Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.N1CCCCC1>C(#N)C>[CH3:14][O:15][CH:16]([O:19][CH3:20])/[CH:17]=[C:9](/[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])\[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CS(=O)c1ccccc1
Reactant: COC(C=O)OC
Solvent: CC#N
Solvent: C1CCNCC1
Product: COC(=O)/C(=C\C(OC)OC)S(=O)c1ccccc1
Temperature: 60 °C
Yield: 99 %

Procedure:
A mixture of methyl 2-(phenylsulfinyl)acetate (1 g, 5.04 mmol), 2,2-dimethoxyacetaldehyde (3.15 ml, 10.09 mmol) and piperidine (0.999 ml, 10.09 mmol) in acetonitrile (20 ml) was heated to 60° C. for 18 hr. After cooling to rt, the volatiles were removed in vacuo and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-40% EtOAc/Hex gradient. The pure fractions were concentrated to afford (E)-methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate (1.42 g, 4.99 mmol, 99% yield) as a light yellow oil. HPLC retention time=1.23 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+Na)=307.06. 1H NMR (500 MHz, chloroform-d) δ ppm 3.40 (s, 3H), 3.41 (s, 3H), 3.69 (s, 3H), 5.71 (d, J=7.2 Hz, 1H), 7.07 (d, J=6.6 Hz, 1H), 7.48 (m, 3H), 7.66 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][O:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1cccc(Oc2ccccc2Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1Cl
Yield: 67.6 %

Procedure:
A mixture of 2-[2-hydroxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.9 g), methyl iodide (2.3 g) and potassium carbonate (2.2 g) in acetone (40 ml) was refluxed under heating for 4.5 hrs. After cooling, the reaction mixture was filtered. The filtrate was evaporated, and the oily residue was dissolved in methanol (30 ml). To the solution was added potassium hydroxide (1 g), and the mixture was refluxed under heating for 30 minutes. After cooling, the reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was recrystallized from a mixture of benzene and n-hexane to give 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.35 g). mp 87°-92° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[N:39]=[C:38]([CH3:40])[CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[N:39]=[C:38]([CH3:40])[CH:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting with 5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid. ESI-MS (m/z): 328 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:31]([NH2:33])=[O:32])=[N:9]2)=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[CH3:55][C:56]([OH:60])([CH:58]=[CH2:59])[CH3:57].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:14]2[CH2:13][CH2:12][C:11]3[C:10]([C:31]([NH2:33])=[O:32])=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2](/[CH:59]=[CH:58]/[C:56]([OH:60])([CH3:57])[CH3:55])=[CH:3][CH:4]=4)[C:16]=3[C:15]=2[CH:17]=1)=[O:30]
Reactant: NC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Reactant: C=CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)/C=C/c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 100 °C
Yield: 21.6 %

Procedure:
A 50 mL round bottomed flask with a magnetic stir bar was charged with 1-(4-bromophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (987 mg, 1.89 mmol), palladium (II) acetate (44 mg, 0.19 mmol), 1,1′-biphenyl-2-yl[di(tert-butyl)]phosphine (254 mg, 0.822 mmol), and dimethylformamide (20 mL). The resulting solution was sparged with argon for 10 minutes. To the solution was added 2-methyl-3-buten-2-ol (823 mg, 6.07 mmol) and triethylamine (614 mg, 6.07 mmol). The solution was sparged with argon for an additional 2 minutes. The flask was sealed with a rubber septum and heated to 100° C. in an oil bath for 90 minutes. The reaction was allowed to cool to room temperature and water was added. The resulting precipitate was collected and purified by silica gel chromatography (100% hexane to 100% ethyl acetate). The pure fractions were combined, concentrated to dryness, triturated with diethyl ether, and dried under vacuum to give 215 mg of 8-[(2-chlorobenzoyl)amino]-1-{4-[(1E)-3-hydroxy-3-methylbut-1-enyl]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (0.408 mmol, 21% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (s, 6 H), 2.88-2.98 (m, 4 H), 4.76 (s, 1 H), 6.48 (d, 1 H), 6.58 (d, 1 H), 7.23 (d, 1 H), 7.30-7.50 (m, 8 H), 7.53-7.59 (m, 3 H), 10.28 (s, 1 H); MS (ESI+) for C30H27ClN4O3 m/z 527 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:18].[H][H]>O1CCCC1.[Ni]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]2=[O:18])=[C:2]([CH3:1])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCCOC1=O
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1N1CCCCOC1=O

