N-dimethylformamide (25 ml) was added sodium cyanide (0.237 g, 4.84 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. Then water (20 ml) was added and the organic phase extracted three times with ethyl acetate (3×100 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:4) to give 4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (1.0 g, 49% yield). 1H-NMR (400 MHz, CDCl3): 8.85 (d, 1H), 8.38 (q, 1H), 8.11 (d, 1H), 7.55 (s, 1H), 7.40 (s, 2H), 2.33 (s, 6H) ppm.
Reaction SMILES: [Tl].C([O-])(=O)C.[F:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C.CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(=O)[O-]
Agent: [Tl]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Following the procedure of Example 2, the enol ether of the formula ##STR2## is reacted with thallium (lll) acetate in an aqueous acetic acid/hexane mixture at 25° to 50° C. until methyl 2-(2-fluoro-4-biphenylyl)propionate is formed. This ester is isolated from the reaction mixture and hydrolyzed to 2-(2-fluoro-4-biphenylyl)propionic acid (generic name, flurbiprofen) by the described procedure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([C:35]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:36])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(c1cccc(Br)n1)N1CCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)N5CCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (6-bromo-pyridin-2-yl)-pyrrolidin-1-yl-methanone.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31](O)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].O>CN(C=O)C>[CH3:48][S:49]([NH:52][C:31](=[O:32])[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:51])=[O:50]
Reactant: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)O)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)NS(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of [4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg), and after 30 min, methanesulfonamide (23 mg) and 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (37 mg) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was added with water to complete the reaction. It was extracted with EtOAc, the obtained organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain N-(methylsulfonyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (56.4 mg) as a white solid.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([OH:22])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[CH:24]1C=CC=CC=1.IC>>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([O:22][CH3:24])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C(O)C(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: c1ccccc1
Solvent: CI
Product: COC1=C2CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C2C[C@@H]2C1=O
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of 1,2β-methylene-4-hydroxyandrost-4-ene-3,17-dione (0.314 g, 1 mmol) in benzene (10 ml) potassium tert-butoxide (0.224 g, 2 mmol) is added and the mixture heated to reflux for 30 min. After cooling, iodomethane (0.710 g, 5 mmol) is added and the mixture boiled for further 2 hours. Then the organic solution is washed with water, dried and evaporated in vacuum. The flash column chromatography of the residue on silica gel using n-hexane/ethylacetate 60:40 affords 0.246 g (75% yield) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH3:16][C:17]1([CH3:40])[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][C:21]([O:36][CH2:37][CH2:38][CH3:39])=[C:22]([C:33](=O)[CH3:34])[CH:23]=2)[O:18]1>>[CH3:40][C:17]1([CH3:16])[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:24]2[C:19](=[CH:20][C:21]([O:36][CH2:37][CH2:38][CH3:39])=[C:22](/[C:33](/[CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:23]=2)[O:18]1
Reactant: CCCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.41 mL, 1.61 mmol) and 1-(2,2 dimethyl-4-phenyl-7-propoxy-2H-chromen-6-yl)-ethanone (Compound 67, 180 mg, 0.54 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1>CSC.CCCCCC.[Cu](I)I>[CH2:1]([CH:8]1[CH2:9][CH2:10][CH2:11][C:6](=[O:12])[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: O=C1C=CCCC1
Agent: I[Cu]I
Solvent: CCCCCC
Solvent: CSC
Product: CCCCC1CCCC(=O)C1
Temperature: -78 °C

Procedure:
A solution of copper iodide (6.3 mmol) in dimethyl sulphide (12 ml) is cooled to 50° C. A solution of butyl lithium (6.2 mmol) is added dropwise accompanied by stirring and stirred for a further 5 to 15 mins. The reaction mixture is cooled to −78° C. and then a solution precooled to −78° C. of cyclohex-2-enone (6 mmol), dissolved in dimethyl sulphide (1 ml), is slowly added dropwise. After stirring for one hour at −78° C. the mixture is quenched with saturated aqueous ammonium chloride solution. The reaction mixture which has been heated to room temperature is extracted with diethyl ether. The combined ether phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulphate. After evaporating-off of the solvent the residue obtained is taken up in hexane, the solution is filtered and concentrated by evaporation. After chromatography of the residue on silica gel with ethyl acetate/hexane 1:4 pure 3-butylcyclohexanone is obtained (Tetrahedron 1989, 45 (2), 425-434).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:26][C:27]1[CH:31]=[CH:30][O:29][CH:28]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: BrCc1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.14 g (3.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 30 ml of anhydrous DMF and, at room temperature, carefully added to a suspension containing 0.24 g (6.05 mmol) of 60% sodium hydride. This mixture was stirred for 30 minutes and 8.2 ml (4.92 mmol) of a freshly prepared 0.6 M solution of 3-bromomethylfuran in ethyl ether were dropwise added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude mixture was extracted between ethyl acetate and water. The organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel affording 1.4 g (97% of yield) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](=[O:25])[CH3:24].O>O1CCCC1>[C:23]([CH:22]([C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14])[C:10](=[S:11])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:25])[CH3:24]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C(=S)Nc1ccc(F)cc1F)c1ccc(Cl)cc1Cl
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
2,4-Difluorophenyl isothiocyanate (0.27 mL, 2.0 mmol) was added to a stirred suspension of sodium hydride (60% in mineral oil) (112 mg, 2.8 mmol) in anhydrous tetrahydrofuran (4 mL) cooled in an ice-water bath under a nitrogen atmosphere. A solution of 1-(2,4-dichlorophenyl)-2-propanone (570 mg, 2.8 mmol) in tetrahydrofuran (4 mL) was added dropwise over 5 min. The resultant yellow solution was stirred at 5-10° C. for 1 h. Water (10 mL) was carefully added, and the reaction mixture was extracted with ethyl acetate (10 mL). The aqueous phase was acidified to pH 3 with 1 N aqueous HCl, then extracted with ethyl acetate (20 mL). The organic extract was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a solid. The solid was triturated with hexanes/ethyl acetate (2:1), collected on a glass frit, and air-dried to give the title compound as a white solid (240 mg). MS: 373 amu (AP+).