Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][C@@H:36]([CH3:40])[CH2:37][NH:38][CH3:39])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][C@@H:36]([CH3:40])[CH2:37][N:38]([CH3:39])[C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CS(=O)(=O)CC(=O)O
Product: C[C@@H](CN(C)C(=O)CS(C)(=O)=O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 61 %

Procedure:
The procedure described in Example 1 was repeated using methanesulfonylacetic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 61% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.95 (s, 3H), 3.15 (s, 3H), 3.37 (dd, 1H), 4.30 (m, 1H), 4.41 (d, 2H), 5.11 (m, 1H), 5.29 (s, 2H), 7.24 (m, 2H), 7.30 (d, 1H), 7.35 (m, 1H), 7.57 (d, 1H), 7.64 (dd, 1H), 7.70 (t, 1H), 7.86 (dt, 1H), 8.11 (d, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.88 (s, 1H); Mass Spectrum MH+ 570.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[C:8][CH2:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11])(=[O:4])[CH2:2][CH3:3]>C(O)C.[Pd]>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])(=[O:4])[CH2:2][CH3:3]
Reactant: C=C(CC#CCOC(=O)CC)CC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)OCCCCC(C)CC(C)(C)C
Yield: 74.5 %

Procedure:
1.11 g (5 mM) of 5-(2,2-dimethylpropyl)-5-hexen-2-ynyl propionate in 50 ml ethanol were hydrogenated in the presence of 0.4 g of 10% palladium on charcoal. After adsorption of the theoretical amount of hydrogen, the mixture was filtered over diatomaceous earth, concentrated and bulb distilled (13.3 Pa) to give 0.85 g of 5,7,7-trimethyloctyl propionate (yield 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:28][CH3:29])=[CH:19][C:20]([CH3:27])=[C:21]([CH:26]=3)[C:22]([O:24]C)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:30][NH2:31]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:28][CH3:29])=[CH:19][C:20]([CH3:27])=[C:21]([CH:26]=3)[C:22]([NH:30][NH2:31])=[O:24])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: NN
Reactant: CCc1cc(C)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: CCO
Product: CCc1cc(C)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate (compound 211.7, 500 mg, 1.28 mmol, 1.00 equiv) in ethanol (20 mL). Hydrazine (4 mL) was added to the reaction mixture. The resulting solution was stirred for 15 h at 80° C., then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield 400 mg (80%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide as a light yellow solid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7])[CH3:2].O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:9](/[C:3](=[CH:1]\[CH3:2])/[CH:4]=[CH:5]/[C:6]([O:8][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18])=[O:7])[CH3:10]
Reactant: C/C=C(/C=C/C(=O)O)CC
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: C/C=C(/C=C/C(=O)ON1C(=O)CCC1=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of (E,E)-4-ethyl-2,4-hexadienoic acid (7 g) and N-hydroxysuccinimide (5.75 g) in dioxane (100 ml) was added dicyclohexylcarbodiimide (10.8 g). The mixture was stirred at ambient temperature overnight and then filtered. The filtrate was concentrated under reduced pressure to give a residue which was recrystallized from a mixture of ether and petroleum ether to give N-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (10.73 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=3)[N:34]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:33]=2)[CH:29]=[CH:28][N:27]=1.[N:63]1([CH2:72][C:73]2([OH:80])[CH2:78][CH2:77][CH2:76][CH:75]([NH2:79])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:63]1([CH2:72][C:73]2([OH:80])[CH2:78][CH2:77][CH2:76][C@@H:75]([NH:79][C:41]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[N:33]=[C:32]4[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[O:42])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(O)(Cn2ncc3ccccc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)N[C@@H]4CCCC(O)(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 1((1H-indazol-1-yl)methyl)-3-aminocyclohexanol (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[CH:9]=[N:8][CH:7]=[CH:6]2.C[S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccncc2cc1C
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cnccc2cc1O
Temperature: 160 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
6-Methoxy-7-methylisoquinoline (239 mg) and sodium thiomethoxide (1.58 g) were suspended in N,N-dimethylformamide (12 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 6-hydroxy-7-methylisoquinoline (21 mg, yield 1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:18]4[CH:23]([CH3:25])[CH3:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36]I.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:36])[CH2:19][C@H:18]4[CH:23]([CH3:24])[CH3:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (71.4 mg, 0.145 mmol) in THF (0.483 mL) at 0° C. was added methyl iodide (31.1 μl, 0.498 mmol) followed by sodium hydride (7.65 mg, 0.319 mmol). The mixture was stirred for 3 hours at room temperature, quenched with ice, and diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C28H36ClN6O [M+H]+ 507. found 507.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22](=[O:25])[NH:23][CH3:24])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>>[CH3:24][NH:23][C:22]([C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:3]=1)=[O:25]
Reactant: CNC(=O)c1cc(Br)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CNC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Yield: 68 %