Procedure:
1.95 g (7.79 mmol) 3-(2-methyl-4-nitro-phenyl)-[1,3]oxazepan-2-one are dissolved in 200 ml of tetrahydrofuran and combined with 700 mg Raney nickel. The mixture is hydrogenated in a Parr apparatus at ambient temperature at 1 bar hydrogen pressure for four hours. Then the catalyst is filtered off and the filtrate is evaporated down i. vac.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].BrC1C=CC(CCCC(NC2C=CC(S(CC)(=O)=O)=C(C=2)CN[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=O)=CC=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.B(O)O>>[C:51]([O:50][C:49]([NH:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CNC(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: OBO
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CNC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 15B (0.541 g, 1.0 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl](0.249 g, 1.1 mmol) and then hydrolyzed to the free boronic acid to give 15C (334 mg, 82%) as a peach colored foam. MS (ESI) m/z 505.03 (M+H)+.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[O:14]1[CH2:19][CH2:18]C(=O)[CH2:16][CH2:15]1.[OH-].[Na+]>O1CCCC1.CO>[C:6]([CH:4]=[C:5]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)([OH:8])=[O:7]
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: O=C1CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=C1CCOCC1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
Methanol (204 ml) was slowly added to a suspension of sodium hydride (5.48 g, 228.2 mmol) in tetrahydrofuran (204 ml) at 0° C. When addition was complete, trimethylphosphonoacetate (34.22 ml, 211.4 mmol) was added to the mixture at such a rate as to maintain the temperature below 12° C. Stirring was continued for a further 10 minutes. To this reaction mixture was added a solution of 2,3,5,6-tetrahydropyran-4-one (16.28 g, 163.0 mmol) in tetrahydrofuran (20 ml), keeping the temperature below 30° C. After the addition was complete, stirring was continued for 30 minutes at room temperature, then methanol (100 ml) and 2M sodium hydroxide (326 ml) was added, and the mixture stirred overnight at room temperature. The resulting solution was concentrated to one half of the original volume, and acidified to pH 1.2 with 6M hydrochloric acid (108 ml). The reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts dried over magnesium sulfate, and solvent removed under reduced pressure to give 4-(carboxymethylene)-2,3,5,6-tetrahydropyran (22.62 g), which was used with no further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]>>[CH3:21][C:22]1[CH:23]=[C:24]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1C
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1C

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3,4-dimethylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 61 of molecular weight 463.58 (C28H33NO5), MS(ESI): 464.22 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>C(OCC)C>[CH3:22][O:16][C:15](=[O:17])[C@H:11]([C@@H:12]([CH3:14])[OH:13])[NH:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: C[C@@H](O)[C@H](NC(=O)COc1ccc(Cl)cc1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)[C@@H](C)O
Reaction time: 0.5 h

Procedure:
After the reaction was completed, the mixture was extracted twice with ethyl ether to eliminate unreacted p-chlorophenoxychloride, and the extracted aqueous phase was acidified with hydrochloric acid to precipitate a product which was then extracted three times with ethyl acetate. The extract was evaporated to dryness, and the residue was recrystallized from ethyl acetate/benzene/hexane to obtain a color-less crystal of N-(p-chlorophenoxy)acetyl-L-threonine. To a solution of 5 m moles of N-(p-chlorophenoxy)acetyl-L-threonine in ethyl ether, a solution of an excess amount of diazomethane in ethyl ether was added, and the mixture was allowed to stand for 30 minutes at a room temperature. The mixture was evaporated to dryness under a reduced pressure to obtain N-(p-chlorophenoxyacetyl)-L-threonine methyl ester. 3.4 m moles of N-(p-chlorophenoxyacetyl)-L-threonine methyl ester was dissolved in dried pyridine, and the resulting solution was added with 3.6 m moles of p-toluenesulfonyl chloride, stirred at 0° C. for two hours and at a room temperature for two hours. The reaction mixture was then partitioned between water and ethyl acetate, and organic phase was washed with 1N hydrochloric acid and water, and dried on anhydrous sodium sulfate. The solution was evaporated to dryness, and the resulting residue was purified by a middle pressure column chromatography with silica gel to obtain N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester. 0.5 m moles of N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester was then dissolved in 10 ml of methanol, the resulting solution was added with 1.5 ml of 1N sodium hydroxide and stirred for 20 minutes at a room temperature, and methanol was distilled off. The residue was acidified with 1N hydrochloric acid, and extracted with ethyl ether, and an organic phase was dried on anhydrous magnesium sulfate. Solvent was distilled off from the mixture to obtain a residue. The residue was then chromatographically purified to obtain the title compound N-(p-chlorophenoxyacetyl)-α,β-dehydrohomoalanine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17]Cl)=[N:15][N:16]=2)[CH:3]=1.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)=[N:15][N:16]=2)[CH:3]=1
Reactant: Cn1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Temperature: 90 °C
Yield: 93.1 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-methyl-1H-indazole (260 mg, 0.794 mmol) and 1-(1-methylethyl)piperazine (1.5 ml, 0.794 mmol) were added to a microwave vial. The reaction mixture was heated under microwave irradiation at 90° C. for 15 mins. The reaction mixture was evaporated under a stream of nitrogen, dissolved in DCM (20 ml) and washed with a 10% solution of 2M hydrochloric acid in water. The layers were separated by hydrophobic frit and the aqueous layer was neutralised to pH=7 with 2M sodium hydroxide then extracted with DCM (20 ml). The organic layer was collected and the solvent removed in vacuo to give the title compound as an orange solid (310 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:24]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH2:13][Br:24])[CH2:3]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12

Procedure:
To a flask containing a solution of 3α-hydroxy-5β-pregnan-20-one (5.15 g, 16.5 mmol) in methanol (100 mL) was added a solution of bromine (1.1 mL) in methanol (30 mL) dropwise in such a rate to maintain the brown color of the bromine until this color was persistent. Then water (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined extracts were dried over Na2SO4. Removal of the solvent resulted in the product as a foamy white solid (6.63 g). Other 21-bromo-pregnan-20-ones (3β-ethynyl-3α-hydroxy-21-bromo-5β-pregnan-20-one, 3β-methyl-3α-hydroxy-21-bromo-5α-pregnan-20-one and 3α-hydroxy-3β-trifluoromethyl-12-bromo-5β-19-norpregnan-20-one) were synthesized using the same method.
Reaction SMILES: N1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>>[CH:17]1[CH:18]=[CH:19][CH:20]=[C:13]2[C:14]=1[C:15]1[NH:16][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]=1[C:2](=[O:3])[NH:12]2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NCc1ccccc1N
Product: O=c1[nH]c2ccccc2c2[nH]c3ccccc3c12