Procedure:
The product of step A and sodium benzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 1:4 dichloromethane/ethyl acetate) provided tert-butyl 6-(methylcarbamoyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (41 mg, 68%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.97 (d, J=7.2 Hz, 2H), 7.59-7.44 (m, 3H), 7.28 (s, 1H), 4.59 (s, 2H), 3.87 (t, J=5.2 Hz, 2H), 3.10 (d, J=4.8 Hz, 3H), 3.00-2.88 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=2)[O:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:10]([C:25]([F:28])([F:26])[F:27])=[N:9]1
Reactant: COC(=O)COc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a solution of methyl 2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetate (140 mg, 0.34 mmol) in MeOH (5 mL), was added lithium hydroxide monohydrate (60 mg, 1.42 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 and H2O. The aqueous was made acidic by the addition of 1 N HCl. The layers were separated and the acidic aqueous was further extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. This white solid was taken up in warm CH2Cl2 and hexane and the resulting solution was cooled in an ice bath. Filtration, washing with hexane and drying of the precipitated solids afforded 2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetic acid (69 mg, 51% yield) as a white solid. MS(ES): 397 [M+H]+.
Reaction SMILES: [F:1][CH:2]([CH3:13])[C:3]([NH:5][CH:6]([CH2:11][OH:12])[C:7]([O:9][CH3:10])=[O:8])=O.COCCN(S(F)(F)F)CCOC.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CO>[F:1][CH:2]([C:3]1[O:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:5]=1)[CH3:13]
Reactant: COC(=O)C(CO)NC(=O)C(C)F
Agent: COCCN(CCOC)S(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc(C(C)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A solution of methyl 2-(2-fluoropropanamido)-3-hydroxypropanoate (0.69 g, 3.60 mmol) in DCM (36.0 ml) was cooled to −20° C. and deoxo-fluor (50% in THF; 0.73 ml, 3.96 mmol, Fluka Chemie GmbH) was added dropwise. The reaction mixture was allowed to stir for 1 hour. Bromotrichloromethane (1.276 ml, 12.96 mmol, Sigma-Aldrich Chemical Company, Inc.) was added followed by addition of DBU (1.936 ml, 12.96 mmol, TCI). The reaction mixture was allowed to warm to 0° C. and stirred for 3 h. The reaction was quenched by the addition of aqueous, saturated NaHCO3 solution and extracted with CH2Cl2. The organic extract was washed with water, brine and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography, eluting with a gradient of 1% to 10% 2M NH3.MeOH in CH2Cl2, to provide methyl 2-(1-fluoroethyl)oxazole-4-carboxylate (0.2746 g, 1.586 mmol, 44.1% yield). MS m/z=173.9 [M]+; Calculated for C7H8FNO3: 173.049
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].[B-][N+](C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1.CCOCC.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH2:11][CH2:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: Cl
Agent: [B-][N+](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1NCC2
Temperature: 25 °C
Yield: 71.2 %

Procedure:
1.75 g of indole-7-carboxylic acid methyl ester and 2.92 g of borane-trimethylamine complex are dissolved in 10 ml of dioxane. To the resulting solution, 2 ml of concentrated hydrochloric acid are added. The reaction solution is heated under reflux for 30 minutes, and then cooled to room temperature. 10 ml of 6N hydrochloric acid are added to the reaction solution, which is then refluxed under heating for 15 minutes, and thereafter cooled to room temperature. The reaction solution is poured into 50 ml of water. The resulting mixture is neutralized with a 2N aqueous sodium hydroxide solution, and then extractd with ether. The organic layer is washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent has been distilled off, 1.26 g of 2,3-dihydroindole-7-carboxylic acid methyl ester are obtained, mp. 70° to 73° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH2:11](Cl)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:12][CH2:11][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCOCc1ccccc1
Reactant: c1cn[nH]c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(COCn2cccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of pyrazole (4.92 g, 72.2 mmol) in THF (100 mL) at −78° C. is added n-BuLi (28.9 mL of 2.5M in hexane) dropwise. The mixture is warmed to RT then re-cooled to −78° C. then Bom-Cl (11.3 g, 72.2 mmol) is added and the mixture is allowed to warm to RT. The solvent is removed under reduced pressure and 1N NaOH (25 mL) is added to the residual solid. The mixture is extracted with ether and the organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by reverse phase-MPLC using a gradient of 25-50% MeCN/water as eluent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[CH:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH3:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Yield: 62.7 %