Procedure:
Specifically, as shown in Scheme 1, reaction of isatin (1) and 2-aminobenzylamine (2) gives 5,11-dihydro-indolo[3,2-c]quinolin-6-one (3), which may be treated with POCl3 to yield 6-chloro-11H-indolo[3,2-c]quinoline (4), which may be further reacted with either an amine of formula R—NH2 or a diamine of formula H2N—R—NH2 to give a corresponding compound of either formula (IA) or formula (IB).
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C:10]=3[C:9]1=[CH:8][CH2:7][C:6]2=[O:24])[CH:2]([CH3:4])[CH3:3].[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C@:5]12[CH2:13][CH2:12][C:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C:10]=3[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC=C12
Agent: [Pd]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
To a pre-reduced suspension of 2% palladium on calcium carbonate catalyst (7.0 g) in benzene (30 cc) add a solution of 13β-isobutyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (20.0 g) in benzene (500 cc) and hydrogenate the mixture at atmospheric pressure until one mole equivalent of hydrogen is consumed. After the catalyst is removed by filtration, evaporate the solvent to obtain a gum which on crystallization from ethanol affords the title product (17.1 g.; 71%), m.p. 117°-119°; ultraviolet absorption peak at 278 mμ (ε14,560).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20]O)=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH2:43]([NH:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: CC(C)CNCC(C)C
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reaction time: 72 h

Procedure:
A solution of N-[4-chloro-5-(3-hydroxy-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (9.0 g, 19.7 mmol) and Et3N (2 mL) in DCM (50 mL) was treated with MsCl (15.3 mL, 19.7 mmol) at 0° C. for 20 min and evaporated to give a yellow solid, containg mostly the desired mesylate (10.7 g). An aliquot of this solid (106.8 mg, 0.2 mmol) was treated with diisobutylamine (25.9 mg, 24.8 μL) in DCM (2 mL) at 0° C. for 10 h, and then at 25° C. for 3 days. Evaporation and prepartive plate chromatography gave the title compound.
Reaction SMILES: Cl.Cl.[N:3]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1([O:24][C:25](=O)[N:26]([C:36]2[CH:41]=[C:40]([O:42][C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]4([C:55](=[O:64])[NH:56][C:57]5[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=5)[CH2:54][CH2:53]4)=[O:51])=[C:45]([F:65])[CH:44]=3)[CH:39]=[CH:38][N:37]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:3]1([CH:7]2[CH2:10][N:9]([C:25]([NH:26][C:36]3[CH:41]=[C:40]([O:42][C:43]4[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]5([C:55]([NH:56][C:57]6[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=6)=[O:64])[CH2:54][CH2:53]5)=[O:51])=[C:45]([F:65])[CH:44]=4)[CH:39]=[CH:38][N:37]=3)=[O:24])[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CN(C2CNC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CC(N2CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a suspension of 3-(azetidin-1-yl)azetidine dihydrochloride (111 mg) in N,N-dimethylformamide (1.5 ml) was added triethylamine (0.167 ml), followed by stirring at room temperature for 15 min. A crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) was added thereto, followed by stirring at room temperature for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated and the residue was purified by LC-MS. Fractions containing the target compound were concentrated, and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and to the resultant solid (31.5 mg) was added diethyl ether (2 ml) to suspend. This was collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as colorless powder (5.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:28](=[O:29])[N:27]([CH3:31])[CH3:26]
Reactant: CN(C)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.Cl.[CH3:34][NH:35][OH:36]>ClCCl>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]([N:35]([OH:36])[CH3:34])=[O:18])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(SCC(=O)O)cc1
Reactant: CNO
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1ccc(SCC(=O)N(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenylthio]-acetic acid in 75 ml of dichloromethane and 0.8 ml. triethylamine, is cooled in an ice bath. To this solution is added 0.5 ml of trimethylacetyl chloride and the solution is stirred at room temperature overnight. Triethylamine (2 ml) is added followed by 1 g of N-methylhydroxylamine hydrochloride and the mixture is kept at room temperature for 20 hours. The mixture is washed with 0.3 N aqueous hydrochloric acid, ice cold dilute sodium bicarbonate and brine. The organic phase is dried over MgSO4 and filtered. The solvent is evaporated at 50° at reduced pressure, the residue is dissolved in diethyl ether and the solutions filtered through 10 g of silica gel to yield 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenylthio]-N-hydroxy-N-methylacetamide; NMR (DMSO-d6 : δ7.1, 5.85, 3.25, 1.95.