Procedure:
A solution of 7-chloro-5-ethynyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.080 g, 0.22 mmol) in ethanol (25 mL) was treated with 10% palladium on carbon (20 mg) and shook vigorously under 45 p.s.i. hydrogen for 2-3 h. The resulting mixture was filtered through Celite and the filtrate concentrated under reduced pressure. Silica gel column chromatography using combinations of hexane-ethyl acetate (typically 3:1 hexane-ethyl acetate) afforded 7-chloro-5-ethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.051 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.28 (t, 3H), 2.74 (q, 2H), 4.23 (s, 2H), 4.81 (s, 2H), 7.12-7.39 (m, 6H). GC-MS: m/z 369 (M)+, 300 (M−69)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 59.7 %

Procedure:
1.55 g (0.00837 mol) of 2-nitro-benzoyl chloride were dissolved in 70 ml of toluene and treated with 2.0 g (0.0104 mol) of 1-benzyl-4-hydroxypiperidine and 2.6 ml (0.0184 mol) of triethylamine. After boiling under reflux for 18 hrs. the suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2->1:1) as the eluent. 1.7 g (60%) of 1-benzyl-piperidin-4-yl 2-nitro-benzoate were obtained as yellow crystals; m.p. 98°-99°.
Reaction SMILES: C(O[C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH3:28])=[C:14]2NC(=O)C)[CH2:6]1)(=O)C.[OH2:29].Cl.C(CC(C)(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[CH3:28][C@H:13]1[CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]2([CH3:16])[C:14]1=[O:29])[C@:20]1([CH3:23])[C:7]([CH2:6][CH2:5][CH2:22][CH2:21]1)=[CH:8][CH2:9]3
Reactant: CC(=O)NC1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)CC(C)(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]2(C)C1=O

Procedure:
The crude methyl enamide acetate (3, 1.94 g) was refluxed in 100 ml each of THF and water with 10 ml of concentrated HCl for 31/2 hours. Following the usual work-up the crude hydroxy methyl ketones (5 and 6) were converted to the 3-acetates. Silica gel thin layer chromotography using isooctane-ethyl acetate (21:4) roughly showed a 3:1 mixture of polar (Rf 0.17) and mobile (Rf 0.21) products, representing a mixture of the 16α-methyl and 16β-methyl-17-ones, respectively. Crystallization of the original 3-hydroxy mixture gave 425 mg of pure 16β-methyl-5-androsten-17-one (6), mp 168°-170°. The mother liquor residue (660 mg) represented a mixture of 16α and 16β-methyl-3-hydroxy-17-ones (5 and 6).
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(CCNc1ccc([N+](=O)[O-])cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-nitropyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methyl{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21](=[O:36])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[C:24]([N+:33]([O-])=O)[CH:23]=1)[CH3:2].O.O.[Sn](Cl)Cl.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[NH2:33][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[C:21]([NH:20][C:4]1[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:14]([F:15])([F:16])[F:17])[C:10]([F:12])([F:13])[F:11])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:36]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Temperature: 60 °C
Yield: 81.6 %

Procedure:
N-[2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-3-nitro-4-(1H-1,2,4-triazol-1-yl)benzamide (1.3 g) was dissolved in ethanol (20 ml). To the solution, tin (II) chloride dihydrate (1.4 g) and conc. hydrochloric acid (1 ml) were added and the mixture was stirred under heating at 60° C. for 4 hours. The reaction solution was neutralized with potassium carbonate while it is vigorously stirred with addition of ethyl acetate and water. The resulting precipitates were filtered using Celite, the aqueous phase was separated from the organic phase and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 3-amino-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (1.0 g, yield 97%).